BioPAX pathway converted from "Degradation of the extracellular matrix" in the Reactome database.

Degradation of the extracellular matrix

This event has been computationally inferred from an event that has been demonstrated in another species.

The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Activation of Matrix Metalloproteinases Activation of Matrix Metalloproteinases This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Initial activation of proMMP1 Initial activation of proMMP1 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153440 1 extracellular region GO 0005576 UniProt:P21692 MMP1 Reactome //www.joaskin.com Sus scrofa NCBI Taxonomy 9823 UniProt P21692 Chain Coordinates 20 EQUAL 469 EQUAL Reactome DB_ID: 10153442 1 54 EQUAL 469 EQUAL Reactome DB_ID: 10153444 1 20 EQUAL 53 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153456 proMMP1 initial activators [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity LOC100154047 [extracellular region] try [extracellular region] CMA1 [extracellular region] ELANE [extracellular region] UniProt A0A287BDI2 UniProt C6L245 UniProt I3LDA9 UniProt I3LK80 GO 0004252 GO molecular function Reactome Database ID Release 77 10153457 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153457 Reactome Database ID Release 77 10153459 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153459 Reactome R-SSC-1592316 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1592316.1 ProMMP1有几个活化剂包括血纤维蛋白溶酶(Eeckhout & Vaes 1977, Werb et al. 1977, Santala et al. 1999), trypsin (Grant et al. 1987, Saunders et al. 2005), plasma kallikrein (Nagase et al. 1982, Saunders et al. 2005), chymase (Saarinen et al. 1994, Suzuki et al. 1995, Saunders et al. 2005), tryptase (Gruber et al. 1989, Suzuki et al. 1995, Saunders et al. 2005), neutrophil elastase, cathepsin G (Saunders et al. 2005) and trypsin-2 (Moilanen et al. 2003). Concanavalin A (ConA) was the first cellular treatment that yielded active MMPs in culture, inducing the cellular activation of MMP1 likely through MMP14 activity (Overall and Sodek 1990).Trypsin-like serine proteinases are believed to remove 34-36 residues from the N-terminus of the secreted pro-enzyme, equivalent to positions 53-55 of the UniProt cannonical sequence which includes a signal peptide. Removal of this region is sufficient to destabilize the Cys92-Zn2+ stabilizing bond (numbered according to the Uniprot canonical sequence, Cys73 when numbered from the N terminus of the secreted peptide as typically represented in the literature) and partially activate enzyme activity. This intermediate form then undergoes autocatalysis at Thr83-Leu84 producing an MMP1 with about 20% of full collagenase activity (Suzuki et al. 1990). Full activation is brought about by a further cleavage at Gln99-Phe100. When first reported, considerable debate surrounded the activation of this archetypical MMP. Divergence of opinion resulted when competing groups studied activation in vitro using chemicals (organomercurials such as aminophenylmecuricacetate), which yield a different autolytic cleavage site in the protease susceptible loop when compared with the site cut by serine proteases such as trypsin. Different specific activities result, but in general the final autolytic cleavage site for all MMPs is the homologous Phe or Tyr at position 100 or 101. When the active enzyme commences here, full activity is realised due to the salt bridge forming between the N-terminal primary amine of the conserved Phe or Tyr with an Asp on helix C that in turn salt bridges to the active site Glu. Termini either side of this position do not result in full activity. 6279161 Pubmed 1982 Identification of plasma kallikrein as an activator of latent collagenase in rheumatoid synovial fluid Nagase, H Cawston, TE De Silva, M Barrett, AJ Biochim BiophysActa 702:133-42 2176865 Pubmed 1990 Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin) Suzuki, K Enghild, JJ Morodomi, T Salvesen, G Nagase, H Biochemistry 29:10261-70 3032947 Pubmed 1987 The activation of human skin fibroblast procollagenase. Sequence identification of the major conversion products Grant, GA Eisen, AZ Marmer, BL Roswit, WT Goldberg, GI J Biol Chem 262:5886-9 15870107 Pubmed 2005 MMP-1 activation by serine proteases and MMP-10 induces human capillary tubular network collapse and regression in 3D collagen matrices Saunders, WB Bayless, KJ Davis, GE J Cell Sci 118:2325-40 8027075 Pubmed 1994 Activation of human interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond by mast cell chymase Saarinen, J Kalkkinen, N Welgus, HG Kovanen, PT J Biol Chem 269:18134-40 2174435 Pubmed 1990 Concanavalin A produces a matrix-degradative phenotype in human fibroblasts. Induction and endogenous activation of collagenase, 72-kDa gelatinase, and Pump-1 is accompanied by the suppression of the tissue inhibitor of matrix metalloproteinases Overall, CM Sodek, J J Biol Chem 265:21141-51 2553780 Pubmed 1989 Synovial procollagenase activation by human mast cell tryptase dependence upon matrix metalloproteinase 3 activation Gruber, BL Marchese, MJ Suzuki, K Schwartz, LB Okada, Y Nagase, H Ramamurthy, NS J Clin Invest 84:1657-62 12731883 Pubmed 2003 Tumor-associated trypsinogen-2 (trypsinogen-2) activates procollagenases (MMP-1, -8, -13) and stromelysin-1 (MMP-3) and degrades type I collagen Moilanen, M Sorsa, T Stenman, M Nyberg, P Lindy, O Vesterinen, J Paju, A Konttinen, YT Stenman, UH Salo, T Biochemistry 42:5414-20 7826345 Pubmed 1995 Activation of precursors for matrix metalloproteinases 1 (interstitial collagenase) and 3 (stromelysin) by rat mast-cell proteinases I and II Suzuki, K Lees, M Newlands, GF Nagase, H Woolley, DE Biochem J 305:301-6 10567688 Pubmed 1999 Activation of interstitial collagenase, MMP-1, by Staphylococcus aureus cells having surface-bound plasmin: a novel role of plasminogen receptors of bacteria Santala, A Saarinen, J Kovanen, P Kuusela, P FEBS Lett 461:153-6 197917 Pubmed 1977 Further studies on the activation of procollagenase, the latent precursor of bone collagenase. Effects of lysosomal cathepsin B, plasmin and kallikrein, and spontaneous activation Eeckhout, Y Vaes, G Biochem J 166:21-31 66627 Pubmed 1977 Endogenous activiation of latent collagenase by rheumatoid synovial cells. Evidence for a role of plasminogen activator Werb, Z Mainardi, CL Vater, CA Harris ED, Jr N Engl J Med 296:1017-23 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Autocatalytic activation of MMP1 Autocatalytic activation of MMP1 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153442 1 54 EQUAL 469 EQUAL Reactome DB_ID: 10153652 1 54 EQUAL 83 EQUAL Reactome DB_ID: 10153433 1 84 EQUAL 469 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10153442 54 EQUAL 469 EQUAL Reactome Database ID Release 77 10153653 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153653 Reactome Database ID Release 77 10153655 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153655 Reactome R-SSC-1602473 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1602473.1 Following initiating proteolytic cleavage by serine proteases the Cys92-Zn2+ bond is destabilized allowing autocleavage at Thr83-Leu84, generating a 42 kDa active form of MMP1 with about 20% of the activity of the 41 kDa form (Suzuki et al. 1990). Full activation is brought about by a further cleavage at Gln99-Phe100. inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Full activation of MMP1 Full activation of MMP1 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153433 1 84 EQUAL 469 EQUAL Reactome DB_ID: 10130739 1 100 EQUAL 469 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153435 MMP2,3,7,10,11 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP11 [extracellular region] MMP2 [extracellular region] MMP7 [extracellular region] UniProt F1RL22 UniProt A0A5G2R860 UniProt F1SV71 Reactome Database ID Release 77 10153436 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153436 Reactome Database ID Release 77 10153438 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153438 Reactome R-SSC-1592297 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1592297.1 The 42 kDa intermediate form of MMP1 is fully activated by cleavage of the Gln99-Phe100 bond, producing a 41 kDa protein. MMP2 (Crabbe et al. 1994), MMP3 (Suzuki et al. 1990, Nagase et al. 1992), MMP7 (Imai et al. 1995), MMP10 (Nicholson et al. 1989) and MMP11 (Murphy et al. 1993) are able to convert the 42 kDa intermediate to fully activated 41 kDa form though they are not able to initiate activation of proMMP1 effectively (Nagase et al. 1992). MMP3 regulates MMP1 collagenase activity in human rheumatoid synovial fibroblasts (Unemori et al. 1991). 7981201 Pubmed 1994 Reciprocated matrix metalloproteinase activation: a process performed by interstitial collagenase and progelatinase A Crabbe, T O'Connell, JP Smith, BJ Docherty, AJ Biochemistry 33:14419-25 2169257 Pubmed 1990 The role of matrix metalloproteinase 3 in the stepwise activation of human rheumatoid synovial procollagenase Suzuki, K Nagase, H Ito, A Enghild, JJ Salvesen, G Biol Chem Hoppe Seyler 371:305-10 2548603 Pubmed 1989 Human and rat malignant-tumor-associated mRNAs encode stromelysin-like metalloproteinases Nicholson, R Murphy, G Breathnach, R 生物化学28:5195 - 203 7896811 Pubmed 1995 Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties Imai, K Yokohama, Y Nakanishi, I Ohuchi, E Fujii, Y Nakai, N Okada, Y J Biol Chem 270:6691-7 1660474 Pubmed 1991 Stromelysin expression regulates collagenase activation in human fibroblasts. Dissociable control of two metalloproteinases by interferon-gamma Unemori, EN Bair, MJ Bauer, EA Amento, EP J Biol Chem 266:23477-82 1480033 Pubmed 1992 Activation mechanisms of the precursors of matrix metalloproteinases 1, 2 and 3 Nagase, H Suzuki, K Morodomi, T Enghild, JJ Salvesen, G Matrix Suppl 1:237-44 8340372 Pubmed 1993 The 28-kDa N-terminal domain of mouse stromelysin-3 has the general properties of a weak metalloproteinase Murphy, G Segain, JP O'Shea, M Cockett, M Ioannou, C Lefebvre, O Chambon, P Basset, P J Biol Chem 268:15435-41 inferred by electronic annotation IEA GO IEA proMMP9 binds TIMP1 proMMP9 binds TIMP1 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153531 1 UniProt:A0A287AZD5 MMP9 UniProt A0A287AZD5 20 EQUAL 707 EQUAL Reactome DB_ID: 10142184 1 UniProt:F1RWV2 TIMP1 UniProt F1RWV2 24 EQUAL 207 EQUAL Reactome DB_ID: 10153612 1 proMMP9:TIMP1 [extracellular region] proMMP9:TIMP1 Reactome DB_ID: 10153531 1 20 EQUAL 707 EQUAL Reactome DB_ID: 10142184 1 24 EQUAL 207 EQUAL Reactome Database ID Release 77 10153612 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153612 Reactome R-SSC-1604377 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1604377.1 Reactome Database ID Release 77 10153614 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153614 Reactome R-SSC-1602454 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1602454.1 ProMMP9 binds Tissue Inhibitor of Metalloproteinases 1 (TIMP1) (Wilheim et al. 1989). By homology with the binding of TIMP2 to the MMP2 hemopexin domain, TIMP1 is thought to binds via its C domain to the MMP9 hemopexin domain. This is a two-way potential regulatory mechanism as the interaction does not prevent the free N-terminal inhibitory domain of TIMP1 from inhibiting other MMPs (Murthpy et al. 1991) while it may prevent the activation of proMMP9. 2551898 Pubmed 1989 SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages Wilhelm, SM Collier, IE Marmer, BL Eisen, AZ Grant, GA Goldberg, GI J Biol Chem 264:17213-21 1868085 Pubmed 1991 The N-terminal domain of tissue inhibitor of metalloproteinases retains metalloproteinase inhibitory activity Murphy, G Houbrechts, A Cockett, MI Williamson, RA O'Shea, M Docherty, AJ Biochemistry 30:8097-102 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Initial activation of proMMP2 by MMP1, 7 Initial activation of proMMP2 by MMP1, 7 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153670 1 UniProt:A0A5G2R860 MMP2 30 EQUAL 660 EQUAL Reactome DB_ID: 10153421 1 67 EQUAL 660 EQUAL Reactome DB_ID: 10153672 1 30 EQUAL 66 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153674 MMP1,7 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] MMP7 [extracellular region] Reactome Database ID Release 77 10153675 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153675 Reactome Database ID Release 77 10153677 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153677 Reactome R-SSC-1604359 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1604359.1 MMP2 can be activated by MMP1 (Crabbe et al. 1994a, Sang et al. 1996) and MMP7 (Crabbe et al. 1994b, Sang et al. 1996). MMP1 initially cleaves either Pro33-Ile34 or Asn66-Leu67. This is followed by autolytic cleavage at Asn109-Tyr110 (Crabbe et al. 1994a, Okada et al. 1990, Sang et al. 1996). MMP1 and MMP7 are not efficient activators of MMP2; significant physiological activation of proMMP2 is performed by the MT-MMPs MMP14 (Sato et al. 1994), MMP15 (Butler et al. 1997, Morrison et al. 2001) and MMP16 (Takino et al. 1995). Residue numbering here refers to the UniProt canonical sequence. 7559440 Pubmed 1995 Identification of the second membrane-type matrix metalloproteinase (MT-MMP-2) gene from a human placenta cDNA library. MT-MMPs form a unique membrane-type subclass in the MMP family Takino, T Sato, H Shinagawa, A Seiki, M J Biol Chem 270:23013-20 8194591 Pubmed 1994 Human progelatinase A can be activated by matrilysin Crabbe, T Smith, B O'Connell, J Docherty, A FEBS Lett 345:14-6 9119036 Pubmed 1997 Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases Butler, Georgina S Will, H Atkinson, SJ Murphy, G Eur J Biochem 244:653-7 8804571 Pubmed 1996 Activation of human progelatinase A by collagenase and matrilysin: activation of procollagenase by matrilysin Sang, QA Bodden, MK Windsor, LJ J Protein Chem 15:243-53 2269296 Pubmed 1990 Matrix metalloproteinase 2 from human rheumatoid synovial fibroblasts. Purification and activation of the precursor and enzymic properties Okada, Y Morodomi, T Enghild, JJ Suzuki, K Yasui, A Nakanishi, I Salvesen, G Nagase, H Eur J Biochem 194:721-30 11584019 Pubmed 2001 Cellular activation of MMP-2 (gelatinase A) by MT2-MMP occurs via a TIMP-2-independent pathway Morrison, CJ Butler, Georgina S Bigg, HF Roberts, CR Soloway, PD Overall, CM J Biol Chem 276:47402-10 8015608 Pubmed 1994 A matrix metalloproteinase expressed on the surface of invasive tumour cells Sato, H Takino, T Okada, Y Cao, J Shinagawa, A Yamamoto, E Seiki, M Nature 370:61-5 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Autocatalytic activation of proMMP2 Autocatalytic activation of proMMP2 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153421 1 67 EQUAL 660 EQUAL Reactome DB_ID: 10151795 1 110 EQUAL 660 EQUAL Reactome DB_ID: 10153423 1 67 EQUAL 109 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10153421 67 EQUAL 660 EQUAL Reactome Database ID Release 77 10153424 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153424 Reactome Database ID Release 77 10153430 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153430 Reactome R-SSC-1592278 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1592278.1 Cleaving the Asn66-Leu67 bond of MMP2 activates it sufficiently to allow autocleavage of the Asn109-Tyr110 bond (Okada et al. 1990, Strongin et al. 1993, Crabbe et al. 1994a, Atkinson et al. 1995, Sang et al. 1996). This activation is inhibited by endostatin (Nyberg et al. 2003). Residue numbering here refers to the UniProt canonical sequence. 8314771 Pubmed 1993 Plasma membrane-dependent activation of the 72-kDa type IV collagenase is prevented by complex formation with TIMP-2 Strongin, AY Marmer, BL Grant, GA Goldberg, GI J Biol Chem 268:14033-9 8530478 Pubmed 1995 Intermolecular autolytic cleavage can contribute to the activation of progelatinase A by cell membranes Atkinson, SJ Crabbe, T Cowell, S Ward, RV Butler, MJ Sato, H Seiki, M Reynolds, JJ Murphy, G J Biol Chem 270:30479-85 12690120 Pubmed 2003 Endostatin inhibits human tongue carcinoma cell invasion and intravasation and blocks the activation of matrix metalloprotease-2, -9, and -13 Nyberg, P Heikkilä, P Sorsa, T Luostarinen, J Heljasvaara, R Stenman, UH Pihlajaniemi, T Salo, T J Biol Chem 278:22404-11 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 77 10153431 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153431 Reactome DB_ID: 10153428 UniProt:A0A286ZIL9 COL18A1 UniProt A0A286ZIL9 1572 EQUAL 11754 EQUAL 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Activation of proMMP7 by MMP3 Activation of proMMP7 by MMP3 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153461 1 UniProt:F1SV71 MMP7 18 EQUAL 267 EQUAL Reactome DB_ID: 10153463 1 18 EQUAL 94 EQUAL Reactome DB_ID: 10151799 1 95 EQUAL 267 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153473 Homologues of CTSL2 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CTSL [extracellular region] CTSL [extracellular region] UniProt F1S4J6 UniProt Q28944 Reactome Database ID Release 77 10153474 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153474 Reactome Database ID Release 77 10153476 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153476 Reactome R-SSC-1592362 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1592362.1 MMP3 activates MMP7 by cleavage of Glu94-Tyr95 (Imai et al. 1997). inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Initial activation of proMMP7 by trypsin Initial activation of proMMP7 by trypsin This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153461 1 18 EQUAL 267 EQUAL Reactome DB_ID: 10153685 1 18 EQUAL 50 EQUAL Reactome DB_ID: 10153683 1 51 EQUAL 267 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153687 MMP7 initial activators [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity try [extracellular region] Reactome Database ID Release 77 10153688 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153688 Reactome Database ID Release 77 10153690 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153690 Reactome R-SSC-1604712 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1604712.1 通过胰蛋白酶oc proMMP7 (proMatrilysin-1)激活curs via an intermediate cleaved at Lys50-Asn51 which undergoes autocatalysis (Crabbe et al. 1992). Leukocyte elastase and plasmin partially activate MMP7 by an uncharacterized mechanism. Highly sulfated glycosaminoglycans (GAG), such as heparin, chondroitin-4,6-sulfate (CS-E), and dermatan sulfate, markedly enhance (>50-fold) the intermolecular autolytic activation of promatrilysin and the activity of fully active matrilysin (Ra et al. 2009). 1390635 Pubmed 1992 Biochemical characterization of matrilysin. Activation conforms to the stepwise mechanisms proposed for other matrix metalloproteinases Crabbe, T Willenbrock, F Eaton, D Hynds, P Carne, AF Murphy, G Docherty, AJ Biochemistry 31:8500-7 19654318 Pubmed 2009 Control of promatrilysin (MMP7) activation and substrate-specific activity by sulfated glycosaminoglycans Ra, HJ Harju-Baker, S Zhang, F Linhardt, RJ Wilson, CL Parks, WC J Biol Chem 284:27924-32 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Autocatalytic activation of MMP7 Autocatalytic activation of MMP7 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153683 1 51 EQUAL 267 EQUAL Reactome DB_ID: 10153750 1 51 EQUAL 94 EQUAL Reactome DB_ID: 10151799 1 95 EQUAL 267 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10153683 51 EQUAL 267 EQUAL Reactome Database ID Release 77 10153751 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153751 Reactome Database ID Release 77 10153753 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153753 Reactome R-SSC-1604763 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1604763.1 Once cleaved at Lys50-Asn51 MMP7 undergoes autocatalysis (Crabbe et al. 1992). Highly sulfated glycosaminoglycans (GAG), such as heparin, chondroitin-4,6-sulfate (CS-E), and dermatan sulfate, markedly enhance (>50-fold) the intermolecular autolytic activation of promatrilysin and the activity of fully active matrilysin (Ra et al. 2009). inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 77 1604786 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=1604786 Reactome R-HSA-1604786 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1604786.1 Converted from EntitySet in Reactome Reactome DB_ID: 1604783 Highly sulphated glycosaminoglycans [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CHS [extracellular region] Heparins [extracellular region] ChEBI 37397 ChEBI 24505 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Activation of proMMP8 Activation of proMMP8 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153520 1 UniProt:F1SV69 MMP8 UniProt F1SV69 21 EQUAL 467 EQUAL Reactome DB_ID: 10151803 1 101 EQUAL 467 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153526 proMMP8 initial activators [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity try [extracellular region] KLK1 [extracellular region] ELANE [extracellular region] UniProt A0A287BI78 Reactome Database ID Release 77 10153527 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153527 Reactome Database ID Release 77 10153529 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153529 Reactome R-SSC-1592398 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1592398.1 proMMP8 is activated by tissue kallikrein, leukocyte elastase, trypsin and cathepsin G (Capodici et al. 1989, Knauper et al. 1990) probably at the predicted bait region, residues 30-36. 2546891 Pubmed 1989 Activation of neutrophil collagenase by cathepsin G Capodici, C Muthukumaran, G Amoruso, MA Berg, RA Inflammation 13:245-58 2159879 Pubmed 1990 Characterization and activation of procollagenase from human polymorphonuclear leucocytes. N-terminal sequence determination of the proenzyme and various proteolytically activated forms Knäuper, V Krämer, S Reinke, H Tschesche, H Eur J Biochem 189:295-300 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Initial activation of proMMP9 by MMPs Initial activation of proMMP9 by MMPs This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153531 1 20 EQUAL 707 EQUAL Reactome DB_ID: 10153535 1 20 EQUAL 59 EQUAL Reactome DB_ID: 10153533 1 60 EQUAL 707 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153537 MMP1 (2, 3, 7, 10, 13) [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] Reactome Database ID Release 77 10153538 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153538 Reactome Database ID Release 77 10153540 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153540 Reactome R-SSC-1592436 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1592436.1 MMP1 (Sang et al. 1995), MMP2 (Fridman et al. 1995), MMP3 (Goldberg et al. 1992, Ogata et al. 1992, Okada et al. 1992), MMP7 (Imai et al. 1995, Sang et al. 1995), MMP10 (Nakamura et al. 1998) and MMP13 (Knauper et al. 1997) activate MMP9 by a stepwise mechanism but the second cleavage is apparently not an autocatalytic event as is the case for MMP1 (Okada et al. 1992). The first site is the Glu59-Met60 bond, generating an inactive 85-86 kDa intermediate (O'Connell et al. 1994), followed by cleavage of the Arg106-Phe107 peptide bond producing the fullly active 82 kDa form of MMP9 (Okada et al. 1992, Fridman et al. 1995). 