BioPAX pathway converted from "TGF-beta receptor signaling activates SMADs" in the Reactome database.

TGF-beta receptor signaling activates SMADs

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 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 Latent TGF-beta-1 is cleaved by furin Latent TGF-beta-1 is cleaved 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: 9858550 1 Golgi lumen GO 0005796 Pre-TGFB1 complex [Golgi lumen] Pre-TGFB1 complex Reactome DB_ID: 9858548 2 UniProt:P17246 Tgfb1 Reactome //www.joaskin.com Rattus norvegicus NCBI Taxonomy 10116 UniProt P17246 Chain Coordinates 30 EQUAL 390 EQUAL Reactome Database ID Release 77 9858550 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858550 Reactome R-RNO-171260 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-171260.1 Reactome DB_ID: 9858554 1 Large latent complex of TGFB1 [Golgi lumen] Large latent complex of TGFB1 Reactome DB_ID: 9858552 2 279 EQUAL 390 EQUAL Reactome Database ID Release 77 9858554 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858554 Reactome R-RNO-177102 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-177102.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9855783 Golgi membrane GO 0000139 UniProt:P23377 Furin UniProt P23377 108 EQUAL 794 EQUAL GO 0004252 GO molecular function Reactome Database ID Release 77 9855784 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9855784 Reactome Database ID Release 77 9858556 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858556 Reactome R-RNO-170844 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170844.1 In the Golgi apparatus, TGF-beta-1 (TGFB1) is activated by furin protease cleavage of the N-terminal pro-peptide portion. This leads to the formation of the N-terminal disulphide-linked dimeric pro-peptides, also known as latency-associated proteins (LAPs) and the C-terminal mature disulphide-linked dimeric TGF-beta-1. However, the N- and C-terminal polypeptides do not physically separate. Rather they stay in one complex. In addition, the LAP forms disulphide links with separate secreted proteins, the Latent TGF-beta binding proteins (LTBPs). LTBPs-linked to LAP and the non-covalently linked mature TGF-beta-1 remain together and form the large latent complex (LLC) 12482908 Pubmed 2003 Making sense of latent TGFbeta activation Annes, JP Munger, JS Rifkin, DB J Cell Sci 116:217-24 7737999 Pubmed 1995 Processing of transforming growth factor beta 1 precursor by human furin convertase Dubois, CM Laprise, MH Blanchette, F Gentry, LE Leduc, R J Biol Chem 270:10618-24 inferred by electronic annotation IEA GO IEA Secretion and activation of the latent large complex of TGF-beta-1 Secretion and activation of the latent large complex of TGF-beta-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: 9858554 1 Reactome DB_ID: 9858504 1 extracellular region GO 0005576 Dimeric TGFB1 [extracellular region] Dimeric TGFB1 Reactome DB_ID: 9858502 2 279 EQUAL 390 EQUAL Reactome Database ID Release 77 9858504 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858504 Reactome R-RNO-170852 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170852.1 Reactome Database ID Release 77 9860032 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9860032 Reactome R-RNO-177107 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-177107.1 The large latent complex (LLC) of TGF-beta-1 (TGFB1) is secreted by exocytosis to the extracellular region. TGF-beta-1 in the LLC cannot interact with the receptors and for this reason we say that it requires "activation". This means release from the LLC. This release is achieved by many mechanisms: proteolytic cleavage of the LTBPs, thrombospondin-1 binding to the LLC, integrin alphaV-beta6 binding to the LLC, reactive oxygen species and low pH. The release of mature dimeric TGF-beta-1 is essentially a mechanical process that demands cleavage and opening of the LLC structure so that the caged mature C-terminal TGF-beta-1 polypeptide is released to reach the receptor. 15564041 Pubmed 2004 TGF-beta activation by traction? Keski-Oja, J Koli, K von Melchner, H Trends Cell Biol 14:657-9 inferred by electronic annotation IEA GO IEA Dimeric TGF-beta-1 binds to the receptor Dimeric TGF-beta-1 binds to the receptor Dimeric TGFB1 binds to TGFBR2 homodimer 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: 9858504 1 Reactome DB_ID: 9858496 2 plasma membrane GO 0005886 UniProt:P38438 Tgfbr2 UniProt P38438 23 EQUAL 567 EQUAL Reactome DB_ID: 9858558 1 Dimeric TGFB1:TGFBR2 homodimer [plasma membrane] Dimeric TGFB1:TGFBR2 homodimer Reactome DB_ID: 9858498 1 TGFBR2 homodimer [plasma membrane] TGFBR2 homodimer Reactome DB_ID: 9858496 2 23 EQUAL 567 EQUAL Reactome Database ID Release 77 9858498 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858498 Reactome R-RNO-170866 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170866.1 Reactome DB_ID: 9858504 1 Reactome Database ID Release 77 9858558 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858558 Reactome R-RNO-170865 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170865.1 Reactome Database ID Release 77 9858588 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858588 Reactome R-RNO-170861 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170861.1 The mature dimeric TGF-beta-1 (TGFB1) binds with high affinity to its signaling receptor, the type II receptor serine/threonine kinase (TGFBR2) (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). While type II receptor can form dimeric complexes in the absence of TGFB1 when overexpressed, it predominantly exists as a monomer on the surface of unstimulated cells under physiological conditions, and dimerization of TGFBR2 is triggered by TGFB1 binding (Zhang et al. 2009). 