8195131 Pubmed 1994 Analysis of the role of the COOH-terminal domain in the activation, proteolytic activity, and tissue inhibitor of metalloproteinase interactions of gelatinase B O'Connell, JP Willenbrock, F Docherty, AJ Eaton, D Murphy, G J Biol Chem 269:14967-73 7780967 Pubmed 1995 Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2) Fridman, R Toth, M Peña, D Mobashery, S Cancer Res 55:2548-55 1311314 Pubmed 1992 Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin Goldberg, GI Strongin, A Collier, IE Genrich, LT Marmer, BL J Biol Chem 267:4583-91 9578462 Pubmed 1998 Activation of the precursor of human stromelysin 2 and its interactions with other matrix metalloproteinases Nakamura, H Fujii, Y Ohuchi, E Yamamoto, E Okada, Y Eur J Biochem 253:67-75 1371271 Pubmed 1992 Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9 Ogata, Y Enghild, JJ Nagase, H J Biol Chem 267:3581-4 9346290 Pubmed 1997 Activation of progelatinase B (proMMP-9) by active collagenase-3 (MMP-13) Knäuper, V Smith, B López-Otin, C Murphy, G Eur J Biochem 248:369-73 7669817 Pubmed 1995 Proteolytic and non-proteolytic activation of human neutrophil progelatinase B Sang, QX Birkedal-Hansen, H Van Wart, HE Biochim BiophysActa 1251:99-108 1400481 Pubmed 1992 Matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) from HT 1080 human fibrosarcoma cells. Purification and activation of the precursor and enzymic properties Okada, Y Gonoji, Y Naka, K Tomita, K Nakanishi, I Iwata, K Yamashita, K Hayakawa, T J临床生物化学267:21712-9 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Activation of MMP9 intermediate form by MMPs Activation of MMP9 intermediate form by MMPs This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153533 1 60 EQUAL 707 EQUAL Reactome DB_ID: 10153679 1 60 EQUAL 106 EQUAL Reactome DB_ID: 10150966 1 107 EQUAL 707 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153537 Reactome Database ID Release 77 10153681 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153681 Reactome R-SSC-1604690 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1604690.1 The intermediate form of MMP9 is activated by cleavage of the Arg106-Phe107 peptide bond producing the fullly active 82-kDa MMP-9 species (Ogata et al. 1992, Fridman et al. 1995). inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Activation of proMMP9 by proteases Activation of proMMP9 by proteases This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153531 1 20 EQUAL 707 EQUAL Reactome DB_ID: 10153692 1 20 EQUAL 106 EQUAL Reactome DB_ID: 10150966 1 107 EQUAL 707 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153726 proMMP9 activating proteases [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity try [extracellular region] Reactome Database ID Release 77 10153727 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153727 Reactome Database ID Release 77 10153729 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153729 Reactome R-SSC-1604722 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1604722.1 proMMP9 can be activated by trypsin and chymotrypsin (Sopata & Dancewicz 1974), tissue kallikrein (Tschesche et al. 1989, Desrivieres et al. 1993), cathepsin G (Murphy et al. 1980), and trypsin-2 (Sorsa et al. 1997). This appears to be a one-step activation; the single peptide bond cleaved by trypsin-2 in proMMP-9 is Arg106-Phe107. Modes of activation by other proteases are unclear. Activation is inhibited by endostatin (Nyberg et al. 2003). 8253870 Pubmed 1993 Activation of the 92 kDa type IV collagenase by tissue kallikrein Desrivieres, S Lu, H Peyri, N Soria, C Legrand, Y Ménashi, S J Cell Physiol 157:587-93 2557753 Pubmed 1989 Tissue kallikrein effectively activates latent matrix degrading metalloenzymes Tschesche, H Michaelis, J Kohnert, U Fedrowitz, J Oberhoff, R Adv Exp Med Biol 247:545-8 6263256 Pubmed 1980 The latent collagenase and gelatinase of human polymorphonuclear neutrophil leucocytes Murphy, G Bretz, U Baggiolini, M Reynolds, JJ Biochem J 192:517-25 4216367 Pubmed 1974 Presence of a gelatin-specific proteinase and its latent form in human leucocytes Sopata, I Dancewicz, AM Biochim BiophysActa 370:510-23 9261109 Pubmed 1997 Activation of type IV procollagenases by human tumor-associated trypsin-2 Sorsa, T Salo, T Koivunen, E Tyynelä, J Konttinen, YT Bergmann, U Tuuttila, A Niemi, E Teronen, O Heikkilä, P Tschesche, H Leinonen, J Osman, S Stenman, UH J Biol Chem 272:21067-74 inferred by electronic annotation IEA GO IEA INHIBITION Reactome DB_ID: 10153428 1572 EQUAL 11754 EQUAL 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Activation of proMMP11 by FURIN Activation of proMMP11 by FURIN This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153657 1 Golgi lumen GO 0005796 UniProt:F1RL22 MMP11 32 EQUAL 488 EQUAL Reactome DB_ID: 10151812 1 98 EQUAL 488 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10119285 Golgi membrane GO 0000139 UniProt:F1RMJ1 FURIN UniProt F1RMJ1 108 EQUAL 794 EQUAL Reactome Database ID Release 77 10119286 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10119286 Reactome Database ID Release 77 10153659 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153659 Reactome R-SSC-1602484 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1602484.1 proMMP11 has a furin recognition sequence and is activated by furin in the Golgi (Pei & Weiss 1996, Santavicca et al. 1996). 7746327 Pubmed 1995 Furin-dependent intracellular activation of the human stromelysin-3 zymogen Pei, D 维斯,SJ Nature 375:244-7 8645182 Pubmed 1996 Characterization of structural determinants and molecular mechanisms involved in pro-stromelysin-3 activation by 4-aminophenylmercuric acetate and furin-type convertases Santavicca, M Noel, A Angliker, H Stoll, I Segain, JP Anglard, P Chretien, M Seidah, N Basset, P Biochem J 315:953-8 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Initial activation of proMMP13 by plasmin and trypsin Initial activation of proMMP13 by plasmin and trypsin This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153661 1 UniProt:F1SV56 MMP13 UniProt F1SV56 20 EQUAL 471 EQUAL Reactome DB_ID: 10153663 1 58 EQUAL 471 EQUAL Reactome DB_ID: 10153665 1 20 EQUAL 57 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10151840 UniProt:C6L245 try 24 EQUAL 247 EQUAL Reactome Database ID Release 77 10153666 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153666 Reactome Database ID Release 77 10153668 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153668 Reactome R-SSC-1602488 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1602488.1 proMMP13 can be activated by plasmin and trypsin initially cleaving at Lys57-Glu58 followed by autoproteolysis at Glu103-Tyr104 (Knauper et al. 1996a). 8663255 Pubmed 1996 Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme Knäuper, V Will, H López-Otin, C Smith, B Atkinson, SJ Stanton, H Hembry, RM Murphy, G J Biol Chem 271:17124-31 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Initial activation of proMMP13 by MMP3 Initial activation of proMMP13 by MMP3 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153661 1 20 EQUAL 471 EQUAL Reactome DB_ID: 10153746 1 20 EQUAL 76 EQUAL Reactome DB_ID: 10153733 1 77 EQUAL 471 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153473 Reactome Database ID Release 77 10153748 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153748 Reactome R-SSC-1604752 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1604752.1 MMP3 initially cleaves proMMP13 at Gly76-Leu77 followed by autoprocessing at Glu103-Tyr104 (Knauper et al. 1996). 8576151 Pubmed 1996 Biochemical characterization of human collagenase-3 Knäuper, V López-Otin, C Smith, B Knight, G Murphy, G J Biol Chem 271:1544-50 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Autocatalytic activation of proMMP13 Autocatalytic activation of proMMP13 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153731 1 55 EQUAL 471 EQUAL Reactome DB_ID: 10153735 1 55 EQUAL 103 EQUAL Reactome DB_ID: 10151791 3 104 EQUAL 471 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10153731 55 EQUAL 471 EQUAL Reactome Database ID Release 77 10153740 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153740 Reactome Database ID Release 77 10153742 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153742 Reactome R-SSC-1604732 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1604732.1 Following initial activation autoproteolysis occurs at Glu103-Tyr104 (Knauper et al. 1996a,1996b). This is inhibited by endostatin (Nyberg et al. 2003). inferred by electronic annotation IEA GO IEA INHIBITION Reactome DB_ID: 10153428 1572 EQUAL 11754 EQUAL 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Activation of MT-MMPs by FURIN Activation of MT-MMPs by FURIN This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Converted from EntitySet in Reactome Reactome DB_ID: 10153648 1 Converted from EntitySet in Reactome Reactome DB_ID: 10153840 1 plasma membrane GO 0005886 MT-MMPs [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP16 [plasma membrane] Reactome Database ID Release 77 10153842 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153842 Reactome R-SSC-1605825 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1605825.1 The process that targets activated MT-MMPs to the plasma membrane is unclear but presumed to involve standard golgi transport mechanisms. The cytoplasmic domain of MT1-MMP is critical for the localization to discrete regions of the cell surface (Urena et al. 1999) and involved in internalization which has a regulatory role. The cytoplasmic domain mediates interactions with specific cell-surface proteins such as C1Q binding protein which may serve to direct the MMP from the golgi to the cell surface (Rozanov et al. 2002). 10036228 Pubmed 1999 The cytoplasmic carboxy-terminal amino acid determines the subcellular localization of proTGF-(alpha) and membrane type matrix metalloprotease (MT1-MMP) Urena, JM Merlos-Suárez, A Baselga, J Arribas, J J Cell Sci 112:773-84 11773076 Pubmed 2002 The hemopexin-like C-terminal domain of membrane type 1 matrix metalloproteinase regulates proteolysis of a multifunctional protein, gC1qR Rozanov, DV Ghebrehiwet, B Postnova, TI Eichinger, A Deryugina, EI Strongin, AY J Biol Chem 277:9318-25 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10203893 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10203893 Reactome R-SSC-1592389 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1592389.1 GO 0022617 GO biological process The matrix metalloproteinases (MMPs), previously known as matrixins, are classically known to be involved in the turnover of extracellular matrix (ECM) components. However, recent high throughput proteomics analyses have revealed that ~80% of MMP substrates are non-ECM proteins including cytokines, growth factor binding protiens, and receptors. It is now clear that MMPs regulate ECM turnover not only by cleaving ECM components, but also by the regulation of cell signalling, and that some MMPs are beneficial and may be drug anti-targets. Thus, MMPs have important roles in many processes including embryo development, morphogenesis, tissue homeostasis and remodeling. They are implicated in several diseases such as arthritis, periodontitis, glomerulonephritis, atherosclerosis, tissue ulceration, and cancer cell invasion and metastasis. All MMPs are synthesized as preproenzymes. Alternate splice forms are known, leading to nuclear localization of select MMPs. Most are secreted from the cell, or in the case of membrane type (MT) MMPs become plasma membrane associated, as inactive proenzymes. Their subsequent activation is a key regulatory step, with requirements specific to MMP subtype. 19817485 Pubmed 2009 Updated biological roles for matrix metalloproteinases and new "intracellular" substrates revealed by degradomics Butler, Georgina S Overall, CM Biochemistry 48:10830-45 19800373 Pubmed 2010 Matrix metalloproteinases: what do they not do? New substrates and biological roles identified by murine models and proteomics Rodríguez, D Morrison, CJ Overall, CM Biochim BiophysActa 1803:39-54 0 19 850268 0 ISBN 2000 Matrix Metalloproteinases and TIMPs Woessner, J Nagase, H Matrix Metalloproteinases and TIMPs (Book) 17562450 Pubmed 2007 The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases Cauwe, B Van den Steen, PE Opdenakker, G Crit Rev Biochem Mol Biol 42:113-85 19616423 Pubmed 2009 Matrix metalloproteinase proteomics: substrates, targets, and therapy Morrison, CJ Butler, Georgina S Rodríguez, D Overall, CM Curr Opin Cell Biol 21:645-53 inferred by electronic annotation IEA GO IEA Collagen degradation Collagen degradation This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type I degradation by MMP1,2,8,13, PRSS2 Collagen type I degradation by MMP1,2,8,13, PRSS2 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10117811 1 Collagen type I fibril [extracellular region] Collagen type I fibril Reactome DB_ID: 10151150 1 裂解胶原蛋白type I fibril [extracellular region] 裂解胶原蛋白type I fibril PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10151842 MMP1,2,8,13, PRSS2 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] try [extracellular region] MMP2 [extracellular region] MMP8 [extracellular region] MMP13 [extracellular region] GO 0004222 GO molecular function Reactome Database ID Release 77 10151843 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10151843 Reactome Database ID Release 77 10151845 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10151845 Reactome R-SSC-1454822 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1454822.1 MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996) known in the literature as collagenases I, II and III respectively are able to digest the intrahelical bonds of collagen type I. MMP2, also known as Gelatinase-A, was found to cleave collagen type I fibrils (Aimes & Quigley 1995). Though this was disputed (Seltzre & Eisen 1999) there is a structural explanation for the apparent discrepancies in experimental data (Patterson et al. 2001). In addition trypsin-2 is able to degrade native soluble type I collagen (Moilanen et al. 2003). Degradation is represented here at a theoretical end point where every alpha strand has been cleaved. 15257288 Pubmed 2004 Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis Chung, L Dinakarpandian, D Yoshida, N Lauer-Fields, JL Fields, GB Visse R Nagase, H EMBO J 23:3020-30 3038863 Pubmed 1987 The collagen substrate specificity of human neutrophil collagenase Hasty, KA Jeffrey, JJ Hibbs, MS Welgus, HG J Biol Chem 262:10048-52 6270089 Pubmed 1981 The collagen substrate specificity of human skin fibroblast collagenase Welgus, HG Jeffrey, JJ Eisen, AZ J Biol Chem 256:9511-5 10383752 Pubmed 1999 Native type I collagen is not a substrate for MMP2 (gelatinase A) Seltzre, JL Eisen, AZ J Invest Dermatol 112:993-4 11513874 Pubmed 2001 Specific collagenolysis by gelatinase A, MMP-2, is determined by the hemopexin domain and not the fibronectin-like domain Patterson, ML Atkinson, SJ Knäuper, V Murphy, G FEBS Lett 503:158-62 7790374 Pubmed 1995 A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodeling Liu, X Wu, H Byrne, M Jeffrey, J Krane, S Jaenisch, R J. Cell Biol. 130:227-37 7890717 Pubmed 1995 Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4- and 1/4-length fragments Aimes, RT Quigley, JP J Biol Chem 270:5872-6 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type I degradation by MMP15 Collagen type I degradation by MMP15 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10117811 1 Reactome DB_ID: 10151150 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10153832 UniProt:A0A287B2J9 MMP15 UniProt A0A287B2J9 132 EQUAL 669 EQUAL Reactome Database ID Release 77 10163645 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163645 Reactome Database ID Release 77 10163651 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163651 Reactome R-SSC-2473596 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2473596.1 The membrane-type MMP MMP15 (MT2-MMP) is a fibrillar collagenase able to degrade collagen type I (Morrison and Overall 2006) and believed able to degrade types II and III (Somerville et al. 2003). 16825197 Pubmed 2006 TIMP independence of matrix metalloproteinase (MMP)-2 activation by membrane type 2 (MT2)-MMP is determined by contributions of both the MT2-MMP catalytic and hemopexin C domains Morrison, CJ Overall, CM J Biol Chem 281:26528-39 12801404 Pubmed 2003 Matrix metalloproteinases: old dogs with new tricks Somerville, RP Oblander, SA Apte, Suneel S Genome Biol 4:216 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Collagen type II degradation by MMP1,3,8,13,PRSS2 Collagen type II degradation by MMP1,3,8,13,PRSS2 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10135403 1 Collagen type II fibril [extracellular region] Collagen type II fibril Reactome DB_ID: 10151202 1 裂解胶原蛋白type II fibril [extracellular region] 裂解胶原蛋白type II fibril PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10152081 MMP1,3,8,13, PRSS2 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] try [extracellular region] MMP8 [extracellular region] MMP13 [extracellular region] Reactome Database ID Release 77 10152082 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10152082 Reactome Database ID Release 77 10152084 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10152084 Reactome R-SSC-1474197 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1474197.1 MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996, Mitchell et al. 1996, Billinghurst et al. 1997) known in the literature as collagenases I, II and III respectively are able to digest the intrahelical bonds of collagen type II, cleaving between amino acids Gly975 and Leu976 of the Uniprot canonical sequence. Human trypsin-2 is also capable of cleaving the triple helix of human cartilage collagen type II (Stenman et al. 2005). 8609233 Pubmed 1996 Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage Mitchell, P G Magna, H A Reeves, L M Lopresti-Morrow, L L Yocum, S A Rosner, P J Geoghegan, K F Hambor, J E J. Clin. Invest. 97:761-8 2005102 Pubmed 1991 Sites of stromelysin cleavage in collagen types II, IX, X, and XI of cartilage Wu, JJ Lark, MW Chun, LE Eyre, DR J Biol Chem 266:5625-8 16192646 Pubmed 2005 Trypsin-2 degrades human type II collagen and is expressed and activated in mesenchymally transformed rheumatoid arthritis synovitis tissue Stenman, M Ainola, M Valmu, L Bjartell, A Ma, G Stenman, UH Sorsa, T Luukkainen, R Konttinen, YT Am J Pathol 167:1119-24 9119997 Pubmed 1997 Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage Billinghurst, RC Dahlberg, L Ionescu, M Reiner, A Bourne, R Rorabeck, C Mitchell, P Hambor, J Diekmann, O Tschesche, H Chen, J Van Wart, H Poole, AR J Clin Invest 99:1534-45 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type II degradation by MMP15 Collagen type II degradation by MMP15 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10135403 1 Reactome DB_ID: 10151202 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10153832 132 EQUAL 669 EQUAL Reactome Database ID Release 77 10163649 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163649 Reactome R-SSC-2473594 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2473594.1 The membrane-type MMP MMP15 (MT2-MMP) is a fibrillar collagenase. MMP15 is able to degrade collagen type I (Morrison & Overall 2006) and believed able to degrade types II and III (Somerville et al. 2003). 8999957 Pubmed 1997 Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules Ohuchi, E Imai, K Fujii, Y Sato, H Seiki, M Okada, Y J Biol Chem 272:2446-51 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type III degradation by MMP1,8,9,13 Collagen type III degradation by MMP1,8,9,13 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10135438 1 Collagen type III fibril [extracellular region] Collagen type III fibril Reactome DB_ID: 10151254 1 裂解胶原蛋白type III fibril [extracellular region] 裂解胶原蛋白type III fibril PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10152093 MMP1,8,9,13 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] MMP8 [extracellular region] MMP13 [extracellular region] MMP9 [extracellular region] Reactome Database ID Release 77 10152094 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10152094 Reactome Database ID Release 77 10152096 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10152096 Reactome R-SSC-1474213 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1474213.1 MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996, Mitchell et al. 1996), called collagenases I, II and III respectively, are all able to cleave the intrahelical bonds of collagen type III, cleaving between amino acids Gly948 and Ile949 of the Uniprot canonical sequence. MMP9 (Bigg et al. Veidal et al. 2010) and MMP10 (Stromelysin-2) are able to degrade collagen type III (Nicholson et al. 1989). 20666994 Pubmed 2010 Matrix metalloproteinase-9-mediated type III collagen degradation as a novel serological biochemical marker for liver fibrogenesis Veidal, SS Vassiliadis, E Barascuk, N Zhang, C Segovia-Silvestre, T Klickstein, L Larsen, MR Qvist, P Christiansen, C Vainer, B Karsdal, MA Liver Int 30:1293-304 17298441 Pubmed 2007 Activity of matrix metalloproteinase-9 against native collagen types I and III Bigg, Heather F Rowan, Andrew D Barker, Michael D Cawston, Tim E FEBS J. 274:1246-55 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type III degradation by MMP14 Collagen type III degradation by MMP14 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10135438 1 Reactome DB_ID: 10151254 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10152088 UniProt:I3L620 TMPRSS6 UniProt I3L620 1 EQUAL 811 EQUAL Reactome Database ID Release 77 10152089 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10152089 Reactome Database ID Release 77 10152091 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10152091 Reactome R-SSC-1474210 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1474210.1 The membrane-type MMP MMP14 (MT1-MMP) is a fibrillar collagenase able to degrade collagen types I, II and III (Ohuchi et al. 1997). inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type III degradation by MMP15 Collagen type III degradation by MMP15 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10135438 1 Reactome DB_ID: 10151254 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10153832 132 EQUAL 669 EQUAL Reactome Database ID Release 77 10163647 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163647 Reactome R-SSC-2473584 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2473584.1 The membrane-type MMP MMP15 (MT2-MMP) is a fibrillar collagenase able to degrade collagen type I (Morrison & Overall 2006) and believed able to degrade collagen types II and III (Somerville et al. 2002). inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type IV degradation by MMP2,3,4,9,10,12 Collagen type IV degradation by MMP2,3,4,9,10,12 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Converted from EntitySet in Reactome Reactome DB_ID: 10153228 1 Collagen IV [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 10151781 1 裂解胶原蛋白type IV networks [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153230 MMP2,3,4,9,10,12 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP2 [extracellular region] MMP7 [extracellular region] MMP9 [extracellular region] MMP12 [extracellular region] UniProt F1SV57 Reactome Database ID Release 77 10153231 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153231 Reactome Database ID Release 77 10153233 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153233 Reactome R-SSC-1564142 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1564142.1 Type IV collagen is the most abundant structural basement membrane (BM) component, providing a scaffold for other major BM proteins such as laminin (Charonis et al. 1985, 1986). There are six different genes encoding type IV collagen chains, alpha-1 to alpha-6(IV) with distinct tissue distributions. Three alpha chains fold to form the triple helical unit of collagen IV. Three chain combinations have been identified, alpha-1X2 alpha-2(IV), alpha-3,alpha-4, alpha-5(IV) and alpha-5X2, alpha-6(IV) (Borza et al. 2001). The first is the major form, found in all basement membranes, the other types have more restricted distributions.

Collagen IV forms a lattice network rather than extended fibrils. It can be digested by MMP2 (Liotta et al. 1981, Salo et al. 1983, Bergers et al. 2000, Monaco et al. 2006), MMP3 (Okada et al. 1986, Wilhelm et al. 1987, Bejarano et al. 1988, Nicholson et al. 1989), MMP7 (Miyazaki et al. 1990, Murphy et al. 1991), MMP9 (Moll et al. 1990, Morodomi et al. 1992, Murphy et al. 1991, Watanabe et al. 1993, Bergers et al. 2000), MMP10 (Nicholson et al. 1989) and MMP12 (Chandler et al. 1996). 3223920 Pubmed 1988 Degradation of basement membranes by human matrix metalloproteinase 3 (stromelysin) Bejarano, PA Noelken, ME Suzuki, K Hudson, BG Nagase, H Biochem J 256:413-9 3997977 Pubmed 1985 Binding of laminin to type IV collagen: a morphological study Charonis, AS Tsilibary, EC Yurchenco, PD Furthmayr, H J Cell Biol 100:1848-53 8920930 Pubmed 1996 Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumour necrosis factor-alpha fusion protein Chandler, S Cossins, J Lury, J Wells, G Biochem Biophys Res Commun 228:421-9 8314909 Pubmed 1993 Matrix metalloproteinase-9 (92 kDa gelatinase/type IV collagenase) from U937 monoblastoid cells: correlation with cellular invasion Watanabe, H Nakanishi, I Yamashita, K Hayakawa, T Okada, Y J Cell Sci 104:991-9 6258630 Pubmed 1981 Partial purification and characterization of a neutral protease which cleaves type IV collagen Liotta, LA Tryggvason, K Garbisa, S Robey, PG Abe, S Biochemistry 20:100-4 2253219 Pubmed 1990 Purification and characterization of extracellular matrix-degrading metalloproteinase, matrin (pump-1), secreted from human rectal carcinoma cell line Miyazaki, K Hattori, Y Umenishi, F Yasumitsu, H Umeda, M Cancer Res 50:7758-64 17088321 Pubmed 2006 Enzymatic processing of collagen IV by MMP-2 (gelatinase A) affects neutrophil migration and it is modulated by extracatalytic domains Monaco, Susanna Sparano, Valentina Gioia, Magda Sbardella, Diego Di Pierro, Donato Marini, Stefano Coletta, Massimo Protein Sci. 15:2805-15 2169335 Pubmed 1990 Tumor promoter-stimulated Mr 92,000 gelatinase secreted by normal and malignant human cells: isolation and characterization of the enzyme from HT1080 tumor cells Moll, UM Youngleib, GL Rosinski, KB Quigley, JP Cancer Res 50:6162-70 3477804 Pubmed 1987 Human skin fibroblast stromelysin: structure, glycosylation, substrate specificity, and differential expression in normal and tumorigenic cells Wilhelm, SM Collier, IE Kronberger, A Eisen, AZ Marmer, BL Grant, GA Bauer, EA Goldberg, GI Proc Natl Acad Sci U S A 84:6725-9 1379048 Pubmed 1992 Purification and characterization of matrix metalloproteinase 9 from U937 monocytic leukaemia and HT1080 fibrosarcoma cells Morodomi, T Ogata, Y Sasaguri, Y Morimatsu, M Nagase, H Biochem J 285:603-11 11375996 Pubmed 2001 The NC1 domain of collagen IV encodes a novel network composed of the alpha 1, alpha 2, alpha 5, and alpha 6 chains in smooth muscle basement membranes Borza, DB Bondar, O Ninomiya, Y Sado, Y Naito, I Todd, P Hudson, BG J Biol Chem 276:28532-40 11025665 Pubmed 2000 Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis Bergers, G Brekken, R McMahon, G Vu, TH Itoh, T Tamaki, K Tanzawa, K Thorpe, P Itohara, S Werb, Z Hanahan, D Nat Cell Biol 2:737-44 1649600 Pubmed 1991 Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP) Murphy, G Cockett, MI Ward, RV Docherty, AJ Biochem J 277:277-9 3095317 Pubmed 1986 A metalloproteinase from human rheumatoid synovial fibroblasts that digests connective tissue matrix components. Purification and characterization Okada, Y Nagase, H Harris ED, Jr J Biol Chem 261:14245-55 6298220 Pubmed 1983 Purification and characterization of a murine basement membrane collagen-degrading enzyme secreted by metastatic tumor cells Salo, T Liotta, LA Tryggvason, K J Biol Chem 258:3058-63 2430974 Pubmed 1986 Inhibition of laminin self-assembly and interaction with type IV collagen by antibodies to the terminal domain of the long arm Charonis, AS Tsilibary, EC Saku, T Furthmayr, H J Cell Biol 103:1689-97 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type V degradation by MMP2,9,10 Collagen type V degradation by MMP2,9,10 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10135541 1 Collagen V [extracellular region] Collagen V Reactome DB_ID: 10153295 1 裂解胶原蛋白type V fibril [extracellular region] 裂解胶原蛋白type V fibril PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153297 MMP2,9,10 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP2 [extracellular region] MMP9 [extracellular region] Reactome Database ID Release 77 10153298 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153298 Reactome Database ID Release 77 10153300 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153300 Reactome R-SSC-1564164 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1564164.1 Type V collagen is a fibril-forming collagen forming a group with collagen types I, II, III and XI (Gelse et al. 2003). Three different alpha chains exist that can combine in three distinct trimers. Collagen V forms fibrils that are associated with type I and to a lesser extent III collagen, as a minor but critical component of bone matrix, corneal stroma and the interstitial matrix of muscle, liver, lung and placenta (Birk et al. 1988). COL5A1-/- mice have an almost complete lack of collagen fibrils reflecting a central role in fibrillogenesis (Wenstrup et al. 2004). Type V collagen mutation results in a range of connective tissue diseases including Ehlers-Danlos syndrome (EDS), which is a heterogeneous group of disorders characterized by joint hypermobility and skin hyperextensibility, thinness and fragility. These result from mutations in the COL5A1 and COL5A2 genes (Michalickova et al. 1998, Schwarze et al. 2000). Type V collagen is digested by MMP2 (Murphy et al. 1981, Veidal et al. 2011), MMP10 (Nicholson et al. 1989), and MMP9 (Murphy et al. 1982, Watanabe et al. 1993, Pourmotabbed et al. 1994, Niyibizi et al. 1994, Veidal et al. 2011). 15383546 Pubmed 2004 Type V collagen controls the initiation of collagen fibril assembly Wenstrup, RJ Florer, JB Brunskill, EW Bell, SM Chervoneva, I Birk, DE J Biol Chem 279:53331-7 14623400 Pubmed 2003 Collagens--structure, function, and biosynthesis Gelse, K Pöschl, E Aigner, T Adv Drug Deliv Rev 55:1531-46 7041891 Pubmed 1981 Metalloproteinases from rabbit bone culture medium degrade types IV and V collagens, laminin and fibronectin Murphy, G Cawston, TE Galloway, WA Barnes, MJ 邦宁,RA Mercer, E Reynolds, JJ Burgeson, RE Biochem J 199:807-11 3346334 Pubmed 1988 Collagen type I and type V are present in the same fibril in the avian corneal stroma Birk, DE Fitch, JM Babiarz, JP Linsenmayer, TF J Cell Biol 106:999-1008 6285893 Pubmed 1982 Partial purification of collagenase and gelatinase from human polymorphonuclear leucocytes. Analysis of their actions on soluble and insoluble collagens Murphy, G Reynolds, JJ Bretz, U Baggiolini, M Biochem J 203:209-21 10796876 Pubmed 2000 Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II) Schwarze, U Atkinson, M Hoffman, G G Greenspan, D S Byers, P H Am. J. Hum. Genet. 66:1757-65 22382088 Pubmed 2012 MMP mediated type V collagen degradation (C5M) is elevated in ankylosing spondylitis Veidal, SS Larsen, DV Chen, X Sun, S Zheng, Q Bay-Jensen, AC Leeming, DJ Nawrocki, A Larsen, MR Schett, G Karsdal, MA Clin Biochem 9425231 Pubmed 1998 Mutations of the alpha2(V) chain of type V collagen impair matrix assembly and produce ehlers-danlos syndrome type I Michalickova, K Susic, M Willing, M C Wenstrup, R J Cole, W G Hum. Mol. Genet. 7:249-55 8305481 Pubmed 1994 Characteristics of 92 kDa type IV collagenase/gelatinase produced by granulocytic leukemia cells: structure, expression of cDNA in E. coli and enzymic properties Pourmotabbed, T Solomon, TL Hasty, KA Mainardi, CL Biochim BiophysActa 1204:97-107 8037728 Pubmed 1994 A 92 kDa gelatinase (MMP-9) cleavage site in native type V collagen Niyibizi, C Chan, R Wu, J J Eyre, D Biochem. Biophys. Res. Commun. 202:328-33 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type VI degradation by MMP2,9,11 Collagen type VI degradation by MMP2,9,11 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10152853 1 Collagen type VI fibril [extracellular region] Collagen type VI fibril Reactome DB_ID: 10153055 1 裂解胶原蛋白类型六世fibril [extracellular region] 裂解胶原蛋白类型六世fibril PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153057 MMP2,9,11 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP11 [extracellular region] MMP2 [extracellular region] MMP9 [extracellular region] Reactome Database ID Release 77 10153058 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153058 Reactome Database ID Release 77 10153060 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153060 Reactome R-SSC-1564112 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1564112.1 Type VI collagen aggregates into distinctive microfibrils known as beaded filaments that form an independent microfibrillar network in virtually all connective tissues except for bone (von der Mark et al. 1984). It plays a role in the maintenance of tissue integrity since it participates in both cell-matrix and matrix-matrix interactions, interacting with many other ECM proteins including fibronectin (Chang et al. 1997), type IV collagen (Kuo et al. 1997), type II collagen, decorin and biglycan (Bidanset et al. 1992). Collagen type VI has been described as a connecting protein (Gelse et al. 2003).

Collagen type VI is resistant to digestion by many MMPs but is cleaved by MMP2 (Myint et al. 1996, Veidal et al. 2011), MMP9 (Veidal et al. 2011) and MMP11 (Motrescu et al. 2008). 6432530 Pubmed 1984 Immunochemistry, genuine size and tissue localization of collagen VI von der Mark, H Aumailley, M Wick, G Fleischmajer, R Timpl, R Eur J Biochem 142:493-502 9183676 Pubmed 1997 Structural colocalisation of type VI collagen and fibronectin in agarose cultured chondrocytes and isolated chondrons extracted from adult canine tibial cartilage Chang, J Nakajima, H Poole, CA J Anat 190:523-32 9334230 Pubmed 1997 Type VI collagen anchors endothelial basement membranes by interacting with type IV collagen Kuo, H J Maslen, C L Keene, D R Glanville, R W J. Biol. Chem. 272:26522-9 1544908 Pubmed 1992 Binding of the proteoglycan decorin to collagen type VI Bidanset, DJ Guidry, C Rosenberg, LC Choi, HU Timpl, R Hook, M J Biol Chem 267:5250-6 8862926 Pubmed 1996 Cleavage of human corneal type VI collagen alpha 3 chain by matrix metalloproteinase-2 Myint, E Brown, DJ Ljubimov, AV Kyaw, M Kenney, MC Cornea 15:490-6 18622425 Pubmed 2008 Matrix metalloproteinase-11/stromelysin-3 exhibits collagenolytic function against collagen VI under normal and malignant conditions Motrescu, ER Blaise, S Etique, N Messaddeq, N Chenard, MP Stoll, I Tomasetto, C 里约热内卢,MC Oncogene 27:6347-55 21935455 Pubmed 2011 MMP mediated degradation of type VI collagen is highly associated with liver fibrosis--identification and validation of a novel biochemical marker assay Veidal, SS Karsdal, MA Vassiliadis, E Nawrocki, A Larsen, MR Nguyen, QH Hägglund, P Luo, Y Zheng, Q Vainer, B Leeming, DJ PLoS One 6:e24753 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 胶原蛋白类型七degradation by MMP1,2,3 胶原蛋白类型七degradation by MMP1,2,3 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153090 1 Collagen type VII fibril [extracellular region] Collagen type VII fibril Reactome DB_ID: 10151308 1 裂解胶原蛋白类型六世I fibril [extracellular region] 裂解胶原蛋白类型六世I fibril PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153092 MMP1,2,3 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] MMP2 [extracellular region] Reactome Database ID Release 77 10153093 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153093 Reactome Database ID Release 77 10153095 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153095 Reactome R-SSC-1564120 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1564120.1 Type VII collagen is the major collagen component of anchoring fibrils, which are essential for the attachment of the epidermis to the dermis. It is degraded by MMP1 (Seltzer et al. 1989), MMP2 (Seltzer et al. 1989, Sawamura et al. 1991, Karelina et al. 2000) and MMP3 (Sawamura et al. 1991). MMP2 is 3000-fold more active than MMP1 (Seltzer et al. 1989). 10652000 Pubmed 2000 Basement membrane zone remodeling during appendageal development in human fetal skin. The absence of type VII collagen is associated with gelatinase-A (MMP2) activity Karelina, TV Bannikov, GA Eisen, AZ J Invest Dermatol 114:371-5 1704217 Pubmed 1991 Increased gene expression of matrix metalloproteinase-3 (stromelysin) in skin fibroblasts from patients with severe recessive dystrophic epidermolysis bullosa Sawamura, D Sugawara, T Hashimoto, I Bruckner-Tuderman, L Fujimoto, D Okada, Y Utsumi, N Shikata, H Biochem Biophys Res Commun 174:1003-8 2537292 Pubmed 1989 Cleavage of type VII collagen by interstitial collagenase and type IV collagenase (gelatinase) derived from human skin Seltzer, JL Eisen, AZ Bauer, EA Morris, NP Glanville, RW Burgeson, RE J Biol Chem 264:3822-6 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type VIII degradation by MMP1 Collagen type VIII degradation by MMP1 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153350 1 Collagen type VIII fibril [extracellular region] Collagen type VIII fibril Reactome DB_ID: 10151422 1 裂解胶原蛋白类型六世II fibril [extracellular region] 裂解胶原蛋白类型六世II fibril PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10130739 100 EQUAL 469 EQUAL Reactome Database ID Release 77 10153351 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153351 Reactome Database ID Release 77 10153353 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153353 Reactome R-SSC-1564169 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1564169.1 Collagen type VIII is a short chain, network-forming collagen,thought to play a role in tissue remodeling and repair (Shuttleworth 1997, Weitkamp et al. 1999). There are two alpha chain subtypes, found in a ratio of two alpha-1 to one alpha-2 chains (Mann et al. 1990) in the typical collagen heterotrimer. Studies suggest that type VIII collagen is a major component of the hexagonal lattice seen in Descemet's membrane (Mann et al. 1990). Mutations in both alpha chains have been associated with Fuchs endothelial corneal dystrophy (FECD), a degenerative disease of the corneal endothelium (Jun et al. 2012).

Collagen type VIII can be degraded by MMP1 (Sage et al. 1983, 1984). 10428768 Pubmed 1999 Human macrophages synthesize type VIII collagen in vitro and in the atherosclerotic plaque Weitkamp, B Cullen, P Plenz, G Robenek, H Rauterberg, J FASEB J 13:1445-57 2226849 Pubmed 1990 The primary structure of a triple-helical domain of collagen type VIII from bovine Descemet's membrane Mann, K Jander, R Korsching, E Kühn, K Rauterberg, J FEBS Lett 273:168-72 6694361 Pubmed 1984 Type VIII collagen. Synthesis by normal and malignant cells in culture 圣人,H Balian, G Vogel, AM Bornstein, P Lab Invest 50:219-31 6630235 Pubmed 1983 Biosynthetic and structural properties of endothelial cell type VIII collagen 圣人,H Trüeb, B Bornstein, P J Biol Chem 258:13391-401 22002996 Pubmed 2012 An alpha 2 collagen VIII transgenic knock-in mouse model of Fuchs endothelial corneal dystrophy shows early endothelial cell unfolded protein response and apoptosis Jun, AS Meng, H Ramanan, N Matthaei, M Chakravarti, S Bonshek, R Black, GC Grebe, R Kimos, M Hum Mol Genet 21:384-93 9438378 Pubmed 1997 Type VIII collagen Shuttleworth, CA Int J Biochem Cell Biol 29:1145-8 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Collagen type XII degradation by MMP12 Collagen type XII degradation by MMP12 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10160095 1 Collagen type XII [extracellular region] Collagen type XII Reactome DB_ID: 10160071 3 UniProt:F1RQI0 COL12A1 UniProt F1RQI0 (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline O5-galactosyl-L-hydroxylysine at unknown position O5-galactosyl-L-hydroxylysine 24 EQUAL 3063 EQUAL Reactome Database ID Release 77 10160095 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10160095 Reactome R-SSC-2142915 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2142915.1 Reactome DB_ID: 10161441 1 裂解胶原蛋白type XII [extracellular region] 裂解胶原蛋白type XII Reactome DB_ID: 10161393 3 (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline at unknown position O5-galactosyl-L-hydroxylysine at unknown position 24 EQUAL -1 EQUAL Reactome Database ID Release 77 10161441 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10161441 Reactome R-SSC-2470728 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2470728.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10151787 UniProt:F1SV57 MMP12 106 EQUAL 470 EQUAL Reactome Database ID Release 77 10161442 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10161442 Reactome Database ID Release 77 10161444 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10161444 Reactome R-SSC-2168046 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2168046.1 Collagen type XII is a member of the fibril-associated collagens with interrupted triple helices (FACIT) group, thought to be bound to the surface of interstitial collagen fibrils (Keene et al.1991). It has only one alpha chain type, with two collagenous (Col1 and Col2) and three noncollagenous domains (NC1-NC3). Whereas the collagenous and the NC1 and NC2 regions are short, the NHE-terminal NC3 is a huge trimeric domain (Yamagata et al. 1991, Wälchli et al. 1993). Collagen XII may enhance the stability of connective tissues by bridging collagen fibrils (Nishiyama et al. 1994, Bader et al. 2009). It may be a stress response molecule, directly influenced by stretch and shear stress. Expression of COL12A1 is directly stimulated by mechanical forces (Flück et al. 2003, Jin et al. 2003, Arai et al. 2008). Expression is predominantly in bone, suggesting involvement of type XII collagen in the regulation of osteoblasts and cell interactions. Transgenic type XII collagen-null mice have skeletal abnormalities. They have decreased bone matrix deposition and delayed maturation. Compared with controls, Col12a knockout osteoblasts are disorganized, being less polarized with disrupted cell-cell interactions, decreased connexin43 expression and impaired gap junction function (Izu et al. 2011).