8242743 Pubmed 1993 Cloning of a TGF beta type I receptor that forms a heteromeric complex with the TGF beta type II receptor Franzen, P ten Dijke, P Ichijo, H Yamashita, H Schulz, P Heldin, Carl-Henrik Miyazono, K Cell 75:681-92 7693660 Pubmed 1993 转化生长因子β受体类型s I, II, and III form hetero-oligomeric complexes in the presence of ligand Moustakas, A Lin, HY Henis, YI Plamondon, J O'Connor-McCourt, MD Lodish, HF J Biol Chem 268:22215-8 19720988 Pubmed 2009 Single-molecule imaging reveals transforming growth factor-beta-induced type II receptor dimerization Zhang, W Jiang, Yaxin Wang, Qiang 妈,Xinyong Xiao, Zeyu Zuo, Wei Fang, Xiaohong Chen, Ye-Guang Proc. Natl. Acad. Sci. U.S.A. 106:15679-83 1333888 Pubmed 1992 TGF beta signals through a heteromeric protein kinase receptor complex Wrana, JL Attisano, L Carcamo, J Zentella, A Doody, J Laiho, M Wang, XF Massague, J Cell 71:1003-14 inferred by electronic annotation IEA GO IEA TGFBR2 recruits TGFBR1 TGFBR2 recruits TGFBR1 Type II receptor recruits type I receptor 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: 9858560 2 TGFBR1:FKBP1A [plasma membrane] TGFBR1:FKBP1A Reactome DB_ID: 9858539 1 UniProt:P80204 Tgfbr1 UniProt P80204 34 EQUAL 503 EQUAL Reactome DB_ID: 9857014 1 cytosol GO 0005829 UniProt:Q62658 Fkbp1a UniProt Q62658 2 EQUAL 108 EQUAL Reactome Database ID Release 77 9858560 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858560 Reactome R-RNO-2187279 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187279.1 Reactome DB_ID: 9858558 1 Reactome DB_ID: 9857014 2 2 EQUAL 108 EQUAL Reactome DB_ID: 9858543 1 TGFB1:TGFBR2:TGFBR1 [plasma membrane] TGFB1:TGFBR2:TGFBR1 Reactome DB_ID: 9858541 1 TGFBR1 homodimer [plasma membrane] TGFBR1 homodimer Reactome DB_ID: 9858539 2 34 EQUAL 503 EQUAL Reactome Database ID Release 77 9858541 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858541 Reactome R-RNO-170864 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170864.1 Reactome DB_ID: 9858498 1 Reactome DB_ID: 9858504 1 Reactome Database ID Release 77 9858543 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858543 Reactome R-RNO-170840 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170840.1 Reactome Database ID Release 77 9858562 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858562 Reactome R-RNO-170846 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170846.1 The protein complex of dimeric TGF-beta-1 with the type II receptor dimer (dimeric TGFB1:TGFBR2 homodimer) recruits the low affinity receptor, type I receptor (TGFBR1), thus forming a hetero-tetrameric receptor bound to the dimeric ligand on the extracellular face of the plasma membrane (TGFB1:TGFBR2:TGFBR1) (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase, forms a complex with TGFBR1 and prevents phosphorylation of TGFBR1 by TGFBR2 in the absence of ligand. FKBP1A dissociates from TGFBR1 after it forms a complex with ligand-activated TGFBR2 (Chen et al. 1997). TGFBR1 can homodimerize in the absence of TGFB1 when overexpressed, but under physiological conditions it exists as a monomer on the surface of unstimulated cells. TGFB1-induced dimerization of TGFBR1 is TGFBR2-dependent (Zhang et al. 2010). 9233797 Pubmed 1997 Mechanism of TGFbeta receptor inhibition by FKBP12 Chen, YG Liu, Fang Massague, J EMBO J 16:3866-76 20625381 Pubmed 2010 Monomeric type I and type III transforming growth factor-? receptors and their dimerization revealed by single-molecule imaging Zhang, W Yuan, Jinghe Yang, Yong Xu, Li Wang, Qiang Zuo, Wei Fang, Xiaohong Chen, Ye-Guang Cell Res. 20:1216-23 inferred by electronic annotation IEA GO IEA TGFBR2 phosphorylates TGFBR1 TGFBR2 phosphorylates TGFBR1 Type II receptor phosphorylates type I receptor 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: 113592 12 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 9858543 1 Reactome DB_ID: 29370 12 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 9858519 1 TGFB1:TGFBR2:p-TGFBR1 [plasma membrane] TGFB1:TGFBR2:p-TGFBR1 Reactome DB_ID: 9858498 1 Reactome DB_ID: 9858517 1 p-TGFBR1 [plasma membrane] p-TGFBR1 Reactome DB_ID: 9858515 2 O-phospho-L-serine at 165 (in Homo sapiens) 165 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-threonine at 185 (in Homo sapiens) 185 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-threonine at 186 (in Homo sapiens) 186 EQUAL O-phospho-L-serine at 187 (in Homo sapiens) 187 EQUAL O-phospho-L-serine at 189 (in Homo sapiens) 189 EQUAL O-phospho-L-serine at 191 (in Homo sapiens) 191 EQUAL 34 EQUAL 503 EQUAL Reactome Database ID Release 77 9858517 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858517 Reactome R-RNO-170863 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170863.1 Reactome DB_ID: 9858504 1 Reactome Database ID Release 77 9858519 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858519 Reactome R-RNO-170841 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170841.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9858543 GO 0005026 GO molecular function Reactome Database ID Release 77 9858544 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858544 Reactome Database ID Release 77 9858546 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858546 Reactome R-RNO-170843 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170843.1 Formation of the hetero-tetrameric TGF-beta-1 receptor complex induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. The constitutively active type II receptor kinase (which auto-phosphorylates in the absence of ligand), trans-phosphorylates specific serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of the type I receptor (Wrana et al. 1994, Souchelnytskyi et al. 1996).

In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta-1 stimulation. Sumoylation enhances TGFBR1 function by facilitating recruitment and phosphorylation of SMAD3 (Kang et al. 2008). 18469808 Pubmed 2008 The type I TGF-beta receptor is covalently modified and regulated by sumoylation Kang, Jong Seok Saunier, Elise F Akhurst, Rosemary J Derynck, Rik Nat. Cell Biol. 10:654-64 8047140 Pubmed 1994 Mechanism of activation of the TGF-beta receptor Wrana, JL Attisano, L Wieser, R Ventura, F Massague, J Nature 370:341-7 8947046 Pubmed 1996 Phosphorylation of Ser165 in TGF-beta type I receptor modulates TGF-beta1-induced cellular responses Souchelnytskyi, S ten Dijke, P Miyazono, K Heldin, Carl-Henrik EMBO J 15:6231-40 inferred by electronic annotation IEA GO IEA An anchoring protein, ZFYVE9 (SARA), recruits SMAD2/3 An anchoring protein, ZFYVE9 (SARA), recruits SMAD2/3 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: 9858523 1 early endosome membrane GO 0031901 UniProt:D3ZDC7 Zfyve9 UniProt D3ZDC7 1 EQUAL 1425 EQUAL Reactome DB_ID: 9858519 1 Converted from EntitySet in Reactome Reactome DB_ID: 9858533 1 SMAD2/3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Smad3 [cytosol] Smad2 [cytosol] UniProt P84025 UniProt O70436 Reactome DB_ID: 9858535 1 TGFB1:p-TGFBR:ZFYVE9:SMAD2/3 [early endosome membrane] TGFB1:p-TGFBR:ZFYVE9:SMAD2/3 Reactome DB_ID: 9858523 1 1 EQUAL 1425 EQUAL Reactome DB_ID: 9858498 1 Reactome DB_ID: 9858517 1 Converted from EntitySet in Reactome Reactome DB_ID: 9858533 1 Reactome DB_ID: 9858504 1 Reactome Database ID Release 77 9858535 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858535 Reactome R-RNO-171266 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-171266.1 Reactome Database ID Release 77 9858537 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858537 Reactome R-RNO-170835 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170835.1 The activated TGF-beta receptor complex is internalized by clathrin-mediated endocytosis into early endosomes. ZFYVE9 (SARA) resides in the membrane of early endosomes. Crystallographic studies suggest that dimeric SARA in the early endosome coordinates two R-SMAD molecules (SMAD2 and/or SMAD3) per one receptor complex. 9865696 Pubmed 1998 SARA, a FYVE domain protein that recruits Smad2 to the TGFbeta receptor Tsukazaki, T Chiang, TA Davison, AF Attisano, L Wrana, JL Cell 95:779-91 inferred by electronic annotation IEA GO IEA 2.7.11.30 Activated type I receptor phosphorylates SMAD2/3 directly Activated type I receptor phosphorylates SMAD2/3 directly 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: 9858535 1 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 9858582 1 TGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3 [early endosome membrane] TGFB1:p-TGFBR:ZFYVE9:p-2S-SMAD2/3 Reactome DB_ID: 9858523 1 1 EQUAL 1425 EQUAL Reactome DB_ID: 9858498 1 Reactome DB_ID: 9858517 1 Converted from EntitySet in Reactome Reactome DB_ID: 9858576 1 p-2S-SMAD2/3 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-Smad2 [cytosol] phospho-Smad3 [cytosol] Reactome DB_ID: 9858504 1 Reactome Database ID Release 77 9858582 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858582 Reactome R-RNO-171180 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-171180.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9858535 GO 0004675 GO molecular function Reactome Database ID Release 77 9858589 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858589 Reactome Database ID Release 77 9858591 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858591 Reactome R-RNO-170868 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170868.1 Activated type I receptor kinase directly phosphorylates two of the C-terminal serine residues of SMAD1, SMAD5 or SMAD8. Binding of these R-SMADs to the L45 loop of the type I receptor is critical for this event. 11100470 Pubmed 2001 Phosphorylation of Smad signaling proteins by receptor serine/threonine kinases Souchelnytskyi, S Rönnstrand, Lars Heldin, Carl-Henrik ten Dijke, P Methods Mol Biol 124:107-20 inferred by electronic annotation IEA GO IEA Phosphorylated SMAD2/3 dissociates from TGFBR Phosphorylated SMAD2/3 dissociates from TGFBR 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: 9858582 1 Reactome DB_ID: 9858584 1 TGFB1:p-TGFBR:ZFYVE9 [early endosome membrane] TGFB1:p-TGFBR:ZFYVE9 Reactome DB_ID: 9858523 1 1 EQUAL 1425 EQUAL Reactome DB_ID: 9858498 1 Reactome DB_ID: 9858517 1 Reactome DB_ID: 9858504 1 Reactome Database ID Release 77 9858584 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858584 Reactome R-RNO-171173 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-171173.1 Converted from EntitySet in Reactome Reactome DB_ID: 9858576 1 Reactome Database ID Release 77 9858586 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858586 Reactome R-RNO-170850 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170850.1 Upon phosphorylation of the R-SMAD (SMAD2/3), the conformation of the C-terminal (MH2) domain of the R-SMAD changes, lowering its affinity for the type I receptor and ZFYVE9 (SARA). As a result, the phosphorylated R-SMAD dissociates from the activated receptor complex (TGFBR). 8980228 Pubmed 1996 MADR2 is a substrate of the TGFbeta receptor and its phosphorylation is required for nuclear accumulation and signaling Macias-Silva, M Abdollah, S Hoodless, PA Pirone, R Attisano, L Wrana, JL Cell 87:1215-24 15350224 Pubmed 2004 Structural basis of heteromeric smad protein assembly in TGF-beta signaling Chacko, BM Qin, BY Tiwari, A Shi, G Lam, S Hayward, LJ De Caestecker, M Lin, K Mol Cell 15:813-23 9346966 Pubmed 1997 Phosphorylation of Ser465 and Ser467 in the C terminus of Smad2 mediates interaction with Smad4 and is required for transforming growth factor-beta signaling Souchelnytskyi, S Tamaki, K Engstrom, U Wernstedt, C ten Dijke, P Heldin, Carl-Henrik J Biol Chem 272:28107-15 9311995 Pubmed 1997 TGF-beta receptor-mediated signalling through Smad2, Smad3 and Smad4 Nakao, A Souchelnytskyi, S Kawabata, M Ishisaki, A Oeda, E Tamaki, K Hanai, J Heldin, Carl-Henrik Miyazono, K ten Dijke, P EMBO J 16:5353-62 inferred by electronic annotation IEA GO IEA Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4 Phosphorylated SMAD2 and SMAD3 form a complex with SMAD4 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: 9858566 1 UniProt:O70437 Smad4 UniProt O70437 1 EQUAL 552 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9858576 2 Reactome DB_ID: 9858578 1 p-2S-SMAD2/3:SMAD4 [cytosol] p-2S-SMAD2/3:SMAD4 Reactome DB_ID: 9858566 1 1 EQUAL 552 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9858576 2 Reactome Database ID Release 77 9858578 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858578 Reactome R-RNO-171175 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-171175.1 Reactome Database ID Release 77 9858580 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858580 Reactome R-RNO-170847 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-170847.1 The phosphorylated C-terminal tail of R-SMAD induces a conformational change in the MH2 domain (Qin et al. 2001, Chacko et al. 2004), which now acquires high affinity towards Co-SMAD i.e. SMAD4 (common mediator of signal transduction in TGF-beta/BMP signaling). The R-SMAD:Co-SMAD complex (Nakao et al. 1997) most likely is a trimer of two R-SMADs with one Co-SMAD (Kawabata et al. 1998). It is important to note that the Co-SMAD itself cannot be phosphorylated as it lacks the C-terminal serine motif.