MMP12 can cleave collagen XII (Didangelos et al. 2011). 21593211 Pubmed 2011 Extracellular matrix composition and remodeling in human abdominal aortic aneurysms: a proteomics approach Didangelos, A Yin, X Mandal, K Saje, A Smith, A Xu, Q Jahangiri, M Mayr, M Mol Cell Proteomics 10:M111.008128 12890494 Pubmed 2003 Shear stress-induced collagen XII expression is associated with atherogenesis Jin, Xin Iwasa, Satoshi Okada, Kyoko Ooi, Akishi Mitsui, Kazuhiro Mitsumata, Masako Biochem. Biophys. Res. Commun. 308:152-8 18957791 Pubmed 2008 Mechanical strain increases expression of type XII collagen in murine osteoblastic MC3T3-E1 cells Arai, Katsuhiko Nagashima, Yuko Takemoto, Taeko Nishiyama, Toshio Cell Struct. Funct. 33:203-10 2026656 Pubmed 1991 Two type XII-like collagens localize to the surface of banded collagen fibrils Keene, DR Lunstrum, GP Morris, NP Stoddard, DW Burgeson, RE J Cell Biol 113:971-8 8207089 Pubmed 1994 Tissue-specific expression of the fibril-associated collagens XII and XIV Wälchli, C Koch, M Chiquet, M Odermatt, BF Trueb B J Cell Sci 107:669-81 7961756 Pubmed 1994 Type XII and XIV collagens mediate interactions between banded collagen fibers in vitro and may modulate extracellular matrix deformability Nishiyama, T McDonough, AM Bruns, RR Burgeson, RE J Biol Chem 269:28193-9 18983916 Pubmed 2009 Zebrafish collagen XII is present in embryonic connective tissue sheaths (fascia) and basement membranes Bader, HL Keene, DR Charvet, B Veit, G Driever, W Koch, M Ruggiero, F Matrix Biol 28:32-43 12581868 Pubmed 2003 Tensile stress-dependent collagen XII and fibronectin production by fibroblasts requires separate pathways Flück, Martin Giraud, Marie Noëlle Tunç, Vildan Chiquet, Matthias Biochim. Biophys. Acta 1593:239-48 1918137 Pubmed 1991 The complete primary structure of type XII collagen shows a chimeric molecule with reiterated fibronectin type III motifs, von Willebrand factor A motifs, a domain homologous to a noncollagenous region of type IX collagen, and short collagenous domains with an Arg-Gly-Asp site Yamagata, M Yamada, Kenneth Yamada, SS Shinomura, T Tanaka, Hiroshi Nishida, Y Obara, M Kimata, K J Cell Biol 115:209-21 21670218 Pubmed 2011 Type XII collagen regulates osteoblast polarity and communication during bone formation Izu, Yayoi Sun, Mei Zwolanek, Daniela Veit, Guido Williams, Valerie Cha, Byeong Jepsen, Karl J Koch, Manuel Birk, David E J. Cell Biol. 193:1115-30 inferred by electronic annotation IEA GO IEA Collagen type XV restin release Collagen type XV restin release This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10161337 1 Collagen type XV multimer [extracellular region] Collagen type XV multimer Reactome DB_ID: 10161389 1 裂解胶原蛋白type XV multimer [extracellular region] 裂解胶原蛋白type XV multimer Reactome DB_ID: 10161363 3 UniProt:F1SSE8 COL15A1 UniProt F1SSE8 (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline at unknown position O5-galactosyl-L-hydroxylysine at unknown position 1212 EQUAL 1388 EQUAL Reactome Database ID Release 77 10161391 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10161391 Reactome R-SSC-2168038 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2168038.1 Collagens type XV and XVIII are closely related non-fibrillar collagens that define the multiplexin (multiple triple helix domains with interruptions) subfamily of collagens. Both are homotrimers characterized by highly interrupted collagenous domains flanked by large globular domains with attached glycosaminoglycan chains. Collagen XV is localized in the outermost layer of the basement membrane (BM) and in the fibrillar matrix. Collagen type XV is the only collagen able to self-assemble into higher-order cruciform structures with intermolecular binding sites (Myers et al. 2007). The interaction is mediated by interactions between triple helical regions (Hurskainen et al. 2010). It is predominantly located in the basement membranes of microvessels, and cardiac and skeletal myocytes (Hägg et al. 1997), where it binds basement membrane and microfibrillar components such as fibulin-2, nidogen-2, vitronectin, laminin, and fibronectin (Sasaki et al. 2000, Hurskainen et al. 2010). It may form a bridge between fibrillar collagens and the basement membrane (Amenta et al. 2005), acting as a molecular shock absorber to stabilize and enhance resilience to compressive and expansive forces (Myers et al. 2007). Lack of Collagen type XV in Col15a1-null mice resulted in increased permeability and impaired microvascular hemodynamics, distinct early-onset and age-dependent defects in heart structure and function, a poorly organized fibrillar collagen matrix with marked interstitial deposition of nonfibrillar protein aggregates, increased tissue stiffness, and irregularly organized cardiomyocytes (Rasi et al. 2010a). Col15a1 knockout also leads to loosely packed axons in C-fibers and polyaxonal myelination. Simultaneous knockout with laminin alpha-4 leads to severely impaired radial sorting and myelination (Rasi et al. 2010b).

The C-terminal non-collagenous region of collagen type XV is known as restin because it resembles endostatin, having antiangiogenic effects (Ramchandran et al. 1999, Sasaki et al. 2000). 20040604 Pubmed 2010 Recombinant human collagen XV regulates cell adhesion and migration Hurskainen, M Ruggiero, F Hägg, P Pihlajaniemi, T Huhtala, P J Biol Chem 285:5258-65 10049780 Pubmed 1999 Antiangiogenic activity of restin, NC10 domain of human collagen XV: comparison to endostatin Ramchandran, R Dhanabal, M Volk, R Waterman, MJ Segal, M Lu, H Knebelmann, B Sukhatme, VP Biochem Biophys Res Commun 255:735-9 15684329 Pubmed 2005 Proteoglycan-collagen XV in human tissues is seen linking banded collagen fibers subjacent to the basement membrane Amenta, PS Scivoletti, NA Newman, MD Sciancalepore, JP Li, D Myers, JC J Histochem Cytochem 53:165-76 17355226 Pubmed 2007 The molecular structure of human tissue type XV presents a unique conformation among the collagens Myers, JC Amenta, PS Dion, AS Sciancalepore, JP Nagaswami, C Weisel, JW Yurchenco, PD Biochem J 404:535-44 9176399 Pubmed 1997 Location of type XV collagen in human tissues and its accumulation in the interstitial matrix of the fibrotic kidney Hägg, PM Hägg, PO Peltonen, S Autio-Harmainen, H Pihlajaniemi, T Am J Pathol 150:2075-86 10966814 Pubmed 2000 Endostatins derived from collagens XV and XVIII differ in structural and binding properties, tissue distribution and anti-angiogenic activity Sasaki, T Larsson, H Tisi, D Claesson-Welsh, Lena Hohenester, E Timpl, R J Mol Biol 301:1179-90 20847313 Pubmed 2010 Collagen XV is necessary for modeling of the extracellular matrix and its deficiency predisposes to cardiomyopathy Rasi, Karolina Piuhola, Jarkko Czabanka, Marcus Sormunen, Raija Ilves, Mika Leskinen, Hanna Rysä, Jaana Kerkelä, Risto Janmey, Paul Heljasvaara, Ritva Peuhkurinen, Keijo Vuolteenaho, Olli Ruskoaho, Heikki Vajkoczy, Peter Pihlajaniemi, Taina Eklund, Lauri Circ. Res. 107:1241-52 20980607 Pubmed 2010 Lack of collagen XV impairs peripheral nerve maturation and, when combined with laminin-411 deficiency, leads to basement membrane abnormalities and sensorimotor dysfunction Rasi, Karolina Hurskainen, Merja 岩石,米卡 Stavén, Saara Sormunen, Raija Heape,安东尼·米 Avila, Robin L Kirschner, Daniel Muona, Anu Tolonen, Uolevi Tanila, Heikki Huhtala, Pirkko Soininen, Raija Pihlajaniemi, Taina J. Neurosci. 30:14490-501 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Collagen type XVIII endostatin release Collagen type XVIII endostatin release This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10161545 1 Collagen type XVIII multimer [extracellular region] Collagen type XVIII multimer Reactome DB_ID: 10161573 1 裂解胶原蛋白type XVIII multimer [extracellular region] 裂解胶原蛋白type XVIII multimer Reactome DB_ID: 10161575 1 (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline at unknown position O5-galactosyl-L-hydroxylysine at unknown position 1 EQUAL 1754 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10161607 Endostatin-releasing proteases [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CTSB [extracellular region] MMP13 [extracellular region] MMP7 [extracellular region] MMP9 [extracellular region] MMP12 [extracellular region] MMP20 [extracellular region] UniProt A1E295 UniProt P79287 Reactome Database ID Release 77 10161608 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10161608 Reactome Database ID Release 77 10161610 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10161610 Reactome R-SSC-2168923 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2168923.1 胶原蛋白类型十八是硫酸乙酰肝素proteoglycan associated with the basement membranes of almost all epithelia and endothelia. It has a large C-terminal noncollagenous domain. Mouse knockouts suggest that it may have a role in maintaining the structural integrity of the extracellular matrix (Utriainen et al. 2004).

Proteolytic cleavage of the C-terminal noncollagenous domain by matrix metalloproteinases (Heljasvaara et al. 2005) releases 18 to 38 kDa C-terminal proteolytic fragments, collectively named endostatin. They have anti-angiogenic activity (O'Reilly et al. 1997, Ständker et al. 1997) and suppress primary tumor and metastasis growth in experimental animal models (Ortega & Werb 2002). It is not clear whether this collagen subtype forms supramolecular assemblies (Myllyharju & Kivirikko, 2004) but thought likely, via a similar mechanism to the related collagen XV (Hurskainen et al. 2010).

Endostatin-like fragments are released from collagen type XVIII by MMP 7 (Lin et al. 2001), 3, 9, 12, 13 (Ferreras et al. 2000) and 20 (Heljasvaara et al. 2005). Several cathepsins and elastase can bring about endostatin release (Ferreras et al. 2000, Felbor et al. 2000). 11119712 Pubmed 2000 Generation and degradation of human endostatin proteins by various proteinases Ferreras, M Felbor, U Lenhard, T Olsen, B R Delaissé, J FEBS Lett. 486:247-51 15950618 Pubmed 2005 代生物活性的血管内皮抑制素fragments from human collagen XVIII by distinct matrix metalloproteases Heljasvaara, R Nyberg, P Luostarinen, J Parikka, M Heikkilä, P Rehn, M Sorsa, T Salo, T Pihlajaniemi, T Exp Cell Res 307:292-304 10716919 Pubmed 2000 Secreted cathepsin L generates endostatin from collagen XVIII Felbor, U Dreier, L Bryant, RA Ploegh, HL Olsen, BR Mothes, W EMBO J 19:1187-94 9008168 Pubmed 1997 Endostatin: an endogenous inhibitor of angiogenesis and tumor growth O'Reilly, MS Boehm, T Shing, Y Fukai, N Vasios G Lane, WS Flynn, E Birkhead, JR Olsen, BR Folkman, J Cell 88:277-85 15254016 Pubmed 2004 Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line Utriainen, A Sormunen, R Kettunen, M Carvalhaes, LS Sajanti, E Eklund, L Kauppinen, R Kitten, GT Pihlajaniemi, T Hum Mol Genet 13:2089-99 14698617 Pubmed 2004 Collagens, modifying enzymes and their mutations in humans, flies and worms Myllyharju, J Kivirikko,KI Trends Genet 20:33-43 11581192 Pubmed 2001 Matrilysin cleavage of corneal collagen type XVIII NC1 domain and generation of a 28-kDa fragment Lin, H C Chang, J H Jain, S Gabison, E E Kure, T Kato, T Fukai, N Azar, D T Invest. Ophthalmol. Vis. Sci. 42:2517-24 9459295 Pubmed 1997 Isolation and characterization of the circulating form of human endostatin Ständker, L Schrader, M Kanse, SM Jürgens, M Forssmann, WG Preissner, KT FEBS Lett 420:129-33 12376553 Pubmed 2002 New functional roles for non-collagenous domains of basement membrane collagens Ortega, Nathalie Werb, Zena J. Cell. Sci. 115:4201-14 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Endostatin degradation by cathepsins Endostatin degradation by cathepsins This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10161575 1 (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline at unknown position O5-galactosyl-L-hydroxylysine at unknown position 1 EQUAL 1754 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10163625 Endostatin-degrading cathepsins [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 77 10163626 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163626 Reactome Database ID Release 77 10163628 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163628 Reactome R-SSC-2471621 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2471621.1 As well as generating endostatin from collagen XVIII, cathepsins L and B quickly degrade it, as do cathepsins D and K. In contrast MMPs that produce endostatin do not cleave it further (Ferreras et al. 2000). inferred by electronic annotation IEA GO IEA Collagen type XIX degradation Collagen type XIX degradation This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10160225 1 Collagen type XIX [extracellular region] Collagen type XIX Reactome DB_ID: 10160201 3 UniProt:A0A5G2R1K4 COL19A1 UniProt A0A5G2R1K4 (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline at unknown position O5-galactosyl-L-hydroxylysine at unknown position 24 EQUAL 1142 EQUAL Reactome Database ID Release 77 10160225 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10160225 Reactome R-SSC-2152272 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2152272.1 Reactome Database ID Release 77 10161630 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10161630 Reactome R-SSC-2172433 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2172433.1 胶原蛋白类型第十九是FACIT (fibril-associated有限公司llagens with interrupted triple helix) collagen family member (Inoguchi et al. 1995) with a large non-collagenous N terminal domain that can self-assemble into higher order structures that are stabilized by intermolecular disulfide cross-links. Collagen type XIX is the least abundant collagen so far purified, comprising ?10-6% of dry weight in human umbilical cord (Myers et al. 2003). It is found in the basement membrane (BM) of normal human tissues. In developing embryos it is transiently expressed in certain muscular tissues and brain areas. Due to this localized expression, it is thought to be involved in the formation of specialized BM zones (Sumiyoshi et al. 2001). Collagen XIX is lost early in the development of invasive tumours, prior to penetration and eventual dissolution of the epithelial BM (Amenta et al. 2003). The NC1 domain of type XIX collagen exerts antitumor activity (Ramont et al. 2007). 12788917 Pubmed 2003 Type XIX collagen purified from human umbilical cord is characterized by multiple sharp kinks delineating collagenous subdomains and by intermolecular aggregates via globular, disulfide-linked, and heparin-binding amino termini Myers, JC Li, D Amenta, PS Clark, CC Nagaswami, C Weisel, JW J Biol Chem 278:32047-57 17308049 Pubmed 2007 The NC1 domain of type XIX collagen inhibits in vivo melanoma growth Ramont, Laurent Brassart-Pasco, Sylvie Thevenard, Jessica Deshorgue, Aurélie Venteo, Lydie Laronze, Jean Yves Pluot, Michel Monboisse, Jean-Claude Maquart, François-Xavier Mol. Cancer Ther. 6:506-14 11169848 Pubmed 2001 Embryonic expression of type XIX collagen is transient and confined to muscle cells Sumiyoshi, H Laub, F 吉冈,H Ramirez, F Dev. Dyn. 220:155-62 7775380 Pubmed 1995 The mRNA for alpha 1(XIX) collagen chain, a new member of FACITs, contains a long unusual 3' untranslated region and displays many unique splicing variants Inoguchi, K 吉冈,H Khaleduzzaman, M Ninomiya, Y J. Biochem. 117:137-46 12579531 Pubmed 2003 Loss of types XV and XIX collagen precedes basement membrane invasion in ductal carcinoma of the female breast Amenta, PS Hadad, S Lee, MT Barnard, N Li, D Myers, JC J Pathol 199:298-308 inferred by electronic annotation IEA GO IEA Collagen type XIII ectodomain shedding Collagen type XIII ectodomain shedding This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10160866 1 Collagen type XIII [plasma membrane] Collagen type XIII Reactome DB_ID: 10160842 3 UniProt:A0A5G2RNE8 COL13A1 UniProt A0A5G2RNE8 (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline at unknown position O5-galactosyl-L-hydroxylysine at unknown position 1 EQUAL 717 EQUAL Reactome Database ID Release 77 10160866 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10160866 Reactome R-SSC-2143423 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2143423.1 Reactome DB_ID: 10161309 1 裂解胶原蛋白type XIII [plasma membrane] 裂解胶原蛋白type XIII Reactome DB_ID: 10161285 3 (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline at unknown position O5-galactosyl-L-hydroxylysine at unknown position Reactome Database ID Release 77 10161309 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10161309 Reactome R-SSC-2471865 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2471865.1 Reactome DB_ID: 10161311 3 (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,4R)-4-hydroxyproline at unknown position (2S,3S)-3-hydroxyproline at unknown position O5-galactosyl-L-hydroxylysine at unknown position 1 EQUAL 717 EQUAL Reactome Database ID Release 77 10161335 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10161335 Reactome R-SSC-2167942 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2167942.1 Type XIII is a non-fibril-forming type II transmembrane protein with a large amino terminal NC1 domain. This domain has a hydrophobic membrane-spanning segment that anchors the molecule to the plasma membrane and a large extracellular, mostly collagenous carboxyterminal domain (Hägg et al. 1998). Recombinant type XIII collagen can form homotrimers with triple-helical collagenous domains (Snellman et al. 2000a). It is detected at low levels in all connective tissue-producing cells; in cultured cells it is localized in focal adhesions (Hägg et al. 2001). The extracellular region has an adhesion-related function (Hägg et al. 2001) that is involved in formation of the neuromuscular junction (Latvanlehto et al. 2010). The purified protein has been shown to interact with Integrin alpha1beta1 (Nykvist et al. 2000). An N-terminal ectodomain portion of type XIII collagen is cleaved in culture medium by a furin-like protease (Snellman et al. 2000b, Väisänen et al. 2004). This ectodomain interacts with fibronectin, nidogen-2 and perlecan (Tu et al. 2002, Väisänen et al. 2006). 16091016 Pubmed 2006 The shed ectodomain of type XIII collagen associates with the fibrillar fibronectin matrix and may interfere with its assembly in vitro Väisänen, Marja-Riitta Väisänen, Timo Tu, Hongmin Pirilä, Päivi Sormunen, Raija Pihlajaniemi, Taina Biochem. J. 393:43-50 10713152 Pubmed 2000 Distinct recognition of collagen subtypes by alpha(1)beta(1) and alpha(2)beta(1) integrins. Alpha(1)beta(1) mediates cell adhesion to type XIII collagen Nykvist, P Tu, H Ivaska, J Käpylä, J Pihlajaniemi, T Heino, J J Biol Chem 275:8255-61 10722741 Pubmed 2000 Type XIII collagen forms homotrimers with three triple helical collagenous domains and its association into disulfide-bonded trimers is enhanced by prolyl 4-hydroxylase Snellman, A Keränen, MR Hägg, PO Lamberg, A Hiltunen, J Kalervo Kivirikko,KI Pihlajaniemi, T J Biol Chem 275:8936-44 20844119 Pubmed 2010 肌源性胶原蛋白十三调节成熟of the skeletal neuromuscular junction Latvanlehto, A Fox, MA Sormunen, R Tu, H Oikarainen, T Koski, A Naumenko, N Shakirzyanova, A Kallio, M Ilves, M Giniatullin, R Sanes——约书亚R Pihlajaniemi, T J Neurosci 30:12230-41 11956183 Pubmed 2002 The type XIII collagen ectodomain is a 150-nm rod and capable of binding to fibronectin, nidogen-2, perlecan, and heparin Tu, Hongmin Sasaki, Takako Snellman, Anne Göhring, Walter Pirilä, Paivi Timpl, Rupert Pihlajaniemi, Taina J. Biol. Chem. 277:23092-9 11223332 Pubmed 2001 Type XIII collagen: a novel cell adhesion component present in a range of cell-matrix adhesions and in the intercalated discs between cardiac muscle cells Hägg, P Väisänen, T Tuomisto, A Rehn, M Tu, H Huhtala, P Eskelinen, S Pihlajaniemi, T Matrix Biol 19:727-42 9624150 Pubmed 1998 Type XIII collagen is identified as a plasma membrane protein Hägg, P Rehn, M Huhtala, P Väisänen, T Tamminen, M Pihlajaniemi, T J Biol Chem 273:15590-7 11013208 Pubmed 2000 A short sequence in the N-terminal region is required for the trimerization of type XIII collagen and is conserved in other collagenous transmembrane proteins Snellman, A Tu, H Väisänen, T Kvist, A P Huhtala, P Pihlajaniemi, T EMBO J. 19:5051-9 15005656 Pubmed 2004 The shed ectodomain of type XIII collagen affects cell behaviour in a matrix-dependent manner Väisänen, Marja-Riitta Väisänen, Timo Pihlajaniemi, Taina Biochem. J. 380:685-93 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Gelatin degradation by MMP1, 2, 3, 7, 8, 9, 12, 13 Gelatin degradation by MMP1, 2, 3, 7, 8, 9, 12, 13 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Converted from EntitySet in Reactome Reactome DB_ID: 10151783 1 裂解胶原蛋白fibrils [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10151805 MMP1-3, 7-9, 12, 13 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] MMP2 [extracellular region] MMP8 [extracellular region] MMP13 [extracellular region] MMP7 [extracellular region] MMP9 [extracellular region] MMP12 [extracellular region] Reactome Database ID Release 77 10151806 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10151806 Reactome Database ID Release 77 10151808 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10151808 Reactome R-SSC-1454757 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1454757.1 Gelatin is formed when collagen becomes partly or completely uncoiled when compared with the regular triple helix structure of fibrillar collagen. In vivo, once collagens are initially cleaved into clasical 3/4 and 1/4 fragments (by collagenases) they rapidly denature at body temperature and are degraded by gelatinases and other nonspecific tissue proteinases (Chung et al. 2004) to a semi-solid colloid gel. MMP2 and MMP9 are the major gelatinases (Collier et al. 1988, Wilhelm et al. 1989) often referred to respectively as Gelatinase A and Gelatinase B (Murphy & Crabbe 1995). However many other MMPs have gelatinase activity, including MMP1 (Murphy et al. 1982, Isaksen & Fagerhol 2001, Chung et al. 2004), MMP3 (Chin et al. 1985, Isaksen & Fagerhol 2001), MMP7 (Isaksen & Fagerhol 2001), MMP8 (Isaksen & Fagerhol 2001) MMP10 (Sanches-Lopez et al. 1993), MMP12 (Chandler et al. 1996), MMP13 (Knäuper et al. 1993, Isaksen & Fagerhol 2001), MMP16 (Shofuda et al. 1997), MMP17 (Wang et al. 1999), MMP18 (Spinucci et al. 1988), MMP19 (Stracke et al. 2000) and MMP22 (Yang & Kurkinen 1998). 8463259 Pubmed 1993 Role of zinc-binding- and hemopexin domain-encoded sequences in the substrate specificity of collagenase and stromelysin-2 as revealed by chimeric proteins Sanchez-Lopez, R Alexander, C M Behrendtsen, O Breathnach, R Werb, Z J. Biol. Chem. 268:7238-47 2845110 Pubmed 1988 Purification of a gelatin-degrading type IV collagenase secreted by ras oncogene-transformed fibroblasts Spinucci, C Zucker, S Wieman, J M Lysik, R M Imhof, B Ramamurthy, N Liotta, L A Nagase, H J. Natl. Cancer Inst. 80:1416-20 2995374 Pubmed 1985 Stromelysin, a connective tissue-degrading metalloendopeptidase secreted by stimulated rabbit synovial fibroblasts in parallel with collagenase. Biosynthesis, isolation, characterization, and substrates Chin, JR Murphy, G Werb, Z J Biol Chem 260:12367-76 2834383 Pubmed 1988 H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen Collier, I E Wilhelm, S M Eisen, A Z Marmer, B L Grant, G A Seltzer, J L Kronberger, A He, C S Bauer, E A Goldberg, G I J. Biol. Chem. 263:6579-87 9092507 Pubmed 1997 Expression of three membrane-type matrix metalloproteinases (MT-MMPs) in rat vascular smooth muscle cells and characterization of MT3-MMPs with and without transmembrane domain Shofuda, K Yasumitsu, H Nishihashi, A Miki, K Miyazaki, K J. Biol. Chem. 272:9749-54 9651395 Pubmed 1998 Cloning and characterization of a novel matrix metalloproteinase (MMP), CMMP, from chicken embryo fibroblasts. CMMP, Xenopus XMMP, and human MMP19 have a conserved unique cysteine in the catalytic domain Yang, M Kurkinen, M J. Biol. Chem. 273:17893-900 10809722 Pubmed 2000 Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19. Evidence for a role as a potent basement membrane degrading enzyme Stracke, J O Hutton, M Stewart, M Pendás, A M Smith, B López-Otin, C Murphy, Gillian Knäuper, V J. Biol. Chem. 275:14809-16 7674939 Pubmed 1995 Gelatinases A and B Murphy, Gillian Crabbe, T Meth. Enzymol. 248:470-84 11577169 Pubmed 2001 Calprotectin inhibits matrix metalloproteinases by sequestration of zinc Isaksen, B Fagerhol, M K MP, Mol. Pathol. 54:289-92 10551873 Pubmed 1999 Catalytic activities and substrate specificity of the human membrane type 4 matrix metalloproteinase catalytic domain Wang, Y Johnson, A R Ye, Q Z Dyer, R D J. Biol. Chem. 274:33043-9 inferred by electronic annotation IEA GO IEA 4 PXLP-K278-PHYKPL tetramer hydrolyses 5PHL PXLP-K278-PHYKPL tetramer hydrolyses 5PHL This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 113521 1 mitochondrial matrix GO 0005759 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 5696409 1 erythro-5-phosphonooxy-L-lysine [ChEBI:16752] erythro-5-phosphonooxy-L-lysine ChEBI 16752 Reactome DB_ID: 113556 1 L-allysine [ChEBI:17917] L-allysine ChEBI 17917 Reactome DB_ID: 5693978 1 ammonia [ChEBI:16134] ammonia ChEBI 16134 Reactome DB_ID: 113548 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10179885 PXLP-K278-PHYKPL tetramer [mitochondrial matrix] PXLP-K278-PHYKPL tetramer Reactome DB_ID: 10179883 4 UniProt: A0A287ATW9 PHYKPL UniProt A0A287ATW9 N6-pyridoxal phosphate-L-lysine at 278 (in Homo sapiens) 278 EQUAL N6-pyridoxal phosphate-L-lysine [MOD:00128] 1 EQUAL 450 EQUAL Reactome Database ID Release 77 10179885 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10179885 Reactome R-SSC-5696429 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5696429.1 GO 0016829 GO molecular function Reactome Database ID Release 77 10179886 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10179886 Reactome Database ID Release 77 10179888 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10179888 Reactome R-SSC-5696408 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5696408.1 在线粒体,ethanolamine-phosphate phospho-lyase and 5-phosphohydroxy-L-lysine phospho-lyase (ETNPPL and PHYKPL respectively) are two closely related pyridoxal-phosphate-dependent, homotetrameric ammoniophospholyases that hydrolyse phosphoethanolamine (PETA) and 5-phosphohydroxylysine (5PHL) respectively (Veiga-da-Cunha et al. 2012). PETA is a component and a precursor of phospholipids whereas 5PHL is a breakdown product of collagen. ETNPPL utilises one pyridoxal 5'-phosphate (PXLP) as cofactor per subunit. 22241472 Pubmed 2012 Molecular identification of hydroxylysine kinase and of ammoniophospholyases acting on 5-phosphohydroxy-L-lysine and phosphoethanolamine Veiga-da-Cunha, M Hadi, Farah Balligand, Thomas Stroobant, Vincent Van Schaftingen, Emile J. Biol. Chem. 287:7246-55 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10203841 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10203841 Reactome R-SSC-1442490 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1442490.1 GO 0030574 GO biological process 胶原原纤维直径和空间组织are dependent on the species, tissue type and stage of development (Parry 1988). The lengths of collagen fibrils in mature tissues are largely unknown but in tendon can be measured in millimetres (Craig et al. 1989). Collagen fibrils isolated from adult bovine corneal stroma had ~350 collagen molecules in transverse section, tapering down to three molecules at the growing tip (Holmes & Kadler 2005).

The classical view of collagenases is that they actively unwind the triple helical chain, a process termed molecular tectonics (Overall 2002, Bode & Maskos 2003), before preferentially cleaving the alpha2 chain followed by the remaining chains (Chung et al. 2004). More recently it has been suggested that collagen fibrils exist in an equilibrium between protected and vulnerable states (Stultz 2002, Nerenberg & Stultz 2008). The prototypical triple-helical structure of collagen does not fit into the active site of collagenase MMPs. In addition the scissile bonds are not solvent-exposed and are therefore inaccessible to the collagenase active site (Chung et al. 2004, Stultz 2002). It was realized that collagen must locally unfold into non-triple helical regions to allow collagenolysis. Observations using circular dichroism and differential scanning calorimetry confirm that there is considerable heterogeneity along collagen fibres (Makareeva et al. 2008) allowing access for MMPs at physiological temperatures (Salsas-Escat et al. 2010).

Collagen fibrils with cut chains are unstable and accessible to proteinases that cannot cleave intact collagen strands (Woessner & Nagase 2000, Somerville et al. 2003). Continued degradation leads to the formation of gelatin (Lovejoy et al. 1999). Degradation of collagen types other than I-III is less well characterized but believed to occur in a similar manner.

Metalloproteinases (MMPs) play a major part in the degradation of several extracellular macromolecules including collagens. MMP1 (Welgus et al. 1981), MMP8 (Hasty et al. 1987), and MMP13 (Knauper et al. 1996), sometimes referred to as collagenases I, II and III respectively, are able to initiate the intrahelical cleavage of the major fibril forming collagens I, II and III at neutral pH, and thus thought to define the rate-limiting step in normal tissue remodeling events. All can cleave additional substrates including other collagen subtypes. Collagenases cut collagen alpha chains at a single conserved Gly-Ile/Leu site approximately 3/4 of the molecule's length from the N-terminus (Fields 1991, Chung et al. 2004). The cleavage site is characterised by the motif G(I/L)(A/L); the G-I/L bond is cleaved. In collagen type I this corresponds to G953-I954 in the Uniprot canonical alpha chain sequences (often given as G775-I776 in literature). It is not clear why only this bond is cleaved, as the motif occurs at several other places in the chain. MMP14, a membrane-associated MMP also known as Membrane-type matrix metalloproteinase 1 (MT-MMP1), is able to cleave collagen types I, II and III (Ohuchi et al. 1997). 18644377 Pubmed 2008 Differential unfolding of alpha1 and alpha2 chains in type I collagen and collagenolysis Nerenberg, PS Stultz, CM J Mol Biol 382:246-56 12353914 Pubmed 2002 Molecular determinants of metalloproteinase substrate specificity: matrix metalloproteinase substrate binding domains, modules, and exosites Overall, CM Mol Biotechnol 22:51-86 18073209 Pubmed 2008 Structural heterogeneity of type I collagen triple helix and its role in osteogenesis imperfecta Makareeva, Elena Mertz, Edward L Kuznetsova, Natalia V Sutter, Mary B DeRidder, Angela M Cabral, Wayne A Barnes, Aileen M McBride, Daniel J Marini, Joan C Leikin, Sergey J. Biol. Chem. 283:4787-98 12887053 Pubmed 2003 Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases Bode, W Maskos, K Biol Chem 384:863-72 1666905 Pubmed 1991 A model for interstitial collagen catabolism by mammalian collagenases Fields, GB J Theor Biol 153:585-602 12079342 Pubmed 2002 Localized unfolding of collagen explains collagenase cleavage near imino-poor sites Stultz, CM J Mol Biol 319:997-1003 3282560 Pubmed 1988 The molecular and fibrillar structure of collagen and its relationship to the mechanical properties of connective tissue Parry, DA Biophys Chem 29:195-209 11076937 Pubmed 2001 Cleavage and shedding of E-cadherin after induction of apoptosis Steinhusen, U Weiske, J Badock, V Tauber, R Bommert, K Huber, O J. Biol. Chem. 276:4972-80 2477190 Pubmed 1989 An estimate of the mean length of collagen fibrils in rat tail-tendon as a function of age Craig, AS Birtles, MJ Conway, JF Parry, DA Connect Tissue Res 19:51-62 20394413 Pubmed 2010 Cleavage site specificity and conformational selection in type I collagen degradation Salsas-Escat, Ramon Nerenberg, Paul S Stultz, Collin M Biochemistry 49:4147-58 21087458 Pubmed 2011 Regulation of matrix metalloproteinase activity in health and disease Hadler-Olsen, E Fadnes, B Sylte, I Uhlin-Hansen, L Winberg, JO FEBS J 278:28-45 9818170 Pubmed 1998 Matrix metalloproteinase degradation of extracellular matrix: biological consequences Shapiro, SD Curr Opin Cell Biol 10:602-8 15588825 Pubmed 2005 The precision of lateral size control in the assembly of corneal collagen fibrils Holmes, DF Kadler, KE J Mol Biol 345:773-84 10074939 Pubmed 1999 晶体结构的金属蛋白酶- 1和-13揭示了structural basis for selectivity of collagenase inhibitors Lovejoy, B Welch, AR Carr, S Luong, C Broka, C Hendricks, RT Campbell, JA Walker, KA Martin, R Van Wart, H Browner, Michelle F Nat结构生物学观点》6:217-21 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Elastin degradation by elastin-degrading extracellular proteinases Elastin degradation by elastin-degrading extracellular proteinases This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153359 1 Elastin [extracellular region] Elastin Reactome DB_ID: 10153367 1 Cleaved elastin [extracellular region] Cleaved elastin PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153373 Elastin-degrading extracellular proteinases [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP2 [extracellular region] MMP7 [extracellular region] MMP9 [extracellular region] ELANE [extracellular region] MMP12 [extracellular region] Reactome Database ID Release 77 10153374 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153374 Reactome Database ID Release 77 10153376 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153376 Reactome R-SSC-1566962 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1566962.1 The elastin component of elastic fibres is degraded to soluble fragments by MMP2 (Murphy et al. 1991), MMP7 (Quantin et al. 1989, Murphy et al. 1991), MMP9 (Murphy et al. 1991, Katsuda et al. 1994) and MMP12 (macrophage elastase) (Shapiro et al. 1993, Taddese et al. 2008), and to a limited extent by MMP3 and 10 (Murphy et al. 1991). In addition, elastin is a substrate for neutrophil elastase (Reilly & Travis 1980).
Eighty-nine tropoelastin cleavage sites were identified for MMP-12, whereas MMP-7 and MMP-9 were found to cleave at only 58 and 63 sites, respectively (Heinz et al. 2010). 20345904 Pubmed 2010 Degradation of tropoelastin by matrix metalloproteinases--cleavage site specificities and release of matrikines Heinz, Andrea Jung, Michael C Duca, Laurent Sippl, W Taddese, Samuel Ihling, Christian Rusciani, Anthony Jahreis,冈瑟 Weiss, Anthony S Neubert, Reinhard H H Schmelzer, Christian E H FEBS J. 277:1939-56 7977651 Pubmed 1994 Matrix metalloproteinase-9 (92-kd gelatinase/type IV collagenase equals gelatinase B) can degrade arterial elastin Katsuda, S Okada, Y Okada, Y Imai, K Nakanishi, I Am J Pathol 145:1208-18 6153274 Pubmed 1980 The degradation of human lung elastin by neutrophil proteinases Reilly, C F Travis, J Biochim. Biophys. Acta 621:147-57 18334288 Pubmed 2008 Mapping of macrophage elastase cleavage sites in insoluble human skin elastin Taddese, Samuel Weiss, Anthony S Neubert, Reinhard H H Schmelzer, Christian E H Matrix Biol. 27:420-8 19010778 Pubmed 2009 Membrane-type 1 matrix metalloproteinase regulates macrophage-dependent elastolytic activity and aneurysm formation in vivo Xiong, Wanfen Knispel, Rebecca MacTaggart, Jason Greiner, Timothy C Weiss, Stephen J Baxter, B Timothy J. Biol. Chem. 284:1765-71 2550050 Pubmed 1989 Pump-1 cDNA codes for a protein with characteristics similar to those of classical collagenase family members Quantin, B Murphy, G Breathnach, R Biochemistry 28:5327-34 8226919 Pubmed 1993 Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages Shapiro, SD Kobayashi, DK Ley, TJ J Biol Chem 268:23824-9 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Elastin degradation by MMP14 Elastin degradation by MMP14 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10153359 1 Reactome DB_ID: 10153367 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10152088 1 EQUAL 811 EQUAL Reactome Database ID Release 77 10163747 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163747 Reactome R-SSC-2514790 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2514790.1 Elastin degradation is regulated by the membrane-associated matrix metalloproteinase MMP14 (Xiong et al. 2009) and associated with aneurisms. inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Fibrillin 1, 2,(3) degradation by MMP2, 9, 12 and 13 Fibrillin 1, 2,(3) degradation by MMP2, 9, 12 and 13 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Converted from EntitySet in Reactome Reactome DB_ID: 10153500 1 Fibrillin 1,2,(3) [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 10163667 1 Cleaved fibrillin 1,2,(3) [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10163669 MMP2,9,12,13 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP2 [extracellular region] MMP13 [extracellular region] MMP9 [extracellular region] MMP12 [extracellular region] Reactome Database ID Release 77 10163670 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163670 Reactome Database ID Release 77 10163672 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163672 Reactome R-SSC-2485148 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2485148.1 All mammals have three fibrillin genes (Davis & Summers 2012). Fibrillin-3 arose as a duplication of fibrillin-2 that did not occur in the rodent lineage. Fibrillin-1 is the major structural component of microfibrils (Kielty et al. 2005). Fibrillin-2 is expressed earlier in development than fibrillin-1 and may be important for elastic fiber formation (Zhang et al. 1994). Fibrillin-3 was isolated from and is predominantly expressed in brain; it is not known whether it forms microfibrils (Corson et al. 2004). Fibrillin-1 and -2 are degraded by MMP2, 9, 12 and 13 (Ashworth et al. 1999, Hindson et al. 1999). Fibrillin-1 is additionally degraded by MMP3 (Ashworth et al. 1999), the membrane-associated MMP14 (Ashworth et al. 1999), neutrophil elastase (ELANE) (Kielty et al. 1994), cathepsin L2 (V) and cathepsin K (Kirschner et al. 2011). 10386589 Pubmed 1999 Fibrillin degradation by matrix metalloproteinases: identification of amino- and carboxy-terminal cleavage sites Hindson, V J Ashworth, J L Rock, M J Cunliffe, S Shuttleworth, C A Kielty, C M FEBS Lett. 452:195-8 15837522 Pubmed 2005 Fibrillin microfibrils Kielty, Cay M Sherratt, Michael J Marson, Andrew Baldock, Clair Adv. Protein Chem. 70:405-36 10229672 Pubmed 1999 Fibrillin degradation by matrix metalloproteinases: implications for connective tissue remodelling Ashworth, J L Murphy, Gillian Rock, M J Sherratt, M J Shapiro, S D Shuttleworth, C A Kielty, C M Biochem. J. 340:171-81 8120105 Pubmed 1994 Structure and expression of fibrillin-2, a novel microfibrillar component preferentially located in elastic matrices Zhang, H Apfelroth, S D Hu, W Davis, E C Sanguineti, C Bonadio, J Mecham, R P Ramirez, F J. Cell Biol. 124:855-63 8076699 Pubmed 1994 Catabolism of intact fibrillin microfibrils by neutrophil elastase, chymotrypsin and trypsin Kielty, C M Woolley, D E Whittaker, S P Shuttleworth, C A FEBS Lett. 351:85-9 22921888 Pubmed 2012 Structure and function of the mammalian fibrillin gene family: Implications for human connective tissue diseases Davis, Margaret R Summers, Kim M Mol. Genet. Metab. 21784848 Pubmed 2011 Classical and neonatal Marfan syndrome mutations in fibrillin-1 cause differential protease susceptibilities and protein function Kirschner, Ryan Hubmacher, Dirk Iyengar, Garud Kaur, Jasvir Fagotto-Kaufmann, Christine Brömme, Dieter Bartels, Rainer Reinhardt, Dieter P J. Biol. Chem. 286:32810-23 14962672 Pubmed 2004 Differential expression of fibrillin-3 adds to microfibril variety in human and avian, but not rodent, connective tissues Corson, Glen M Charbonneau, Noe L Keene, Douglas R Sakai, Lynn Y Genomics 83:461-72 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Fibronectin degradation by MMP1, 3, 7, 12, 13, 19, CTSS Fibronectin degradation by MMP1, 3, 7, 12, 13, 19, CTSS This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10129288 1 Fibronectin matrix [extracellular region] Fibronectin matrix Reactome DB_ID: 10153384 1 Cleaved fibronectin matrix [extracellular region] Cleaved fibronectin matrix PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153390 MMP1, 3, 7, 12, 13, 19, CTSS [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] CTSS [extracellular region] MMP19 [extracellular region] MMP13 [extracellular region] MMP7 [extracellular region] MMP12 [extracellular region] UniProt F1SS93 UniProt F1SPJ1 Reactome Database ID Release 77 10153391 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153391 Reactome Database ID Release 77 10153393 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10153393 Reactome R-SSC-1566981 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1566981.1 MMP1会降低纤连蛋白(Fukai et al . 1995年),as can MMP3 (Gunja-Smith et al. 1985, Nicholson et al. 1989, Wilhelm et al. 1993, Fukai et al. 1995), MMP7 (Quantin et al. 1989, Miyazaki et al. 1990, Fukai et al. 1995, von Bredow et al. 1995), MMP10 (Nicholson et al. 1989), MMP12 (Gronski et al. 1997), MMP13 (Knauper et al. 1997), MMP14 (Shi & Sottile 2011) and 19 (Stracke et al. 2000). Cathepsin S is able to degrade fibronectin (Taleb et al. 2006). Studies have shown that fibronectin turnover is not prevented by protease inhibitors (Sottile & Hocking 2002) suggesting that caveolin-1-mediated endocytosis and intracellular degradation are involved (Salicioni et al. 2002, Sottile & Chandler 2004). 7589259 Pubmed 1995 Degradation of fibronectin fibrils by matrilysin and characterization of the degradation products von Bredow, DC Nagle, RB Bowden, GT Cress, AE Exp Cell Res 221:83-91 16825321 Pubmed 2006 Cathepsin s promotes human preadipocyte differentiation: possible involvement of fibronectin degradation Taleb, Soraya Cancello, Raffaella Clément, Karine Lacasa, Daniele Endocrinology 147:4950-9 12388756 Pubmed 2002 Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell-matrix adhesions Sottile, Jane Hocking, Denise C Mol. Biol. Cell 13:3546-59 22159414 Pubmed 2011 MT1-MMP regulates the turnover and endocytosis of extracellular matrix fibronectin Shi, Feng Sottile, Jane J. Cell. Sci. 124:4039-50 15563605 Pubmed 2005 Fibronectin matrix turnover occurs through a caveolin-1-dependent process Sottile, Jane Chandler, Jennifer Mol. Biol. Cell 16:757-68 9065415 Pubmed 1997 The role of the C-terminal domain of human collagenase-3 (MMP-13) in the activation of procollagenase-3, substrate specificity, and tissue inhibitor of metalloproteinase interaction Knäuper, V Cowell, S Smith, B López-Otin, C O'Shea, M Morris, H Zardi, L Murphy, G J Biol Chem 272:7608-16 7547873 Pubmed 1995 Release of biological activities from quiescent fibronectin by a conformational change and limited proteolysis by matrix metalloproteinases Fukai, F Ohtaki, M Fujii, N Yajima, H Ishii, T Nishizawa, Y Miyazaki, K Katayama, T Biochemistry 34:11453-9 8408046 Pubmed 1993 Matrix metalloproteinase-3 (stromelysin-1). Identification as the cartilage acid metalloprotease and effect of pH on catalytic properties and calcium affinity Wilhelm, SM Shao, ZH Housley, TJ Seperack, PK Baumann, AP Gunja-Smith, Z Woessner JF, Jr J Biol Chem 268:21906-13 9115292 Pubmed 1997 Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase Gronski TJ, Jr Martin, RL Kobayashi, DK Walsh, BC 霍尔曼,MC Huber, M Van Wart, HE Shapiro, SD J Biol Chem 272:12189-94 11867643 Pubmed 2002 The low density lipoprotein receptor-related protein mediates fibronectin catabolism and inhibits fibronectin accumulation on cell surfaces Salicioni, Ana M Mizelle, Kellie S Loukinova, Elena Mikhailenko, Irina Strickland, Dudley K Gonias, Steven L J. Biol. Chem. 277:16160-6 2930500 Pubmed 1989 中性proteoglycan-degrading的净化metalloproteinase from human articular cartilage tissue and its identification as stromelysin matrix metalloproteinase-3 Gunja-Smith, Z Nagase, H Woessner JF, Jr Biochem J 258:115-9 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Fibronectin degradation by MMP14, TMPRSS6 Fibronectin degradation by MMP14, TMPRSS6 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10129288 1 Reactome DB_ID: 10153384 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10152088 1 EQUAL 811 EQUAL Reactome Database ID Release 77 10163806 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163806 Reactome R-SSC-2533950 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2533950.1 MMP14 (MT1-MMP) can degrade fibronectin (Shi & Sottile 2011). Studies have shown that fibronectin turnover is not prevented by protease inhibitors (Sottile & Hocking 2002) and suggest that caveolin-1-mediated endocytosis and intracellular degradation are involved (Salicioni et al. 2002, Sottile & Chandler 2004). Transmembrane protease serine 6 (Matriptase-2, TMPRSS6) is a transmembrane serine proteinase able to hydrolyze endogenous proteins such as type I collagen, fibronectin, and fibrinogen (Velasco et al. 2002). 12149247 Pubmed 2002 Matriptase-2, a membrane-bound mosaic serine proteinase predominantly expressed in human liver and showing degrading activity against extracellular matrix proteins Velasco, Gloria Cal, Santiago Quesada, Víctor Sánchez, Luis M López-Otín, Carlos J. Biol. Chem. 277:37637-46 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Fibronectin degradation by CTSG Fibronectin degradation by CTSG This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10129288 1 Reactome DB_ID: 10153384 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10158504 UniProt:A0A287BDI2 LOC100154047 21 EQUAL 255 EQUAL Reactome Database ID Release 77 10158505 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10158505 Reactome Database ID Release 77 10167172 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167172 Reactome R-SSC-3785684 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-3785684.1 Plasma fibronectin (FN1) is degraded by cathepsin G (CTSG) into a characteristic pattern of gelatin-binding peptides of M, = 64000, 40000, and 30000 (Vartio et al. 1981, Vartio 1982). CTSG is activated by UV exposure and can activate matrix metalloproteinases MMP1 and MMP2, but increased levels of MMP activity did not correlate with increased FN degradation in normal human fibroblasts (NHFs) following exposure to UVB (50 mJ/cm2) irradiation, while addtion of CTSG inhibitor decreased FN degradation, suggesting that CTSG is directly responsible for FN1 degradation (Son et al. 2009). 18835135 Pubmed 2009 Cathepsin G increases MMP expression in normal human fibroblasts through fibronectin fragmentation, and induces the conversion of proMMP-1 to active MMP-1 Son, Eui Dong Kim, Hyaekyoung Choi, Hyunjung Lee, So Hee Lee, Jin Young Kim, Sujung Closs, B Lee, Sera Chung, Jin Ho Hwang, Jae Sung J. Dermatol. Sci. 53:150-2 6450204 Pubmed 1981 Susceptibility of soluble and matrix fibronectins to degradation by tissue proteinases, mast cell chymase and cathepsin G Vartio, T Seppä, H Vaheri, A J. Biol. Chem. 256:471-7 7075587 Pubmed 1982 Characterization of the binding domains in the fragments cleaved by cathepsin G from human plasma fibronectin Vartio, T Eur. J. Biochem. 123:223-33 inferred by electronic annotation IEA GO IEA 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Fibronectin degradation by ADAM8 Fibronectin degradation by ADAM8 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10129288 1 Reactome DB_ID: 10167194 1 Cleaved fibronectin matrix Ala(271)/Val(272) [extracellular region] Cleaved fibronectin matrix Ala(271)/Val(272) PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10167198 UniProt:K7GNP1 ADAM8 UniProt K7GNP1 17 EQUAL 824 EQUAL Reactome Database ID Release 77 10167199 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167199 Reactome Database ID Release 77 10167201 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167201 Reactome R-SSC-3788061 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-3788061.1 ADAM8 can cleave fibronectin in human cartilage extracts at Ala271/Val272, within a linker region between the fifth and sixth type I domains, producing ?30-kd and ?50–85-kd fragments with distinctive neoepitopes VRAA271 and 272VYQP that are associated with osteoarthritis (Zack et al. 2006, 2009). 19714641 Pubmed 2009 ADAM-8 isolated from human osteoarthritic chondrocytes cleaves fibronectin at Ala(271) Zack, Marc D Malfait, Anne-Marie Skepner, Adam P Yates, Matthew P Griggs, David W Hall, Troii Hills, Robert L Alston, James T Nemirovskiy, Olga V Radabaugh, Melissa R Leone, Joseph W Arner, Elizabeth C Tortorella, Micky D Arthritis Rheum. 