ZFYVE16 (endofin) promotes SMAD heterotrimer formation. ZFYVE16 can bind TGFBR1 and facilitate SMAD2 phosphorylation, and it can also bind SMAD4, but the exact mechanism of ZFYVE16 (endofin) action in the context of TGF-beta receptor signaling is not known (Chen et al. 2007). 9670020 Pubmed 1998 Smad蛋白质作为单体存在体内,undergo homo- and hetero-oligomerization upon activation by serine/threonine kinase receptors Kawabata, M Inoue, H Hanyu, A Imamura, T Miyazono, K EMBO J 17:4056-65 11779505 Pubmed 2001 Structural basis of Smad1 activation by receptor kinase phosphorylation Qin, BY Chacko, BM Lam, SS de Caestecker, MP Correia, JJ Lin, K Mol Cell 8:1303-12 11779503 Pubmed 2001 Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling. Wu, JW Hu, M Chai, J Seoane, J Huse, M Li, C Rigotti, DJ Kyin, S Muir, TW Fairman, R Massague, J Shi, Y Mol Cell 8:1277-89 17272273 Pubmed 2007 Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-beta signaling Chen, Ye-Guang Wang, Zhi Ma, Jing Zhang, Long Lu, Zhongxian J. Biol. Chem. 282:9688-95 inferred by electronic annotation IEA GO IEA Downregulation of TGF-beta receptor signaling Downregulation of TGF-beta receptor signaling 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 I-SMAD competes with SMAD2/3 for type I receptor (TGFBR1) I-SMAD competes with SMAD2/3 for type I receptor (TGFBR1) 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: 9858743 1 UniProt:O88406 Smad7 UniProt O88406 1 EQUAL 426 EQUAL Reactome DB_ID: 9858519 1 Reactome DB_ID: 9858751 1 TGFB1: p-TGFBR: I-SMAD7 [plasma membrane] TGFB1: p-TGFBR: I-SMAD7 Reactome DB_ID: 9858743 1 1 EQUAL 426 EQUAL Reactome DB_ID: 9858519 1 Reactome Database ID Release 77 9858751 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858751 Reactome R-RNO-173476 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-173476.1 Reactome Database ID Release 77 9858753 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858753 Reactome R-RNO-173512 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-173512.1 GO 0030512 GO biological process I-SMADs (SMAD6 and SMAD7) reside in the nucleus presumably to be sequestered from the TGF-beta receptor complex and thus avoid inappropriate silencing of the signaling pathway. Upon activation of the signaling pathway, I-SMADs exit the nucleus and are recruited to the signaling TGF-beta receptor complex. I-SMADs directly bind to the so-called L45 loop of the type I receptor, the site of binding of R-SMADs. Thus, I-SMADs competitively inhibit the activation/phosphorylation of R-SMADs. 9215638 Pubmed 1997 The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling Hayashi, H Abdollah, S Qiu, Y Cai, J Xu, YY Grinnell, BW Richardson, MA Topper, JN Gimbrone MA, Jr Wrana, JL Falb, D Cell 89:1165-73 9335507 Pubmed 1997 Identification of Smad7, a TGFbeta-inducible antagonist of TGF-beta signalling Nakao, A Afrakhte, M Moren, A Nakayama, T Christian, JL Heuchel, R Itoh, S Kawabata, M Heldin, NE Heldin, Carl-Henrik ten Dijke, P Nature 389:631-5 inferred by electronic annotation IEA GO IEA STRAP stabilizes interaction of activated TGF-beta receptor complex with SMAD7 STRAP stabilizes interaction of activated TGF-beta receptor complex with SMAD7 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: 9858743 1 1 EQUAL 426 EQUAL Reactome DB_ID: 9902748 1 TGFB1:p-TGFBR:STRAP [plasma membrane] TGFB1:p-TGFBR:STRAP Reactome DB_ID: 9902746 1 UniProt:Q5XIG8 Strap UniProt Q5XIG8 1 EQUAL 350 EQUAL Reactome DB_ID: 9858519 1 Reactome Database ID Release 77 9902748 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9902748 Reactome R-RNO-2127564 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2127564.1 Reactome DB_ID: 9902750 1 TGFB1: p-TGFBR: STRAP: SMAD7 [plasma membrane] TGFB1: p-TGFBR: STRAP: SMAD7 Reactome DB_ID: 9858743 1 1 EQUAL 426 EQUAL Reactome DB_ID: 9902748 1 Reactome Database ID Release 77 9902750 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9902750 Reactome R-RNO-2128993 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2128993.1 Reactome Database ID Release 77 9902752 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9902752 Reactome R-RNO-2128994 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2128994.1 带结合及受体和SMAD7,stabilizes interaction of phosphorylated TGF-beta receptor complex with SMAD7.This reaction may involve oligomerization of STRAP. STRAP and SMAD7 act synergistically to inhibit the transcription of TGF-beta target genes by preventing SMAD2 and SMAD3 from binding phosphorylated TGFBR1. 10757800 Pubmed 2000 STRAP and Smad7 synergize in the inhibition of transforming growth factor beta signaling Datta, PK Moses, HL Mol Cell Biol 20:3157-67 inferred by electronic annotation IEA GO IEA BAMBI interferes with the interaction of type I receptor with type II receptor BAMBI interferes with the interaction of type I receptor with type II receptor 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: 9858739 1 UniProt:Q91XN4 Bambi UniProt Q91XN4 21 EQUAL 260 EQUAL Reactome DB_ID: 9858743 1 1 EQUAL 426 EQUAL Reactome DB_ID: 9858519 1 Reactome DB_ID: 9858745 1 TGFB1: TGFBR2: p-TGFBR1: BAMBI: SMAD7 [plasma membrane] TGFB1: TGFBR2: p-TGFBR1: BAMBI: SMAD7 Reactome DB_ID: 9858739 1 21 EQUAL 260 EQUAL Reactome DB_ID: 9858743 1 1 EQUAL 426 EQUAL Reactome DB_ID: 9858519 1 Reactome Database ID Release 77 9858745 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858745 Reactome R-RNO-173509 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-173509.1 Reactome Database ID Release 77 9858747 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858747 Reactome R-RNO-173483 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-173483.1 BAMBI (BMP and activin membrane-bound inhibitor) is a transmembrane protein closely related to TGF-beta family receptors type I, but without serine/threonine kinase activity. In Xenopus, BAMBI expression is regulated by BMP4. BAMBI interferes with BMP, activin and TGF-beta receptor complex signaling. BAMBI binds various TGF-beta type I receptors, showing the highest affinity for TGFBR1. BAMBI can also bind TGFBR2 and activin receptor type II (Onichtchouk et al. 1999). BAMBI binds SMAD7, and this interaction involves MH1 and MH2 domains of SMAD7 and the intracellular domain of BAMBI. BAMBI and SMAD7 cooperate in the repression of TGF-beta receptor complex signaling, but BAMBI-mediated recruitment of SMAD7 to activated TGF-beta receptor complex, as BAMBI preferentially binds activated TGFBR1, does not lead to TGFBR1 degradation (Yan et al. 2009). BAMBI may downregulate TGF-beta receptor complex signaling by replacing one TGFBR1 molecule in the TGF-beta receptor heterotetramer (Onichtchouk et al. 1999). Alternatively, BAMBI-mediated recruitment of SMAD7 may compete with binding of SMAD2 and SMAD3 (R-SMADs) to the activated TGF-beta receptor complex, thus interfering with the activation of R-SMADs (Yan et al. 2009). 