60:2704-13 16948117 Pubmed 2006 Identification of fibronectin neoepitopes present in human osteoarthritic cartilage Zack, Marc D Arner, Elizabeth C Anglin, Charles P Alston, James T Malfait, Anne-Marie Tortorella, Micky D Arthritis Rheum. 54:2912-22 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 NID1 degradation by MMP19 NID1 degradation by MMP19 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10163177 1 UniProt:F1RGY5 NID1 UniProt F1RGY5 29 EQUAL 1247 EQUAL Reactome DB_ID: 10167307 1 29 EQUAL -1 EQUAL Reactome DB_ID: 10167309 1 -1 EQUAL 1247 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10151816 UniProt:F1SPJ1 MMP19 98 EQUAL 508 EQUAL Reactome Database ID Release 77 10167310 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167310 Reactome Database ID Release 77 10167312 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167312 Reactome R-SSC-3791319 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-3791319.1 Nidogen-1 (entactin) is a member of the nidogen family of basement membrane glycoproteins. It interacts with several other components of basement membranes, notably it connects the collagen and laminin networks to each other (Yurchenko & Patton 2009). MMPs 3, 7 (Mayer et al. 1993), 1, 9, (Sires et al. 1993), 12 (Gronski et al. 1997), 14, 15 (d'Ortho et al. 1997), 19 (Stracke et al. 2000) and leukocyte elastase (Mayer et al. 1993) can all degrade Nidogen-1. 19355968 Pubmed 2009 Developmental and pathogenic mechanisms of basement membrane assembly Yurchenco, PD Patton, BL Curr Pharm Des 15:1277-94 8223643 Pubmed 1993 Sites of nidogen cleavage by proteases involved in tissue homeostasis and remodelling Mayer, U Mann, K Timpl, R Murphy, G Eur J Biochem 217:877-84 8380588 Pubmed 1993 Degradation of entactin by matrix metalloproteinases. Susceptibility to matrilysin and identification of cleavage sites Sires, UI Griffin, GL Broekelmann, TJ Mecham, RP Murphy, G Chung, AE Welgus, HG Senior, RM J Biol Chem 268:2069-74 9461298 Pubmed 1997 Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases d'Ortho, MP Will, H Atkinson, S Butler, G Messent, A Gavrilovic, J Smith, B Timpl, R Zardi, L Murphy, G Eur J Biochem 250:751-7 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Brevican degradation by ADAMTS4, ADAMTS5 Brevican degradation by ADAMTS4, ADAMTS5 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10158185 1 UniProt:F1RP38 BCAN UniProt F1RP38 O-xylosyl-L-serine (ChEBI:63513) at unknown position O-xylosyl-L-serine ChEBI 63513 modification 23 EQUAL 911 EQUAL Reactome DB_ID: 10167215 1 O-xylosyl-L-serine (ChEBI:63513) at unknown position 396 EQUAL 911 EQUAL Reactome DB_ID: 10167203 1 O-xylosyl-L-serine (ChEBI:63513) at unknown position 23 EQUAL 395 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10167235 ADAMTS4, ADAMTS5 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ADAMTS4 [extracellular region] ADAMTS5 [extracellular region] UniProt F1S1A7 UniProt F1SHP0 Reactome Database ID Release 77 10167236 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167236 Reactome Database ID Release 77 10167238 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167238 Reactome R-SSC-3788075 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-3788075.1 Brevican, lectican家族的一员,就是其中之一of the most abundant proteoglycans in normal adult brain tissues. It is thought to form lattice structures by linking hyaluronan and tenascin-R through its N- and C-terminal globular domains, respectively. As brain extracellular matrix (ECM) contains no collagen fibrils, this matrix of hyaluronan/brevican/tenascin-R is considered essential to maintain the integrity of brain ECM. Degradation of brevican by proteinases disrupts ECM structures and facilitates invasion of glioma cells (Yamaguchi 2000). The major brevican cleavage site observed under physiological conditions (Yamada et al. 1994) and during glioma invasion (Zhang et al. 1998) is the Glu395-Ser396 bond present within the central domain of the core protein, forming an ~50-kDa N-terminal fragment. This bond is cleaved by ADAMTS4 and 5 (Nakamura et al. 2000, Matthews et al. 2000, Nakada et al. 2005). Matrix metalloproteinases that digest brevican preferentially cleave the Ala360-Phe361 bond. (Nakamura et al. 2000, Nakada et al. 2005, Lettau et al. 2010). 9502798 Pubmed 1998 Expression of a cleaved brain-specific extracellular matrix protein mediates glioma cell invasion In vivo Zhang, H Kelly, G Zerillo, C Jaworski, D M Hockfield, S J. Neurosci. 18:2370-6 8144512 Pubmed 1994 Molecular cloning of brevican, a novel brain proteoglycan of the aggrecan/versican family Yamada, H Watanabe, K Shimonaka, M Yamaguchi, Y J. Biol. Chem. 269:10119-26 10986281 Pubmed 2000 Brevican is degraded by matrix metalloproteinases and aggrecanase-1 (ADAMTS4) at different sites Nakamura, H Fujii, Y Inoki, I Sugimoto, K Tanzawa, K Matsuki, H Miura, R Yamaguchi, Y Okada, Y J. Biol. Chem. 275:38885-90 10766023 Pubmed 2000 Lecticans: organizers of the brain extracellular matrix Yamaguchi, Y Cell. Mol. Life Sci. 57:276-89 20142769 Pubmed 2010 Matrix metalloproteinase-19 is highly expressed in astroglial tumors and promotes invasion of glioma cells Lettau, Imke Hattermann, Kirsten Held-Feindt, Janka Brauer, Rena Sedlacek, Radislav Mentlein, Rolf J. Neuropathol. Exp. Neurol. 69:215-23 16133547 Pubmed 2005 Human glioblastomas overexpress ADAMTS-5 that degrades brevican Nakada, Mitsutoshi Miyamori, Hisashi Kita, Daisuke Takahashi, Tomoya Yamashita, Junkoh Sato, Hiroshi Miura, Ryu Yamaguchi, Yu Okada, Yasunori Acta Neuropathol. 110:239-46 10801887 Pubmed 2000 Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member Matthews, R T Gary, S C Zerillo, C Pratta, M Solomon, K Arner, E C Hockfield, S J. Biol. Chem. 275:22695-703 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Brevican degradation by MMP1, 2, 3, 7,8,10,13,19 Brevican degradation by MMP1, 2, 3, 7,8,10,13,19 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10158185 1 O-xylosyl-L-serine (ChEBI:63513) at unknown position 23 EQUAL 911 EQUAL Reactome DB_ID: 10167290 1 O-xylosyl-L-serine (ChEBI:63513) at unknown position 361 EQUAL 911 EQUAL Reactome DB_ID: 10167278 1 O-xylosyl-L-serine (ChEBI:63513) at unknown position 23 EQUAL 360 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10167302 MMP1, 2, 3, 7,8,10,13,19 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] MMP2 [extracellular region] MMP8 [extracellular region] MMP19 [extracellular region] MMP7 [extracellular region] MMP13 [extracellular region] Reactome Database ID Release 77 10167303 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167303 Reactome Database ID Release 77 10167305 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167305 Reactome R-SSC-3791149 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-3791149.1 Brevican, lectican家族的一员,就是其中之一of the most abundant proteoglycans in normal adult brain tissues. It is thought to form lattice structures by linking hyaluronan and tenascin-R through its N- and C-terminal globular domains, respectively. As brain extracellular matrix (ECM) contains no collagen fibrils, this matrix of hyaluronan/brevican/tenascin-R is considered essential to maintain the integrity of brain ECM. Degradation of brevican by proteinases disrupts ECM structures and facilitates invasion of glioma cells (Yamaguchi 2000). The major brevican cleavage site observed under physiological conditions (Yamada et al. 1994) and during glioma invasion (Zhang et al. 1998) is the Glu395-Ser396 bond present within the central domain of the core protein, forming an ~50-kDa N-terminal fragment. This bond is cleaved by ADAMTS4 and 5 (Nakamura et al. 2000, Matthews et al. 2000, Nakada et al. 2005). Matrix metalloproteinases that digest brevican (MMP-1, -2, -3, -7, -8, -10, -13 and -19) preferentially cleave the Ala360-Phe361 bond. (Nakamura et al. 2000, Nakada et al. 2005, Lettau et al. 2010). inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 DCN (decorin) degradation by MMP2, MMP3, MMP7 DCN (decorin) degradation by MMP2, MMP3, MMP7 DCN is cleaved by MMP2, 3 and 7 Decorin is cleaved by MMP2, 3 & 7 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10162613 1 UniProt:F1SQ10 DCN UniProt F1SQ10 31 EQUAL 359 EQUAL Reactome DB_ID: 10163838 1 31 EQUAL -1 EQUAL Reactome DB_ID: 10163840 1 1 EQUAL 359 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10163842 MMP2, MMP3, MMP7 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP2 [extracellular region] MMP7 [extracellular region] Reactome Database ID Release 77 10163843 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163843 Reactome Database ID Release 77 10163845 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10163845 Reactome R-SSC-2534248 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2534248.1 DCN consists of a core protein of ?40 kDa attached to a single chondroitin or dermatan sulfate glycosaminoglycan (GAG) chain. It interacts with collagen types I, II (Vogel et al. 1984), III (Witos et al. 2011), VI (Bidanset et al. 1992) and XIV (Ehnis et al. 1997). DCN acts as a sink for all three isoforms of TGF-Beta, binding them while already bound to collagen (Markmann et al. 2000). Degradation of DCN by matrix metalloproteinases MMP2, 3 or 7 results in the release of TGF-beta (Imai et al. 1997). In addition, DCN binds to EGFR (Iozzo et al. 1999) causing prolonged down-regulation of EGFR-mediated mobilization of intracellular calcium (Csordás et al. 2000). 9988678 Pubmed 1999 Decorin is a biological ligand for the epidermal growth factor receptor Iozzo, R V Moscatello, D K McQuillan, D J Eichstetter, I J. Biol. Chem. 274:4489-92 6439184 Pubmed 1984 Specific inhibition of type I and type II collagen fibrillogenesis by the small proteoglycan of tendon Vogel, K G Paulsson, M Heinegård, D Biochem. J. 223:587-97 9148753 Pubmed 1997 Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release Imai, K Hiramatsu, A Fukushima, D Pierschbacher, M D Okada, Y Biochem. J. 322:809-14 21789315 Pubmed 2011 Collagen I and III and their decorin modified surfaces studied by atomic force microscopy and the elucidation of their affinity toward positive apolipoprotein B-100 residue by quartz crystal microbalance Witos, Joanna Saint-Guirons, Julien Meinander, Kristoffer D'Ulivo, Lucia Riekkola, Marja-Liisa Analyst 136:3777-82 9252349 Pubmed 1997 Localization of a binding site for the proteoglycan decorin on collagen XIV (undulin) Ehnis T Dieterich, W Bauer, M Kresse, H Schuppan, D J. Biol. Chem. 272:20414-9 11102752 Pubmed 2000 改变gr decorin表情的影响owth factor-beta-mediated collagen gel retraction and biglycan induction Markmann, A Hausser, H Schönherr, E Kresse, H Matrix Biol. 19:631-6 10913155 Pubmed 2000 Sustained down-regulation of the epidermal growth factor receptor by decorin. A mechanism for controlling tumor growth in vivo Csordás, G Santra, M Reed, C C Eichstetter, I McQuillan, D J Gross, D Nugent, M A Hajnóczky, G Iozzo, R V J. Biol. Chem. 275:32879-87 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 DCN (decorin) degradation by MMP14 DCN (decorin) degradation by MMP14 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10162613 1 31 EQUAL 359 EQUAL Reactome DB_ID: 10163838 1 31 EQUAL -1 EQUAL Reactome DB_ID: 10163840 1 1 EQUAL 359 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10152088 1 EQUAL 811 EQUAL Reactome Database ID Release 77 10167333 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167333 Reactome R-SSC-3828025 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-3828025.1 MMP14 (MT1-MMP) is able to degrade decorin in keratocytes during bFGF-induced corneal neovascularization. 19571574 Pubmed 2009 MT1-MMP-mediated cleavage of decorin in corneal angiogenesis Mimura, Tatsuya Han, Kyu Yeon Onguchi, Tatsuya Chang, Jin-Hong Kim, Tae-im Kojima, Takashi Zhou, Zhongjun Azar, Dimitri T J. Vasc. Res. 46:541-50 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 E-cadherin degradation by MMP9, KLK7 E-cadherin degradation by MMP9, KLK7 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10167314 1 CDH1(155-882):Ca2+ dimer [plasma membrane] CDH1(155-882):Ca2+ dimer Reactome DB_ID: 10127063 2 UniProt:A0A287BPL8 CDH1 UniProt A0A287BPL8 155 EQUAL 882 EQUAL Reactome DB_ID: 74112 10 calcium(2+) [ChEBI:29108] calcium(2+) ChEBI 29108 Reactome Database ID Release 77 10167314 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167314 Reactome R-SSC-2534182 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2534182.1 Reactome DB_ID: 10167318 1 钙粘蛋白链二聚体片段155 - 700(等离子体embrane] E-cadherin strand dimer fragment 155-700 Reactome DB_ID: 10167316 2 155 EQUAL 700 EQUAL Reactome DB_ID: 74112 5 Reactome Database ID Release 77 10167318 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167318 Reactome R-SSC-2534301 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2534301.1 Reactome DB_ID: 10167322 1 E-cadherin strand dimer fragment 701-882 [plasma membrane] E-cadherin strand dimer fragment 701-882 Reactome DB_ID: 10167320 2 701 EQUAL 882 EQUAL Reactome DB_ID: 74112 5 Reactome Database ID Release 77 10167322 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167322 Reactome R-SSC-2534305 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2534305.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10167328 MMP9, KLK7 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity KLK7 [extracellular region] MMP9 [extracellular region] UniProt A0A287ANS1 Reactome Database ID Release 77 10167329 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167329 Reactome Database ID Release 77 10167331 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10167331 Reactome R-SSC-3827958 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-3827958.1 钙粘蛋白(背景)横向membran本地化e of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions bind between the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007). Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region. Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa c-terminal fragment. 15519846 Pubmed 2004 Magic touch: how does cell-cell adhesion trigger actin assembly? Bershadsky, Alexander Trends Cell Biol. 14:589-93 12456712 Pubmed 2003 Nectin and afadin: novel organizers of intercellular junctions Takai, Y Nakanishi, H J Cell Sci 116:17-27 15958533 Pubmed 2005 ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and beta-catenin translocation Maretzky, Thorsten Reiss, Karina Ludwig, Andreas Buchholz, Julian Scholz, Felix Proksch, Erhardt De Strooper, B Hartmann, D Saftig, P Proc. Natl. Acad. Sci. U.S.A. 102:9182-7 12584255 Pubmed 2003 gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation Herreman, A Van Gassen, Geert Bentahir, Mustapha Nyabi, Omar Craessaerts, K Mueller, Ulrike Annaert, W De Strooper, B J. Cell. Sci. 116:1127-36 8608588 Pubmed 1996 Cell adhesion: the molecular basis of tissue architecture and morphogenesis Gumbiner, B M Cell 84:345-57 16293110 Pubmed 2005 Once upon a time there was beta-catenin in cadherin-mediated signalling Gavard, Julie Mège, René-Marc Biol. Cell 97:921-6 16564015 Pubmed 2006 Type II cadherin ectodomain structures: implications for classical cadherin specificity Patel, Saurabh D Ciatto, Carlo Chen, Chien Peter Bahna, Fabiana Rajebhosale, Manisha Arkus, Natalie Schieren, Ira Jessell, Thomas M Honig, Barry Price, Stephen R Shapiro, L Cell 124:1255-68 17093058 Pubmed 2007 Depletion of E-cadherin disrupts establishment but not maintenance of cell junctions in Madin-Darby canine kidney epithelial cells Capaldo, Christopher T Macara, Ian G Mol. Biol. Cell 18:189-200 11112695 Pubmed 2001 Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1 Noë, V Fingleton, B Jacobs, K Crawford, HC Vermeulen, S Steelant, W Bruyneel, E Matrisian, LM Mareel, M J Cell Sci 114:111-118 17354228 Pubmed 2007 激肽释放酶7提高胰腺癌细胞再次ion by shedding E-cadherin Johnson, Sarah K Ramani, Vishnu C Hennings, Leah Haun, Randy S Cancer 109:1811-20 11928810 Pubmed 2002 Plasmin produces an E-cadherin fragment that stimulates cancer cell invasion Ryniers, Filip Stove, Christophe Goethals, Marc Brackenier, Liesbeth Noë, Veerle 马克,马克 Vandekerckhove, J Mareel, Marc 说这话,Erik Biol. Chem. 383:159-65 11964443 Pubmed 2002 C-cadherin ectodomain structure and implications for cell adhesion mechanisms Boggon, TJ Murray, John Chappuis-Flament, Sophie Wong, Ellen Gumbiner, Barry M Shapiro, L Science 296:1308-13 21422226 Pubmed 2011 Dynamics of adherens junctions in epithelial establishment, maintenance, and remodeling Baum, Buzz Georgiou, Marios J. Cell Biol. 192:907-17 18726070 Pubmed 2008 The cell-cell adhesion molecule E-cadherin van Roy, F Berx, G Cell. Mol. Life Sci. 65:3756-88 18434311 Pubmed 2008 The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation Najy, Abdo J Day, Kathleen C Day, Mark L J. Biol. Chem. 283:18393-401 12393869 Pubmed 2003 The role of calpain in the proteolytic cleavage of E-cadherin in prostate and mammary epithelial cells Rios-Doria, Jonathan Day, Kathleen C Kuefer, Rainer Rashid, Michael G Chinnaiyan, Arul M Rubin, MA Day, Mark L J. Biol. Chem. 278:1372-9 12716934 Pubmed 2003 Nicastrin is required for assembly of presenilin/gamma-secretase complexes to mediate Notch signaling and for processing and trafficking of beta-amyloid precursor protein in mammals Li, Tong Ma, Guojun Cai, Huaibin Price, Donald L Wong, Philip C J. Neurosci. 23:3272-7 2007622 Pubmed 1991 E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells Frixen, U H Behrens, J Sachs, M Eberle, G Voss, B Warda, A Löchner, D Birchmeier, W J. Cell Biol. 113:173-85 17332331 Pubmed 2007 Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells Symowicz, Jaime Adley, Brian P Gleason, Kara J Johnson, Jeffrey J Ghosh, Supurna Fishman, David A Hudson, Laurie G Stack, M Sharon Cancer Res. 67:2030-9 12600316 Pubmed 2003 Sticky business: orchestrating cellular signals at adherens junctions Perez-Moreno, Mirna Jamora, Colin Fuchs, Elaine Cell 112:535-48 11953314 Pubmed 2002 A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions Marambaud, Philippe Shioi, Junichi Serban, Geo Georgakopoulos, Anastasios Sarner, Shula Nagy, Vanja Baki, Lia Wen, Paul Efthimiopoulos, Spiros Shao, Zhiping Wisniewski, Thomas Robakis, Nikolaos K EMBO J. 21:1948-56 8058792 Pubmed 1994 E-cadherin null mutant embryos fail to form a trophectoderm epithelium Larue, L Ohsugi, M Hirchenhain, J Kemler, R Proc. Natl. Acad. Sci. U.S.A. 91:8263-7 15561586 Pubmed 2004 Regulation of desmosome assembly and adhesion Yin, Taofei Green, Kathleen J Semin. Cell Dev. Biol. 15:665-77 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 E-cadherin degradation by ADAM10, ADAM15 E-cadherin degradation by ADAM10, ADAM15 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10167314 1 Reactome DB_ID: 10167318 1 Reactome DB_ID: 10167322 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10168181 UniProt:F1RGQ1 ADAM15 UniProt F1RGQ1 207 EQUAL 863 EQUAL Reactome Database ID Release 77 10168182 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10168182 Reactome Database ID Release 77 10168184 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10168184 Reactome R-SSC-4224014 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-4224014.1 钙粘蛋白(背景)横向membran本地化e of differentiated epithelia, providing the structural foundation for adherens junctions, multiprotein complexes that link cell-cell contacts to the actin cytoskeleton and various signaling molecules (Perez-Moreno et al. 2003, Baum & Georgiou 2011). The extracellular domain has five cadherin-type repeat ectodomain (EC) modules; the most membrane-distal EC mediates binding with CDH1 on adjacent cells (Boggon et al. 2002). Calcium ions cross-link the EC domains of two CDH1 peptides to form a dimer with a rod-like conformation (Boggon et al. 2002) which is required for cell-cell interaction (Gumbiner 1996, Patel et al. 2006). The cytoplasmic tail of E-cadherin binds to the armadillo repeat protein beta-catenin, a target of the Wnt signaling pathway and a cofactor for TCF/LEF-mediated transcription (Gavard & Mège 2005). Beta-catenin in turn binds alpha-catenin, which interacts with the actin microfilament network, actin and the actin-binding proteins vinculin, formins, alpha-actinin, zonula occludin protein, and afadin (Bershadsky 2004). Cell–cell adhesions also contain desmosomes, which link cell contacts to intermediate filaments, and nectin-based, calcium-independent adhesions, which are linked to actin (Takai & Nakanishi 2003, Yin and Green 2004). The critical importance of E-cadherin to normal development and tissue function is demonstrated by embryonic lethal E-cadherin gene mouse knockouts (Larue et al. 1994). Loss of cadherin-based cell-cell adhesion is a hallmark of carcinogenesis, correlating with tumour progression, allowing cells to escape normal growth control signals, resulting in loss of differentiation and increased cell proliferation associated with invasive behaviour (Frixen et al. 1991, Capaldo & Macara 2007).