10519551 Pubmed 1999 Silencing of TGF-beta signalling by the pseudoreceptor BAMBI Onichtchouk, D Chen, Y G Dosch, R Gawantka, V Delius, H Massagué, J Niehrs, C Nature 401:480-5 19758997 Pubmed 2009 Human BAMBI cooperates with Smad7 to inhibit transforming growth factor-beta signaling Yan, X Lin, Z Chen, F Zhao, X Chen, H Ning, Y Chen, YG J Biol Chem 284:30097-104 inferred by electronic annotation IEA GO IEA SMAD7 binds to SMURF2 SMAD7 binds to SMURF2 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: 9860345 1 nucleoplasm GO 0005654 UniProt:F1M3F2 Smurf2 UniProt F1M3F2 1 EQUAL 748 EQUAL Reactome DB_ID: 9860343 1 1 EQUAL 426 EQUAL Reactome DB_ID: 9860347 1 SMAD7:SMURF2 [nucleoplasm] SMAD7:SMURF2 Reactome DB_ID: 9860345 1 1 EQUAL 748 EQUAL Reactome DB_ID: 9860343 1 1 EQUAL 426 EQUAL Reactome Database ID Release 77 9860347 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9860347 Reactome R-RNO-2167870 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2167870.1 Reactome Database ID Release 77 9860349 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9860349 Reactome R-RNO-178208 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-178208.1 SMURF2, an E3 ubiquitin protein ligase, binds to SMAD7 in the nucleus. WW2 and WW3 domains of SMURF2 are both required for binding PY motif (PPXY sequence) of SMAD7. Endogenous human SMAD7 and SMURF2 were shown to form a complex in human U4A/Jak1 cells, derived from a sarcoma cell line 2fTGH. The interaction was studied in more detail by expressing tagged recombinant human SMURF2 and mouse Smad7 in human embryonic kidney cell line HEK293 (Kavsak et al. 2000, Ogunjimi et al. 2005). 11163210 Pubmed 2000 Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation Kavsak, P Rasmussen, RK Causing, CG Bonni, S Zhu, H Thomsen, GH Wrana, JL Mol Cell 6:1365-75 16061177 Pubmed 2005 Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain Ogunjimi, AA Briant, DJ Pece-Barbara, N Le Roy, C Di Guglielmo, GM Kavsak, P Rasmussen, RK Seet, BT Sicheri, F Wrana, JL Mol Cell 19:297-308 inferred by electronic annotation IEA GO IEA Degradation of TGF-beta receptor complex Degradation of TGF-beta receptor complex 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: 9903975 1 TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7 [plasma membrane] TGFB1:TGFBR2:Ub-p-TGFBR1:Ub-SMAD7 Reactome DB_ID: 9858751 1 Converted from EntitySet in Reactome Reactome DB_ID: 9845194 2 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Rps27a-ps28 [cytosol] Ubc [cytosol] Rps27a [cytosol] Uba52 [cytosol] UniProt F1LU69 UniProt Q63429 UniProt P62982 UniProt P62986 Reactome Database ID Release 77 9903975 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9903975 Reactome R-RNO-2169047 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2169047.1 Reactome Database ID Release 77 9903977 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9903977 Reactome R-RNO-2169046 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2169046.1 招聘SMURF1 (Ebisawa et al . 2001),蓝精灵2 (Kavsak et al. 2000) or NEDD4L (Kuratomi et al. 2005) to the activated TGF-beta receptor complex by SMAD7 and subsequent ubiquitination of SMAD7 and/or TGFBR1 triggers degradation of SMAD7 and TGFBR1 through proteasome and lysosome-dependent routes, resulting in downregulation of signaling by TGF-beta receptors. 15496141 Pubmed 2005 NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor Kuratomi, G Komuro, A Goto, K Shinozaki, M Miyazawa, K Miyazono, K Imamura, T Biochem J 386:461-70 11278251 Pubmed 2001 Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation Ebisawa, T Fukuchi, M Murakami, G Chiba, T Tanaka, K Imamura, T Miyazono, K J Biol Chem 276:12477-80 inferred by electronic annotation IEA GO IEA SMURF2 binds SMAD2 SMURF2 binds SMAD2 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: 9858757 1 1 EQUAL 748 EQUAL Reactome DB_ID: 9858527 1 UniProt:O70436 Smad2 2 EQUAL 467 EQUAL Reactome DB_ID: 9858759 1 SMAD2:SMURF2 [cytosol] SMAD2:SMURF2 Reactome DB_ID: 9858757 1 1 EQUAL 748 EQUAL Reactome DB_ID: 9858527 1 2 EQUAL 467 EQUAL Reactome Database ID Release 77 9858759 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858759 Reactome R-RNO-2176457 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2176457.1 Reactome Database ID Release 77 9904089 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904089 Reactome R-RNO-2176445 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2176445.1 SMURF2 binds SMAD2 irrespective of TGF-beta signaling (Zhang et al. 2001). 11158580 Pubmed 2001 Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase Zhang, Y Chang, C Gehling, DJ Hemmati-Brivanlou, A Derynck, R Proc Natl Acad Sci U S A 98:974-9 inferred by electronic annotation IEA GO IEA 6.3.2.19 SMURF2 ubiquitinates SMAD2 SMURF2 ubiquitinates SMAD2 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: 9858759 1 Converted from EntitySet in Reactome Reactome DB_ID: 9845194 1 Reactome DB_ID: 9858757 1 1 EQUAL 748 EQUAL Reactome DB_ID: 9858761 1 Ub-SMAD2 [cytosol] Ub-SMAD2 Reactome DB_ID: 9858527 1 2 EQUAL 467 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9845194 1 Reactome Database ID Release 77 9858761 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858761 Reactome R-RNO-2176443 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2176443.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9858759 GO 0004842 GO molecular function Reactome Database ID Release 77 9858762 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858762 Reactome Database ID Release 77 9858764 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9858764 Reactome R-RNO-173542 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-173542.1 SMAD2 is polyubiquitinated by SMURF2 and targeted for proteasome-mediated degradation. inferred by electronic annotation IEA GO IEA Degradation of ubiquitinated SMAD2 Degradation of ubiquitinated SMAD2 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: 9858761 1 Reactome Database ID Release 77 9904091 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904091 Reactome R-RNO-2176452 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2176452.1 Ubiquitinated SMAD2 undergoes proteasome-dependent degradation. Therefore, SMURF2 decreases the level of SMAD2 in the cell, irrespective of TGF-beta signaling, and may regulate the competence of a cell to respond to TGF-beta signaling (Zhang et al. 2001). These findings are contradicted by a recent study of Smurf2 knockout mice, where Smad2 protein levels were found to be unaltered in the absence of Smurf2 (Tang et al. 2011). 22045334 Pubmed 2011 Ablation of Smurf2 reveals an inhibition in TGF-? signalling through multiple mono-ubiquitination of Smad3 Tang, LY Yamashita, M Coussens, NP Tang, Y Wang, X Li, C Deng, CX Cheng, SY Zhang, YE EMBO J 30:4777-89 inferred by electronic annotation IEA GO IEA SMAD3 binds STUB1 (CHIP) SMAD3 binds STUB1 (CHIP) 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: 9858531 1 UniProt:P84025 Smad3 1 EQUAL 425 EQUAL Reactome DB_ID: 9887722 1 UniProt:D4A4T0 Stub1 UniProt D4A4T0 1 EQUAL 303 EQUAL Reactome DB_ID: 9904280 1 SMAD3:STUB1 [cytosol] SMAD3:STUB1 Reactome DB_ID: 9858531 1 1 EQUAL 425 EQUAL Reactome DB_ID: 9887722 1 1 EQUAL 303 EQUAL Reactome Database ID Release 77 9904280 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904280 Reactome R-RNO-2187365 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187365.1 Reactome Database ID Release 77 9904287 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904287 Reactome R-RNO-2187375 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187375.1 STUB1 (CHIP), an E3 ubiquitin ligase, binds SMAD3 irrespective of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005). 