Full-length 120-kDa CDH1 protein is cleaved in the ectodomain close to the plasma membrane by a number of metalloproteases, generating an extracellular 38-kDa C-terminal fragment (CTF) termed CTF1 which can be further processed by a gamma-secretase-like activity to a soluble 33-kDa CTF2 (Marambaud et al. 2002, Roy & Berx 2008). MMP3, MMP7 (Noë et al. 2001, canine MMPs), MMP9 (Symowicz et al. 2007), plasmin (Ryniers et al. 2002, canine plasmin), Kallikrien 7 (Johnson et al. 2007), ADAM10 (Maretzky et al. 2005) and ADAM15 (Najy et al. 2008) all cleave CDH1 extracellularly, close to the transmembrane region.

Presenilin-1 (Marambaud et al. 2002), the catalytic subunit of gamma-secretase (Herreman et al. 2003, Li et al. 2003), cleaves CDH1 producing a soluble 33-kDa fragment termed CTF2. Other enzymes like caspase-3 (Steinhusen et al. 2001) and calpain-1 (Rios-Doria et al. 2003) cleave E-cadherin in its cytoplasmic part releasing an intracellular 37 kDa c-terminal fragment. inferred by electronic annotation IEA GO IEA MMP1,3,13 (2, 7-12, 19) binding by Alpha-2 macroglubulin MMP1,3,13 (2, 7-12, 19) binding by Alpha-2 macroglubulin MMP binding by alpha2-macroglobulin This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Converted from EntitySet in Reactome Reactome DB_ID: 10151822 1 MMP1, 3, 13, (2, 7-12, 19) [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP1 [extracellular region] MMP13 [extracellular region] Reactome DB_ID: 10119055 1 A2M tetramer [extracellular region] A2M tetramer Reactome DB_ID: 10119053 4 UniProt:F1SLX2 A2M UniProt F1SLX2 24 EQUAL 1474 EQUAL Reactome Database ID Release 77 10119055 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10119055 Reactome R-SSC-158255 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-158255.1 Reactome DB_ID: 10151824 1 Alpha 2-macroglobulin:MMP1, 3, 13, (2, 7-12, 19) [extracellular region] Alpha 2-macroglobulin:MMP1, 3, 13, (2, 7-12, 19) Converted from EntitySet in Reactome Reactome DB_ID: 10151822 1 Reactome DB_ID: 10119055 1 Reactome Database ID Release 77 10151824 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10151824 Reactome R-SSC-2559501 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2559501.1 Reactome Database ID Release 77 10151826 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10151826 Reactome R-SSC-1454781 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1454781.1 α2-macroglobulin (A2M)是一种等离子glycoprotein consisting of 4 near-identical subunits (Andersen et al. 1995). A2M inhibits almost all endopeptidases regardless of their specificities (Barrett 1981). A2M binding to an endopeptidase is triggered by cleavage of a peptide bond in the 'bait region' of A2M, triggering a conformational change in A2M that in turn entraps the peptidase without blocking the active site (Barrett & Starkey 1973). This blocks enzyme activity against large protein substrates while not preventing activity on low molecular weight substrates.

Once bound, A2M-proteinase complexes are endocytosed by low density lipoprotein receptor-related protein-1 (LRP1) (Strickland et al. 1990).

Active metalloproteinases (MMPs) that can be entrapped by A2M include MMP3 (Enghild et al. 1989) MMP1 (Grinnell et al. 1998) and MMP 13 (Beekman et al. 1999).

The significance of this mechanism as a regulator of MMP activity is unclear (Baker et al. 2002, Nagase et al. 2006). 6176834 Pubmed 1981 Alpha 2-macroglobulin Barrett, A J Meth. Enzymol. 80:737-54 4201304 Pubmed 1973 The interaction of alpha 2-macroglobulin with proteinases. Characteristics and specificity of the reaction, and a hypothesis concerning its molecular mechanism Barrett, A J Starkey, P M Biochem. J. 133:709-24 9579544 Pubmed 1998 Collagenase-1 complexes with alpha2-macroglobulin in the acute and chronic wound environments Grinnell, F Zhu, M Parks, W C J. Invest. Dermatol. 110:771-6 10415727 Pubmed 1999 Fluorogenic MMP activity assay for plasma including MMPs complexed to alpha 2-macroglobulin Beekman, B Drijfhout, J W Ronday, H K TeKoppele, J M Ann. N. Y. Acad. Sci. 878:150-8 1698775 Pubmed 1990 Sequence identity between the alpha 2-macroglobulin receptor and low density lipoprotein receptor-related protein suggests that this molecule is a multifunctional receptor Strickland, DK Ashcom, JD Williams, S Burgess, WH Migliorini, M Argraves, WS J Biol Chem 265:17401-4 12235282 Pubmed 2002 Metalloproteinase inhibitors: biological actions and therapeutic opportunities Baker, AH Edwards, DR Murphy, G J Cell Sci 115:3719-27 16405877 Pubmed 2006 Structure and function of matrix metalloproteinases and TIMPs Nagase, H Visse R Murphy, G Cardiovasc Res 69:562-73 7559647 Pubmed 1995 Low resolution X-ray structure of human methylamine-treated alpha 2-macroglobulin Andersen, G R Koch, T J Dolmer, K Sottrup-Jensen, L Nyborg, J J. Biol. Chem. 270:25133-41 2470748 Pubmed 1989 Interaction of human rheumatoid synovial collagenase (matrix metalloproteinase 1) and stromelysin (matrix metalloproteinase 3) with human alpha 2-macroglobulin and chicken ovostatin. Binding kinetics and identification of matrix metalloproteinase cleavage sites Enghild J J Salvesen, G Brew, Keith Nagase, H J. Biol. Chem. 264:8779-85 inferred by electronic annotation IEA GO IEA MMP2, MMP7, MMP9 bind CD44 MMP2, MMP7, MMP9 bind CD44 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10151830 1 UniProt:F1SGT4 CD44 UniProt F1SGT4 21 EQUAL 742 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10151832 1 MMP2, MMP7, MMP9 [extracellular region] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MMP2 [extracellular region] MMP7 [extracellular region] MMP9 [extracellular region] Reactome DB_ID: 10151834 1 CD44:MMP2, MMP7, MMP9 [plasma membrane] CD44:MMP2, MMP7, MMP9 Reactome DB_ID: 10151830 1 21 EQUAL 742 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10151832 1 Reactome Database ID Release 77 10151834 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10151834 Reactome R-SSC-2559499 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-2559499.1 Reactome Database ID Release 77 10151836 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10151836 Reactome R-SSC-1454791 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1454791.1 Certain normally extracellular MMPs can transiently localize at the cell periphery in association with adhesion receptors or proteoglycans. ProMMP9, MMP9, MMP2 and MMP7 (Ahmed et al. 2002, Samanna et al. 2006, Yu et al. 2002) localize at the cell membrane with the single-pass transmembrane glycoprotein CD44, known to be involved in hyaluronan-cell interactions, lymphocyte homing and cell adhesion (Toole 1990). Membrane-associated MMP7 can bring about the shedding of several membrane proteins such as epidermal growth factor (EGF), soluble Fas ligand (FasL), E-cadherin and TNF-alpha from their membrane-bound precursors, thereby promoting cancer progression (Li et al. 2006). MMP9 is able to cleave CD44, inhibiting cell migration and reducing the malignant potential of tumour cells (Chetty et al. 2012). 11872628 Pubmed 2002 Overexpression of alpha(v)beta6 integrin in serous epithelial ovarian cancer regulates extracellular matrix degradation via the plasminogen activation cascade Ahmed, N Pansino, F Clyde, Riley Murthi, P Quinn, M A Rice, G E Agrez, M V Mok, S Baker, M S Carcinogenesis 23:237-44 16631740 Pubmed 2006 Alpha-V-dependent outside-in signaling is required for the regulation of CD44 surface expression, MMP-2 secretion, and cell migration by osteopontin in human melanoma cells Samanna, V Wei, H Ego-Osuala, D Chellaiah, M A Exp. Cell Res. 312:2214-30 16380641 Pubmed 2006 Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis Ii, Masanori Yamamoto, Hiroyuki Adachi, Yasushi Maruyama, Yumiko Shinomura, Yasuhisa Exp. Biol. Med. (Maywood) 231:20-7 22024282 Pubmed 2012 MMP-9 induces CD44 cleavage and CD44 mediated cell migration in glioblastoma xenograft cells Chetty, Chandramu Vanamala, Sravan K Gondi, Christopher S Dinh, Dzung H Gujrati, Meena Rao, Jasti S Cell. Signal. 24:549-59 11825873 Pubmed 2002 CD44 anchors the assembly of matrilysin/MMP-7 with heparin-binding epidermal growth factor precursor and ErbB4 and regulates female reproductive organ remodeling Yu, WH Woessner, J McNeish, JD Stamenkovic, I Genes Dev 16:307-23 1707285 Pubmed 1990 Hyaluronan and its binding proteins, the hyaladherins Toole, B P Curr. Opin. Cell Biol. 2:839-44 inferred by electronic annotation IEA GO IEA Basigin binds Matrix metalloproteinase-1 Basigin binds Matrix metalloproteinase-1 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10130739 1 100 EQUAL 469 EQUAL Reactome DB_ID: 10127715 1 UniProt:A0A5K1V4A5 BSG UniProt A0A5K1V4A5 22 EQUAL 385 EQUAL Reactome DB_ID: 10130741 1 BSG:MMP1(100-469) [plasma membrane] BSG:MMP1(100-469) Reactome DB_ID: 10130739 1 100 EQUAL 469 EQUAL Reactome DB_ID: 10127715 1 22 EQUAL 385 EQUAL Reactome Database ID Release 77 10130741 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10130741 Reactome R-SSC-375089 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-375089.1 Reactome Database ID Release 77 10130743 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10130743 Reactome R-SSC-375135 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-375135.1 Basigin (BSG, CD147, EMPRIN) is a glycoprotein expressed on the surface of most tumor cells. It stimulates stromal cells to produce elevated levels of several matrix metalloproteinases (MMP), including interstitial collagenase (MMP1). MMPs have been implicated in several aspects of tumor progression, including invasion through basement membranes and interstitial matrices, angiogenesis, and tumor cell growth. Basigin not only stimulates the production of MMP1 but also forms a complex with MMP1 at the tumor cell surface. This interaction may be important in modifying the tumor cell pericellular matrix to promote invasion. 10706100 Pubmed 2000 EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface Guo, H Li, R Zucker, S Toole, BP Cancer Res 60:888-91 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 OPN (osteopontin) degradation by MMP3, MMP7 OPN (osteopontin) degradation by MMP3, MMP7 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10129472 1 UniProt:P14287 SPP1 UniProt P14287 17 EQUAL 314 EQUAL Reactome DB_ID: 10168066 1 1 EQUAL 314 EQUAL Reactome DB_ID: 10168064 1 17 EQUAL -1 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10151799 95 EQUAL 267 EQUAL Reactome Database ID Release 77 10168067 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10168067 Reactome Database ID Release 77 10168069 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10168069 Reactome R-SSC-4086205 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-4086205.1 OPN是MMP3的衬底和MMP7。三个cleavage sites were identified, Gly166-Leu167, Ala201-Tyr202 (MMP-3 only), and Asp210-Leu211. The resulting OPN fragments facilitate adhesion and migration in vitro through activation of beta1-containing integrins (Agnihotri et al. 2001). OPN has also been shown to be a substrate for liver transglutaminase and plasma transglutaminase factor IIIa, resulting in protein crosslinking (Prince et al. 1991), enhanced cell adhesion, spreading, focal contact formation and migration 1676261 Pubmed 1991 Osteopontin, a substrate for transglutaminase and factor XIII activity Prince, C W Dickie, D Krumdieck, C L Biochem. Biophys. Res. Commun. 177:1205-10 11375993 Pubmed 2001 Osteopontin, a novel substrate for matrix metalloproteinase-3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin) Agnihotri, R Crawford, H C Haro, H Matrisian, L M Havrda, M C Liaw, L J. Biol. Chem. 276:28261-7 inferred by electronic annotation IEA GO IEA CAPN:4xCa2+:CAPNS cleave cytoskeletal proteins CAPN:4xCa2+:CAPNS cleave cytoskeletal proteins This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 8848706 1 cytosol GO 0005829 substrate protein for calpains [cytosol] substrate protein for calpains Reactome DB_ID: 8848709 2 calpain-cleaved protein [cytosol] calpain-cleaved protein PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10188542 CAPN:4xCa2+:CAPNS [cytosol] CAPN:4xCa2+:CAPNS Converted from EntitySet in Reactome Reactome DB_ID: 10188490 1 CAPNS [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CAPNS1 [cytosol] CAPNS1 [cytosol] CAPNS1 [cytosol] UniProt P04574 UniProt A0A5S6GT88 Reactome DB_ID: 10188540 1 CAPN:4xCa2+ [cytosol] CAPN:4xCa2+ Converted from EntitySet in Reactome Reactome DB_ID: 10188538 1 CAPN [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity CAPN1 [cytosol] UniProt P35750 Reactome DB_ID: 74016 4 Reactome Database ID Release 77 10188540 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10188540 Reactome R-SSC-8848668 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8848668.1 Reactome Database ID Release 77 10188542 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10188542 Reactome R-SSC-8848666 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8848666.1 GO 0004198 GO molecular function Reactome Database ID Release 77 10188543 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10188543 Reactome Database ID Release 77 10188549 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10188549 Reactome R-SSC-8848658 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8848658.1 钙蛋白酶(EC 3.4.22.17;CAPN,家族、家庭二氧化碳)constitute a distinct group of intracellular cysteine proteases found in almost all eukaryotes and a few bacteria. Calpains can be described as cytosolic proteases exhibiting Ca2+-dependent limited proteolytic activity which function to transform or modulate their substrate proteins' structures and activities; they are therefore called modulator proteases. As calpains selectively cleave proteins in response to calcium signals, they have the potential to influence cellular functions such as signal transduction, cytoskeletal remodelling, cell motility, membrane repair, cell cycle progression, gene expression and apoptosis (Sorimachi et al. 2010). Calpain deficiencies are linked to a variety of defects in many different organisms, including lethality, muscular dystrophies, gastropathy and diabetes (Sorimachi et al. 2011).