15781469 Pubmed 2005 CHIP controls the sensitivity of transforming growth factor-beta signaling by modulating the basal level of Smad3 through ubiquitin-mediated degradation Xin, H Xu, X Li, L Ning, H Rong, Y Shang, Y Wang, Y Fu, XY Chang, Z J Biol Chem 280:20842-50 14701756 Pubmed 2004 芯片介导Smad蛋白质的降解和锅entially regulates Smad-induced transcription Li, L Xin, H Xu, X Huang, M Zhang, X Chen, Y Zhang, S Fu, XY Chang, Z Mol Cell Biol 24:856-64 inferred by electronic annotation IEA GO IEA 6.3.2.19 STUB1 (CHIP) ubiquitinates SMAD3 STUB1 (CHIP) ubiquitinates SMAD3 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: 9904280 1 Converted from EntitySet in Reactome Reactome DB_ID: 9845194 1 Reactome DB_ID: 9904282 1 Ub-SMAD3 [cytosol] Ub-SMAD3 Reactome DB_ID: 9858531 1 1 EQUAL 425 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9845194 1 Reactome Database ID Release 77 9904282 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904282 Reactome R-RNO-2187371 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187371.1 Reactome DB_ID: 9887722 1 1 EQUAL 303 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9904280 Reactome Database ID Release 77 9904283 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904283 Reactome Database ID Release 77 9904285 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904285 Reactome R-RNO-2187368 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187368.1 STUB1 (CHIP) ubiquitinates SMAD3 in the absence of TGF-beta stimulation (Li et al. 2004, Xin et al. 2005). inferred by electronic annotation IEA GO IEA Degradation of ubiquitinated SMAD3 Degradation of ubiquitinated SMAD3 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: 9904282 1 Reactome Database ID Release 77 9904289 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904289 Reactome R-RNO-2187382 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187382.1 SMAD3, ubiquitinated by STUB1 (CHIP), is degraded in a proteasome-dependent manner. STUB1-mediated downregulation of SMAD3 level happens in the absence of TGF-beta stimulation. STUB1 may therefore keep the basal level of SMAD3 low in the absence of TGF-beta signaling (Li et al. 2004, Xin et al. 2005). inferred by electronic annotation IEA GO IEA PMEPA1 sequesters phosphorylated SMAD2/3 PMEPA1 sequesters phosphorylated SMAD2/3 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: 9904268 1 UniProt:M0RCH9 Pmepa1 UniProt M0RCH9 1 EQUAL 287 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9858576 1 Reactome DB_ID: 9904270 1 p-2S-SMAD2/3:PMEPA1 [early endosome membrane] p-2S-SMAD2/3:PMEPA1 Reactome DB_ID: 9904268 1 1 EQUAL 287 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9858576 1 Reactome Database ID Release 77 9904270 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904270 Reactome R-RNO-2187343 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187343.1 Reactome Database ID Release 77 9904272 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904272 Reactome R-RNO-2187355 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187355.1 PMEPA1 binds phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimers (Watanabe et al. 2010). 20129061 Pubmed 2010 TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling Watanabe, Y Itoh, S Goto, T Ohnishi, E Inamitsu, M Itoh, F Satoh, K Wiercinska, E Yang, W Shi, L Tanaka, A Nakano, N Mommaas, AM Shibuya, H ten Dijke, P Kato, M Mol Cell 37:123-34 inferred by electronic annotation IEA GO IEA PMEPA1 sequesters unphosphorylated SMAD2/3 PMEPA1 sequesters unphosphorylated SMAD2/3 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: 9904274 1 1 EQUAL 287 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9858533 1 Reactome DB_ID: 9904276 1 SMAD2/3:PMEPA1 [plasma membrane] SMAD2/3:PMEPA1 Reactome DB_ID: 9904274 1 1 EQUAL 287 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9858533 1 Reactome Database ID Release 77 9904276 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904276 Reactome R-RNO-2187341 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187341.1 Reactome Database ID Release 77 9904278 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904278 Reactome R-RNO-2187358 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187358.1 PMEPA1 binds unphosphorylated SMAD2 and SMAD3 and prevents their phosphorylation in response to TGF-beta stimulation (Watanabe et al. 2010). inferred by electronic annotation IEA GO IEA MTMR4 binds phosphorylated SMAD2/3 MTMR4 binds phosphorylated SMAD2/3 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: 9904295 1 UniProt:D3ZW40 Mtmr4 UniProt D3ZW40 1 EQUAL 1195 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9858576 1 Reactome DB_ID: 9904297 1 p-2S-SMAD2/3:MTMR4 [early endosome membrane] p-2S-SMAD2/3:MTMR4 Reactome DB_ID: 9904295 1 1 EQUAL 1195 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 9858576 1 Reactome Database ID Release 77 9904297 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904297 Reactome R-RNO-2187399 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187399.1 Reactome Database ID Release 77 9904302 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904302 Reactome R-RNO-2187405 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187405.1 A protein phosphatase MTMR4, residing in the early endosome membrane, binds phosphorylated SMAD2 and SMAD3 (Yu et al. 2010). 20061380 Pubmed 2010 MTMR4 attenuates transforming growth factor beta (TGFbeta) signaling by dephosphorylating R-Smads in endosomes Yu, J Pan, L Qin, X Chen, H Xu, Y Chen, Y Tang, H J Biol Chem 285:8454-62 inferred by electronic annotation IEA GO IEA 3.1.3.16 MTMR4 dephosphorylates SMAD2/3 MTMR4 dephosphorylates SMAD2/3 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: 9904297 1 Reactome DB_ID: 29356 1 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 9904295 1 1 EQUAL 1195 EQUAL Reactome DB_ID: 29372 1 hydrogenphosphate [ChEBI:43474] hydrogenphosphate [PO3(OH)](2-) HYDROGENPHOSPHATE ION hydrogen phosphate [P(OH)O3](2-) HPO4(2-) phosphate INORGANIC PHOSPHATE GROUP ChEBI 43474 Converted from EntitySet in Reactome Reactome DB_ID: 9858533 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9904297 GO 0004722 GO molecular function Reactome Database ID Release 77 9904298 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904298 Reactome Database ID Release 77 9904300 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9904300 Reactome R-RNO-2187401 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2187401.1 MTMR4 protein phosphatase dephosphorylates SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimers and inhibiting transmission of TGF-beta signal to the nucleus (Yu et al. 2010). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 9951526 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9951526 Reactome R-RNO-2173788 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2173788.1 TGF-beta receptor signaling is downregulated by proteasome and lysosome-mediated degradation of ubiquitinated TGFBR1, SMAD2 and SMAD3, as well as by dephosphorylation of TGFBR1, SMAD2 and SMAD3.

In the nucleus, SMAD2/3:SMAD4 complex stimulates transcription of SMAD7, an inhibitory SMAD (I-SMAD). SMAD7 binds phosphorylated TGFBR1 and competes with the binding of SMAD2 and SMAD3 (Hayashi et al. 1997, Nakao et al. 1997). Binding of SMAD7 to TGBR1 can be stabilized by STRAP, a protein that simultaneously binds SMAD7 and TGFBR1 (Datta et al. 2000). BAMBI simultaneously binds SMAD7 and activated TGFBR1, leading to downregulation of TGF-beta receptor complex signaling (Onichtchouk et al. 1999, Yan et al. 2009).

In addition to competing with SMAD2/3 binding to TGFBR1, SMAD7 recruits protein phosphatase PP1 to phosphorylated TGFBR1, by binding to the PP1 regulatory subunit PPP1R15A (GADD34). PP1 dephosphorylates TGFBR1, preventing the activation of SMAD2/3 and propagation of TGF-beta signal (Shi et al. 2004).

SMAD7 associates with several ubiquitin ligases, SMURF1 (Ebisawa et al. 2001, Suzuki et al. 2002, Tajima et al. 2003, Chong et al. 2010), SMURF2 (Kavsak et al. 2000, Ogunjimi et al. 2005), and NEDD4L (Kuratomi et al. 2005), and recruits them to phosphorylated TGFBR1 within TGFBR complex. SMURF1, SMURF2 and NEDD4L ubiquitinate TGFBR1 (and SMAD7), targeting TGFBR complex for proteasome and lysosome-dependent degradation (Ebisawa et al. 2001, Kavsak et al. 2000, Kuratomi et al. 2005). The ubiquitination of TGFBR1 can be reversed by deubiquitinating enzymes, UCHL5 (UCH37) and USP15, which may be recruited to ubiquitinated TGFBR1 by SMAD7 (Wicks et al. 2005, Eichhorn et al. 2012).

Basal levels of SMAD2 and SMAD3 are maintained by SMURF2 and STUB1 ubiquitin ligases. SMURF2 is able to bind and ubiquitinate SMAD2, leading to SMAD2 degradation (Zhang et al. 2001), but this has been questioned by a recent study of Smurf2 knockout mice (Tang et al. 2011). STUB1 (CHIP) binds and ubiquitinates SMAD3, leading to SMAD3 degradation (Li et al. 2004, Xin et al. 2005). PMEPA1 can bind and sequester unphosphorylated SMAD2 and SMAD3, preventing their activation in response to TGF-beta signaling. In addition, PMEPA1 can bind and sequester phosphorylated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 heterotrimer complexes (Watanabe et al. 2010). A protein phosphatase MTMR4, residing in the membrane of early endosomes, can dephosphorylate activated SMAD2 and SMAD3, preventing formation of SMAD2/3:SMAD4 complexes (Yu et al. 2010).
12519765 Pubmed 2003 Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-beta signaling by Smad7 Tajima, Y Goto, K Yoshida, M Shinomiya, K Sekimoto, T Yoneda, Y Miyazono, K Imamura, T J Biol Chem 278:10716-21 22344298 Pubmed 2012 USP15 stabilizes TGF-? receptor I and promotes oncogenesis through the activation of TGF-? signaling in glioblastoma Eichhorn, PJ Rodón, L Gonzàlez-Juncà, A Dirac, A Gili, M Martínez-Sáez, E Aura, C Barba, I Peg, V Prat, A Cuartas, I Jimenez, J García-Dorado, D Sahuquillo, J Bernards, R Baselga, J Seoane, J Nat Med 18:429-35 16027725 Pubmed 2005 The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-beta signalling Wicks, SJ Haros, K Maillard, M Song, L Cohen, RE Dijke, PT Chantry, A Oncogene 24:8080-4 12151385 Pubmed 2002 Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane Suzuki, C Murakami, G Fukuchi, M Shimanuki, T Shikauchi, Y Imamura, T Miyazono, K J Biol Chem 277:39919-25 14718519 Pubmed 2004 GADD34-PP1c recruited by Smad7 dephosphorylates TGFbeta type I receptor Shi, W Sun, C He, B Xiong, W Shi, X Yao, D Cao, X J Cell Biol 164:291-300 20937913 Pubmed 2010 Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity Chong, PA Lin, H Wrana, JL Forman-Kay, JD Proc Natl Acad Sci U S A 107:18404-9 inferred by electronic annotation IEA GO IEA CBL binds TGFBR2 CBL binds TGFBR2 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: 9860402 1 UniProt:D3ZV15 Cbl Cbl c-Cbl Cbl UniProt D3ZV15 1 EQUAL 906 EQUAL Reactome DB_ID: 9858496 1 23 EQUAL 567 EQUAL Reactome DB_ID: 9911793 1 TGFBR2:CBL [plasma membrane] TGFBR2:CBL Reactome DB_ID: 9860402 1 1 EQUAL 906 EQUAL Reactome DB_ID: 9858496 1 23 EQUAL 567 EQUAL Reactome Database ID Release 77 9911793 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9911793 Reactome R-RNO-4332229 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-4332229.1 Reactome Database ID Release 77 9911795 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9911795 Reactome R-RNO-4332235 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-4332235.1 The E3 ubiquitin ligase CBL binds the cytoplasmic tail of plasma membrane-bound TGFBR2 (TGF-beta receptor 2) but not TGFBR1 (TGF-beta receptor 1). The tyrosine kinase binding (TKB) domain of CBL is involved in this interaction (Zuo et al. 2013). 23290524 Pubmed 2013 c-Cbl-mediated neddylation antagonizes ubiquitination and degradation of the TGF-? type II receptor Zuo, Wei Huang, Fei Chiang, Y Jeffrey Li, Meng Du, Jun Ding, Yi Zhang, Ting Lee, Hyuk Woo Jeong, Lak Shin Chen, Yuling Deng, Haiteng Feng, Xin-Hua Luo, Shiwen Gao, Chunji Chen, Ye-Guang Mol. Cell 49:499-510 inferred by electronic annotation IEA GO IEA 6.3.2.19 CBL neddylates TGFBR2 CBL neddylates TGFBR2 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: 9911793 1 Reactome DB_ID: 9911806 2 NEDD8-AcM-UBE2M [cytosol] NEDD8-AcM-UBE2M Reactome DB_ID: 9911804 1 UniProt:D3ZNQ6 Ube2m UniProt D3ZNQ6 Inter-chain Crosslink via S-(glycyl)-L-cysteine (Cys-Gly) at 111 and 76 (in Homo sapiens) 111 EQUAL S-(glycyl)-L-cysteine (Cys-Gly) ChEBI 24411 modification N-acetyl-L-methionine at 1 (in Homo sapiens) 1 EQUAL N-acetyl-L-methionine [MOD:00058] 1 EQUAL 183 EQUAL Reactome DB_ID: 9911800 1 UniProt:Q71UE8 Nedd8 UniProt Q71UE8 Inter-chain Crosslink via S-(glycyl)-L-cysteine (Cys-Gly) at 76 and 111 (in Homo sapiens) 76 EQUAL ChEBI 23511 modification 1 EQUAL 76 EQUAL Reactome Database ID Release 77 9911806 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9911806 Reactome R-RNO-4419896 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-4419896.1 Reactome DB_ID: 9860402 1 1 EQUAL 906 EQUAL Reactome DB_ID: 9911820 2 N-acetyl-L-methionine at 1 (in Homo sapiens) 1 EQUAL 1 EQUAL 183 EQUAL Reactome DB_ID: 9911818 1 Neddylated TGFBR2 [plasma membrane] Neddylated TGFBR2 Reactome DB_ID: 9911809 1 Inter-chain Crosslink via neddylated lysine at 76 and 556 (in Homo sapiens) 76 EQUAL neddylated lysine ChEBI 30777 modification 1 EQUAL 76 EQUAL Reactome DB_ID: 9911812 1 Inter-chain Crosslink via neddylated lysine at 567 and 76 (in Homo sapiens) 567 EQUAL 1 EQUAL 76 EQUAL Reactome DB_ID: 9911816 1 Inter-chain Crosslink via neddylated lysine at 556 and 76 (in Homo sapiens) 556 EQUAL Inter-chain Crosslink via neddylated lysine at 567 and 76 (in Homo sapiens) 567 EQUAL 23 EQUAL 567 EQUAL Reactome Database ID Release 77 9911818 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9911818 Reactome R-RNO-4419904 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-4419904.