The human genome has 15 genes (named using formal nomenclature as CAPN1, CAPN2, etc.) that encode a calpain-like protease domain. The two best-characterised members of the calpain family, CAPN1 and 2, are ubiquitously expressed and locate to the cytosol of the cell (Goll et al. 2003). All other calpains annotated here are assumed to be functionally similar to these two based on their structural similarites. They are heterodimers, consisting of a common small regulatory subunit (CAPNS1 or CAPNS2; ca. 30kDa) and a large, isoform-specific catalytic subunit. Three-dimensional structural analyses reveal the calpain protease domain comprises two core domains that fuse to form a functional protease only when bound to ca. four Ca2+ ions via well-conserved amino acids. So, despite the fact that they have divergent domain structures, calpains share this mechanistic functional character (Croall & Ersfeld 2007, Sorimachi et al. 2011, Ono & Sorimachi 2012).

Calpain activity is tightly regulated by the endogenous inhibitor calpastatin (CAST), which is capable of reversibly binding and inhibiting four molecules of calpain in the presence of calcium. This suggests calpains are transiently activated by high Ca2+ concentrations such as a Ca2+ influx, and then return to an inactive state ready for reactivation (Campbell & Davies 2012). 23035980 Pubmed 2012 Structure-function relationships in calpains Campbell, Robert L Davies, Peter L Biochem. J. 447:335-51 12843408 Pubmed 2003 calpain系统 Goll, Darrell E Thompson, ValeryY F Li, Hongqi Wei, Wei Cong, Jinyang Physiol. Rev. 83:731-801 21030783 Pubmed 2010 Expanding members and roles of the calpain superfamily and their genetically modified animals Sorimachi, Hiroyuki Hata, Shoji Ono, Yasuko Exp. Anim. 59:549-66 21670566 Pubmed 2011 Calpain chronicle--an enzyme family under multidisciplinary characterization Sorimachi, Hiroyuki Hata, Shoji Ono, Yasuko Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 87:287-327 21864727 Pubmed 2012 Calpains: an elaborate proteolytic system Ono, Yasuko Sorimachi, Hiroyuki Biochim. Biophys. Acta 1824:224-36 17608959 Pubmed 2007 The calpains: modular designs and functional diversity Croall, Dorothy E Ersfeld, Klaus Genome Biol. 8:218 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 77 10188550 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10188550 Reactome DB_ID: 10188547 UniProt:P12675 CAST UniProt P12675 1 EQUAL 708 EQUAL ACTIVATION Reactome Database ID Release 77 2648999 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=2648999 Reactome R-HSA-2648999 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2648999.1 Reactome DB_ID: 74016 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 MMP2 cleaves OPTC MMP2 cleaves OPTC This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10194281 1 UniProt:Q8MIS4 OPTC UniProt Q8MIS4 20 EQUAL 332 EQUAL Reactome DB_ID: 10194287 1 115 EQUAL 332 EQUAL Reactome DB_ID: 10194283 1 20 EQUAL 87 EQUAL Reactome DB_ID: 10194285 1 88 EQUAL 114 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10151795 110 EQUAL 660 EQUAL Reactome Database ID Release 77 10194288 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10194288 Reactome Database ID Release 77 10194290 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10194290 Reactome R-SSC-8940554 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8940554.1 Opticin (OPTC) is a member of the small leucine-rich repeat proteoglycan family (Reardon et al. 2000). It is found in the vitreous cavity of the eye where it co-localizes with the fine network of collagen fibrils that maintains the gel state of the vitreous and the inner-limiting lamina, and in other tissues, including the brain, heart, and cartilage (Le Goff et al. 2012). It forms a homodimer in solution through its leucine-rich repeats (Le Goff et al. 2003). OPTC has anti-angiogenic activity which is mediated by binding to vitreous collagen fibrils, which are composed of collagens II, IX, and V/XI (Bishop 2000). This binding competitively inhibits endothelial cell interactions with collagen I via Alpha-1Beta-1and Alpha-2Beta-1 integrins, preventing proangiogenic signaling via these integrins (Le Goff et al. 2012). OPTC is expressed and translocated to the nucleus of chronic lymphocytic leukemia cells (Mikaelsson et al.2013).

OPTC can be degraded by Matrix metalloprotease (MMP) -1, -2, -3, -7, -8, -9, -13 and by ADAMTS4 and ADAMTS5, with MMP2 and MMP7 having highest activity towards the recombinant protein (Montfort et al. 2008, Ma et al. 2012, Tio et al. 2014). MMP2 cleaves OPTC at T87/S88 and G114/L115 (Tio et al. 2014). 18164633 Pubmed 2008 Identification of opticin, a member of the small leucine-rich repeat proteoglycan family, in human articular tissues: a novel target for MMP-13 in osteoarthritis Monfort, J Tardif, G Roughley, P Reboul, P Boileau, C Bishop, P N Pelletier, J-P Martel-Pelletier, J Osteoarthr. Cartil. 16:749-55 10636917 Pubmed 2000 Identification in vitreous and molecular cloning of opticin, a novel member of the family of leucine-rich repeat proteins of the extracellular matrix Reardon, A J Le Goff, M Briggs, M D McLeod, D Sheehan, J K Thornton, D J Bishop, P N J. Biol. Chem. 275:2123-9 12951322 Pubmed 2003 Characterization of opticin and evidence of stable dimerization in solution Le Goff, Magali M Hindson, Vincent J Jowitt, Thomas A Scott, Paul G Bishop, Paul N J. Biol. Chem. 278:45280-7 24499526 Pubmed 2013 Opticin, a small leucine-rich proteoglycan, is uniquely expressed and translocated to the nucleus of chronic lymphocytic leukemia cells Mikaelsson, Eva Osterborg, Anders Tahmasebi Fard, Zahra Mahmoudi, Ahmad Mahmoudian, Jafar Jeddi-Tehrani, Mahmood Akhondi, Mehdi Shokri, Fazel Bishop, Paul N Rabbani, Hodjattallah Mellstedt, Håkan Exp Hematol Oncol 2:23 22669977 Pubmed 2012 Opticin exerts its anti-angiogenic activity by regulating extracellular matrix adhesiveness Le Goff, Magali M Sutton, Matthew J Slevin, Mark Latif, Ayse Humphries, Martin J Bishop, Paul N J. Biol. Chem. 287:28027-36 23845380 Pubmed 2014 表征opticin蛋白酶消化involved in osteoarthritis development Tío, Laura Martel-Pelletier, Johanne Pelletier, Jean-Pierre Bishop, Paul N Roughley, Peter Farran, Aina Benito, Pere Monfort, Jordi Joint Bone Spine 81:137-41 10749380 Pubmed 2000 Structural macromolecules and supramolecular organisation of the vitreous gel Bishop, P N Prog Retin Eye Res 19:323-44 22534113 Pubmed 2012 Opticin production is reduced by hypoxia and VEGF in human retinal pigment epithelium via MMP-2 activation Ma, Jin Zhu, Tie Pei Moe, Morten C Ye, Panpan Yao, Ke Cytokine 59:100-7 inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 MMP7 cleaves OPTC MMP7 cleaves OPTC This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10194281 1 20 EQUAL 332 EQUAL Reactome DB_ID: 10194287 1 115 EQUAL 332 EQUAL Reactome DB_ID: 10194292 1 20 EQUAL 32 EQUAL Reactome DB_ID: 10194294 1 33 EQUAL 87 EQUAL Reactome DB_ID: 10194285 1 88 EQUAL 114 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10151799 95 EQUAL 267 EQUAL Reactome Database ID Release 77 10194296 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10194296 Reactome R-SSC-8940561 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8940561.1 Opticin (OPTC) is a a member of the small leucine-rich repeat proteoglycan family (Reardon et al. 2000). It is found in the vitreous cavity of the eye where it co-localizes with the fine network of collagen fibrils that maintains the gel state of the vitreous and the inner-limiting lamina, and in other tissues, including the brain, heart, and cartilage (Le Goff et al. 2012). It forms a homodimer in solution through its leucine-rich repeats (Le Goff et al. 2003). OPTC has anti-angiogenic activity which is mediated by binding to vitreous collagen fibrils, which are composed of collagens II, IX, and V/XI (Bishop 2000). This binding competitively inhibits endothelial cell interactions with collagen I via Alpha-1Beta-1and Alpha-2Beta-1 integrins, preventing proangiogenic signaling via these integrins (Le Goff et al. 2012). OPTC is expressed and translocated to the nucleus of chronic lymphocytic leukemia cells (Mikaelsson et al.2013).

OPTC can be degraded by Matrix metalloprotease (MMP) -1, -2, -3, -7, -8, -9, -13 and by ADAMTS-4 and ADAMTS-5, with MMP2 and MMP7 having highest activity towards the recombinant protein (Montfort et al. 2008, Ma et al. 2012, Tio et al. 2014). MMP7 cleaves recombinant human OPTN at four positions, A20/S21LP (removing the signal peptide), E32/Q33, T87/S88, and G114/L115. inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 MMP13 cleaves OPTC MMP13 cleaves OPTC This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10194281 1 20 EQUAL 332 EQUAL Reactome DB_ID: 10194287 1 115 EQUAL 332 EQUAL Reactome DB_ID: 10194449 1 20 EQUAL 114 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10151791 104 EQUAL 471 EQUAL Reactome Database ID Release 77 10194450 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10194450 Reactome Database ID Release 77 10194452 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10194452 Reactome R-SSC-8942302 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8942302.1 Opticin (OPTC) is a a member of the small leucine-rich repeat proteoglycan family (Reardon et al. 2000). It is found in the vitreous cavity of the eye where it co-localizes with the fine network of collagen fibrils that maintains the gel state of the vitreous and the inner-limiting lamina, and in other tissues, including the brain, heart, and cartilage (Le Goff et al. 2012). It forms a homodimer in solution through its leucine-rich repeats (Le Goff et al. 2003). Opticin has anti-angiogenic activity which is mediated by binding to vitreous collagen fibrils, which are composed of collagens II, IX, and V/XI (Bishop 2000). This binding competitively inhibits endothelial cell interactions with collagen I via Alpha-1Beta-1and Alpha-2Beta-1 integrins, preventing proangiogenic signaling via these integrins (Le Goff et al. 2012). OPTC is expressed and translocated to the nucleus of chronic lymphocytic leukemia cells (Mikaelsson et al.2013).

OPTC can be degraded by Matrix metalloprotease (MMP) -1, -2, -3, -7, -8, -9, -13 and by ADAMTS-4 and ADAMTS-5, with MMP2 and MMP7 having highest activity towards the recombinant protein (Montfort et al. 2008, Ma et al. 2012, Tio et al. 2014). MMP13 cleaves recombinant bovine OPTC at G104/L105 (major product), and P109/A110 (minor product) (Montfort et al. 2008).The major cleavage site corresponds to G114/L115 in human opticin. inferred by electronic annotation IEA GO IEA 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 MMP2, MMP9 cleave SCUBE3 MMP2, MMP9 cleave SCUBE3 This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Reactome DB_ID: 10194546 1 UniProt:A0A287ABH5 SCUBE3 UniProt A0A287ABH5 21 EQUAL 993 EQUAL Reactome DB_ID: 10194550 1 1 EQUAL 993 EQUAL Reactome DB_ID: 10194548 1 21 EQUAL -1 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10153297 Reactome Database ID Release 77 10194552 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10194552 Reactome R-SSC-8943959 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8943959.1 信号peptide-CUB-EGF-like domain-containing防ein 3 (SCUBE3) is a secreted glycoprotein that is highly expressed in osteoblasts. It can form homooligomers and heterooligomers with SCUBE1, which stably associate with the peripheral cell surface. In normal lung it is mainly expressed in bronchial epithelial cells. Its expression is upregulated in some lung cancer tumors and correlates with invasive ability in a lung cancer cell line model (Wu et al. 2004, 2011). SCUBE3 knockdown is associated with lower tumor vascular permeability, inhibiting the metastatic potential of Non-small-cell lung carcinoma (Chou et al. 2013).

SCUBE3 can be cleaved by the gelatinases Matrix metalloprotease-2 (MMP2) and MMP9, releasing two major fragments. The C-terminal fragment contains a complement proteins C1r/C1s, Uegf and Bmp1 (CUB) domain. The secreted SCUBE3 protein and the C-terminal CUB domain fragment can bind the Transforming growth factor beta type II receptor (TGFBR2) and activate signaling (Wu et al. 2011). SCUBE3 may act as an FGF co-receptor, augmenting FGF8 signaling (Tu et al. 2014) . Overexpressesion of Scube3 has been linked to significant murine cardiac hypertrophy (Yang et al. 2007). The C-terminal portion of SCUBE3 can physically interact with Transforming growth factor beta-1 (TGFB1) and promote TGFB1-mediated transcriptional activation in vitro (Yang et al. 2007). Consistent with this, the phosphorylated and total protein levels of Smad2, a well-known TGFB1 downstream signaling molecule, are elevated in Scube3 transgenic mouse heart under pressure overload. SCUBE3 may be a component of the regulatory mechanisms for active TGFB1 bioavailability, either systemically or locally in cardiac tissues, under baseline conditions and during pathological stresses. A Scube3 mutant mouse line (carrying a missense mutation in exon 8) has phenotypic alterations that suggest a role of Scube3 in bone metabolism and morphology, hearing, and renal function. The observed morphological abnormalities of the skeleton, impaired bone metabolism and hearing impairments are comparable with the rare metabolic bone disorder Paget disease, which is associated with the chromosomal region that includes SCUBE3 (Fuchs et al. 2016). 21441952 Pubmed 2011 SCUBE3 is an endogenous TGF-β receptor ligand and regulates the epithelial-mesenchymal transition in lung cancer Wu, Y-Y Peck, K Chang, Y-L Pan, S-H Cheng, Y-F Lin, J-C Yang, R-B Hong, T-M Yang, P-C Oncogene 30:3682-93 23420440 Pubmed 2013 SCUBE3 regulation of early lung cancer angiogenesis and metastatic progression Chou, Cheng-Hung Cheng, Yi-Fang Siow, Tiing Yee Kumar, Amit Peck, Konan Chang, Chen Clin. Exp. Metastasis 30:741-52 15234972 Pubmed 2004 A novel secreted, cell-surface glycoprotein containing multiple epidermal growth factor-like repeats and one CUB domain is highly expressed in primary osteoblasts and bones Wu, Bo-Tsung Su, Yueh-Hsing Tsai, Ming-Tzu Wasserman, SM Topper, JN Yang, RB J. Biol. Chem. 279:37485-90 17442284 Pubmed 2007 Transgenic overexpression of the secreted, extracellular EGF-CUB domain-containing protein SCUBE3 induces cardiac hypertrophy in mice Yang, Hsin-Yu Cheng, Ching-Feng Djoko, Bambang Lian, Wei-Shiung Tu, Cheng-Fen Tsai, Ming-Tzu Chen, Yen-Hui Chen, Chien-Chang Cheng, Chien-Jui Yang, RB Cardiovasc. Res. 75:139-47 27815347 Pubmed 2016 The First Scube3 Mutant Mouse Line with Pleiotropic Phenotypic Alterations 福克斯,赫尔穆特• Sabrautzki, Sibylle Przemeck, Gerhard K H Leuchtenberger, Stefanie Lorenz-Depiereux, Bettina Becker, Lore Rathkolb, Birgit Horsch, Marion Garrett, Lillian Östereicher, Manuela A Hans, Wolfgang Abe, Koichiro Sagawa, Nobuho Rozman, Jan Vargas-Panesso, Ingrid L Sandholzer, Michael Lisse, Thomas S Adler, Thure Aguilar-Pimentel, Juan Antonio Calzada-Wack, Julia Ehrhard, Nicole Elvert, Ralf Gau, Christine Hölter, Sabine M Micklich, Katja Moreth, Kristin Prehn, Cornelia Puk, Oliver Racz, Ildiko Stoeger, Claudia Vernaleken, Alexandra Michel, Dian Diener, Susanne Wieland, Thomas Adamski, J Bekeredjian, Raffi Busch, Dirk H Favor, John Graw, Jochen Klingenspor, Martin Lengger, Christoph Maier, Holger Neff, Frauke Ollert, Markus Stoeger, Tobias Yildirim, Ali Önder Strom, TM Zimmer, Andreas Wolf, Eckhard Wurst, Wolfgang Klopstock, Thomas Beckers, Johannes Gailus-Durner, Valerie Hrabe de Angelis, M G3 (Bethesda) 6:4035-4046 inferred by electronic annotation IEA GO IEA SCUBE1, SCUBE3 oligomerize SCUBE1, SCUBE3 oligomerize This event has been computationally inferred from an event that has been demonstrated in another species.

More details and caveats of the event inference in Reactome. For details on PANTHER see also: http://www.pantherdb.org/about.jsp Converted from EntitySet in Reactome Reactome DB_ID: 10194558 1 SCUBE1,SCUBE3 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity SCUBE3 [plasma membrane] SCUBE1 [plasma membrane] UniProt A0A287BBU5 Converted from EntitySet in Reactome Reactome DB_ID: 10194564 1 SCUBE1,SCUBE3 polymer, SCUBE3 polymer [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 77 10194566 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10194566 Reactome R-SSC-8943987 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8943987.1 信号peptide-CUB-EGF-like domain-containing防ein 3 (SCUBE3) is a secreted glycoprotein that is highly expressed in osteoblasts. It can form homooligomers and heterooligomers with SCUBE1, which stably associate with the peripheral cell surface (Wu et al. 2004). Overexpressesion of Scube3 has been linked to significant murine cardiac hypertrophy (Yang et al. 2007). The C-terminal portion of SCUBE3 can physically interact with Transforming growth factor beta-1 (TGFB1) and promote TGFB1-mediated transcriptional activation in vitro (Yang et al. 2007). Consistent with this, the phosphorylated and total protein levels of Smad2, a well-known TGFB1 downstream signaling molecule, are elevated in Scube3 transgenic mouse heart under pressure overload. SCUBE3 may be a component of the regulatory mechanisms for active TGFB1 bioavailability, either systemically or locally in cardiac tissues, under baseline conditions and during pathological stresses. A Scube3 mutant mouse line (carrying a missense mutation in exon 8) has phenotypic alterations that suggest a role of Scube3 in bone metabolism and morphology, hearing, and renal function. The observed morphological abnormalities of the skeleton, impaired bone metabolism and hearing impairments are comparable with the rare metabolic bone disorder Paget disease, which is associated with the chromosomal region that includes SCUBE3 (Fuchs et al. 2016). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10203181 数据库标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=10203181 Reactome R-SSC-1474228 1 Reactome稳定的标识符。使用这个URL连接到the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-1474228.1 基质金属蛋白酶(MMPs),之前参考red to as matrixins because of their role in degradation of the extracellular matrix (ECM), are zinc and calcium dependent proteases belonging to the metzincin family. They contain a characteristic zinc-binding motif HEXXHXXGXXH (Stocker & Bode 1995) and a conserved Methionine which forms a Met-turn. Humans have 24 MMP genes giving rise to 23 MMP proteins, as MMP23 is encoded by two identical genes. All MMPs contain an N-terminal secretory signal peptide and a prodomain with a conserved PRCGXPD motif that in the inactive enzyme is localized with the catalytic site, the cysteine acting as a fourth unpaired ligand for the catalytic zinc atom. Activation involves delocalization of the domain containing this cysteine by a conformational change or proteolytic cleavage, a mechanism referred to as the cysteine-switch (Van Wart & Birkedal-Hansen 1990). Most MMPs are secreted but the membrane type MT-MMPs are membrane anchored and some MMPs may act on intracellular proteins. Various domains determine substrate specificity, cell localization and activation (Hadler-Olsen et al. 2011). MMPs are regulated by transcription, cellular location (most are not activated until secreted), activating proteinases that can be other MMPs, and by metalloproteinase inhibitors such as the tissue inhibitors of metalloproteinases (TIMPs). MMPs are best known for their role in the degradation and removal of ECM molecules. In addition, cleavage of the ECM and other cell surface molecules can release ECM-bound growth factors, and a number of non-ECM proteins are substrates of MMPs (Nagase et al. 2006). MMPs can be divided into subgroups based on domain structure and substrate specificity but it is clear that these are somewhat artificial, many MMPs belong to more than one functional group (Vise & Nagase 2003, Somerville et al. 2003). 12730128 Pubmed 2003 Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry Visse R Nagase, H Circ Res 92:827-39 21917992 Pubmed 2011 Extracellular matrix degradation and remodeling in development and disease Lu, P Takai, K Weaver, VM Werb, Z Cold Spring Harb Perspect Biol 3: 7583637 Pubmed 1995 Structural features of a superfamily of zinc-endopeptidases: the metzincins Stöcker, W Bode, W Curr Opin Struct Biol 5:383-90 2164689 Pubmed 1990 The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family Van Wart, HE Birkedal-Hansen, H Proc Natl Acad Sci U S A 87:5578-82 inferred by electronic annotation IEA GO IEA