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9911793 Reactome Database ID Release 77 9911821 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9911821 Reactome Database ID Release 77 9911823 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9911823 Reactome R-RNO-4332236 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-4332236.1 CBL neddylates TGFBR2 on lysine residues K556 and K567. The E3 ubiquitin ligase activity of CBL is necessary for this modification, and the kinase activity of TGFBR2 is also required. CBL-mediated neddylation prolongs the half-life of TGFBR2, thereby enhancing signaling by the TGF-beta receptor complex. CBLB, a CBL-related protein, may cooperate with CBL in TGFBR2 neddylation (Zuo et al. 2013). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 9951498 数据库标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser?DB=gk_current&ID=9951498 Reactome R-RNO-2173789 1 Reactome稳定的标识符。使用这个URL connect to the web page of this instance in Reactome: //www.joaskin.com/cgi-bin/eventbrowser_st_id?ST_ID=R-RNO-2173789.1 GO 0007179 GO biological process 转化生长因子β1 (TGF绑定beta 1, i.e. TGFB1) to TGF beta receptor type 2 (TGFBR2) activates TGF beta receptor signaling cascade. TGFB1 is posttranslationally processed by furin (Dubois et al. 1995) to form a homodimer and secreted to the extracellular space as part of the large latent complex (LLC). After the LLC disassembles in the extracellular space, dimeric TGFB1 becomes capable of binding to TGFBR2 (Annes et al. 2003, Keski Oja et al. 2004). Formation of TGFB1:TGFBR2 complex creates a binding pocket for TGF-beta receptor type-1 (TGFBR1) and TGFBR1 is recruited to the complex by binding to both TGFB1 and TGFBR2. This results in an active heterotetrameric TGF-beta receptor complex that consists of TGFB1 homodimer bound to two heterodimers of TGFBR1 and TGFBR2 (Wrana et al. 1992, Moustakas et al. 1993, Franzen et al. 1993). TGF-beta signaling can also occur through a single heterodimer of TGFBR1 and TGFBR2, although with decreased efficiency (Huang et al. 2011). TGFBR1 and TGFBR2 interact through their extracellular domains, which brings their cytoplasmic domains together. Ligand binding to extracellular receptor domains is cooperative, but no conformational change is seen from crystal structures of either TGFB1- or TGFB3-bound heterotetrameric receptor complexes (Groppe et al. 2008, Radaev et al. 2010).

Activation of TGFBR1 by TGFBR2 in the absence of ligand is prevented by FKBP1A (FKBP12), a peptidyl-prolyl cis-trans isomerase. FKBP1A forms a complex with inactive TGFBR1 and dissociates from it only after TGFBR1 is recruited by TGFB1-bound TGFBR2 (Chen et al. 1997).

Both TGFBR1 and TGFBR2 are receptor serine/threonine kinases. Formation of the hetero-tetrameric TGF-beta receptor complex (TGFBR) in response to TGFB1 binding induces receptor rotation, so that TGFBR2 and TGFBR1 cytoplasmic kinase domains face each other in a catalytically favourable configuration. TGFBR2 trans-phosphorylates serine residues at the conserved Gly-Ser-rich juxtapositioned domain (GS domain) of TGFBR1 (Wrana et al. 1994, Souchelnytskyi et al. 1996), activating TGFBR1.
In addition to phosphorylation, TGFBR1 may also be sumoylated in response to TGF-beta stimulation. Sumoylation enhances TGFBR1 kinase activity (Kang et al. 2008).

The activated TGFBR complex is internalized by clathrin-mediated endocytosis into early endosomes. With the assistance of SARA, an early endosome membrane protein, phosphorylated TGFBR1 within TGFBR complex recruits SMAD2 and/or SMAD3 , i.e. R-SMADs (Tsukazaki et al. 1998). TGFBR1 phosphorylates recruited SMAD2/3 on two C-terminal serine residues (Souchelnytskyi et al. 2001). The phosphorylation changes the conformation of SMAD2/3 MH2 domain, promoting dissociation of SMAD2/3 from SARA and TGFBR1 (Souchelnytskyi et al. 1997, Macias-Silva et al. 1996, Nakao et al. 1997) and formation of SMAD2/3 trimers (Chacko et al. 2004). The phosphorylated C-terminal tail of SMAD2/3 has high affinity for SMAD4 (Co-SMAD), inducing formation of SMAD2/3:SMAD4 heterotrimers, composed of two phosphorylated R-SMADs (SMAD2 and/or SMAD3) and SMAD4 (Co-SMAD). SMAD2/3:SMAD4 heterotrimers are energetically favored over R-SMAD trimers (Nakao et al. 1997, Qin et al. 2001, Kawabata et al. 1998, Chacko et al. 2004).
SMAD2/3:SMAD4 heterotrimers translocate to the nucleus where they act as transcriptional regulators. 18243111 Pubmed 2008 Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding Groppe, Jay Hinck, Cynthia S Samavarchi-Tehrani, P Zubieta, Chloe Schuermann, Jonathan P Taylor, Alexander B Schwarz, Patricia M Wrana, JL Hinck, Andrew P Mol. Cell 29:157-68 20207738 Pubmed 2010 Ternary complex of transforming growth factor-beta1 reveals isoform-specific ligand recognition and receptor recruitment in the superfamily Radaev, Sergei Zou, Zhongcheng Huang, Tao Lafer, Eileen M Hinck, Andrew P Sun, Peter D J. Biol. Chem. 285:14806-14 21423151 Pubmed 2011 TGF-? signalling is mediated by two autonomously functioning T?RI:T?RII pairs Huang, Tao David, Laurent Mendoza, Valentín Yang, Yong Villarreal, Maria De, Keya Sun, LuZhe Fang, Xiaohong López-Casillas, Fernando Wrana, JL Hinck, Andrew P EMBO J. 30:1263-76 inferred by electronic annotation IEA GO IEA