BioPAX pathway converted from "MAPK1/MAPK3 signaling" in the Reactome database.

MAPK1/MAPK3 signaling

ERK1/ERK2 pathway 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 RAF/MAP kinase cascade RAF/MAP kinase cascade 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 RAS processing RAS processing 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 3.4.22.41 3.4.22.40 3.4.22.34 3.4.22.8 3.4.22.28 3.4.22.16 3.4.22.27 3.4.22.38 3.4.22.1 3.4.22.15 3.4.22.14 RCE1 cleaves S-Farn proRAS proteins RCE1 cleaves S-Farn proRAS 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: 10406503 1 endoplasmic reticulum membrane GO 0005789 UniProt:A0A6I8S624 hras Reactome //www.joaskin.com Xenopus tropicalis NCBI Taxonomy 8364 UniProt A0A6I8S624 S-farnesyl-L-cysteine (farnesyl group) at 186 (in Homo sapiens) 186 EQUAL S-farnesyl-L-cysteine [MOD:00111] ChEBI 24017 modification Chain Coordinates 1 EQUAL 189 EQUAL Reactome DB_ID: 10406492 1 S-farnesyl-L-cysteine (farnesyl group) at 186 (in Homo sapiens) 186 EQUAL 1 EQUAL 186 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10406533 UniProt:B7ZT68 rce1 UniProt B7ZT68 ubiquitinylated lysine (PolyUb [cytosol]) at unknown position ubiquitinylated lysine [MOD:01148] 2 EQUAL 329 EQUAL GO 0004197 GO molecular function Reactome Database ID Release 77 10406534 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=10406534 Reactome Database ID Release 77 10406536 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=10406536 Reactome R-XTR-9647999 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-XTR-9647999.1 After prenylation, RAS proteins undergo C-terminal endoproteolysis by RAS-converting enzyme I (RCE1), which removes the aaX residues of the CaaX motif (Otto et al, 1999; Hollander et al, 2000; reviewed in Hampton et al, 2018; Ahearn et al, 2018). RCE1-mediated cleavage is required for RAS plasma membrane localization and function (Michaelson et al, 2005). RCE1 is ubiquitinated in its active form, and deubiquitination by USP17L2 abrogates its catalytic activity and inhibits signaling through the RAS-RAF MAP kinase pathway (Burrows et al, 2009). RCE1 has thus been investigated as a potential therapeutic target in RAS driven disease. Despite some promising studies, the effects of RCE1 inactivation appear unpredictable and can lead to unexpected activation of RAS signaling through mechanisms that are not fully understood (Bergo et al, 2002; Aiyagari et al, 2003; Kim et al, 1999; Chen et al, 1998; Chen et al, 1999; Wahlstrom et al, 2007). 29311131 Pubmed 2018 Posttranslational Modifications of RAS Proteins Ahearn, Ian Zhou, Mo Philips, Mark R Cold Spring Harb Perspect Med 8: 11739732 Pubmed 2002 Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation Bergo, Martin O Ambroziak, Patricia Gregory, Cria George, Amanda Otto, James C Kim, Edward Nagase, Hiroki Casey, Patrick J Balmain, Allan Young, SG Mol. Cell. Biol. 22:171-81 10667208 Pubmed 1999 Selective inhibition of ras-transformed cell growth by a novel fatty acid-based chloromethyl ketone designed to target Ras endoprotease Chen, Yulong Ann. N. Y. Acad. Sci. 886:103-8 19188362 Pubmed 2009 USP17 regulates Ras activation and cell proliferation by blocking RCE1 activity Burrows, James F Kelvin, Alyson A McFarlane, Cheryl Burden, Roberta E McGrattan, Michael J De la Vega, Michelle Govender, Ureshnie Quinn, Derek J Dib, Karim Gadina, Massimo Scott, Christopher J Johnston, James A J. Biol. Chem. 284:9587-95 9851253 Pubmed 1998 Inhibition of K-ras-transformed rodent and human cancer cell growth via induction of apoptosis by irreversible inhibitors of Ras endoprotease Chen, Yulong Cancer Lett. 131:191-200 11038283 Pubmed 2000 人类ras-converting酶(hRCE1) endoproteolytic activity on K-ras-derived peptides Hollander, Irwin Frommer, Eileen Mallon, Robert Anal. Biochem. 286:129-37 12433685 Pubmed 2003 Hematologic effects of inactivating the Ras processing enzyme Rce1 Aiyagari, Abigail L Taylor, Brigit R Aurora, Vikas Young, SG Shannon, Kevin M Blood 101:2250-2 10085068 Pubmed 1999 Cloning and characterization of a mammalian prenyl protein-specific protease Otto, James C Kim, Edward Young, SG Casey, Patrick J J. Biol. Chem. 274:8379-82 29424242 Pubmed 2018 Rce1: mechanism and inhibition Hampton, Shahienaz E Dore, Timothy M Schmidt, Walter K Crit. Rev. Biochem. Mol. Biol. 53:157-174 15659645 Pubmed 2005 Postprenylation CAAX processing is required for proper localization of Ras but not Rho GTPases Michaelson, David Ali, Wasif Chiu, Vi K Bergo, Martin Silletti, Joseph Wright, Latasha Young, SG Philips, Mark Mol. Biol. Cell 16:1606-16 10085069 Pubmed 1999 Disruption of the mouse Rce1 gene results in defective Ras processing and mislocalization of Ras within cells Kim, Edward Ambroziak, Patricia Otto, James C Taylor, Brigit Ashby, Matthew Shannon, Kevin Casey, Patrick J Young, SG J. Biol. Chem. 274:8383-90 inferred by electronic annotation IEA GO IEA 3.4.19.12 USP17L2 deubiquitinates RCE1 USP17L2 deubiquitinates RCE1 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: 10406533 1 ubiquitinylated lysine (PolyUb [cytosol]) at unknown position 2 EQUAL 329 EQUAL Reactome DB_ID: 29356 1 cytosol GO 0005829 water [ChEBI:15377] water ChEBI 15377 Reactome DB_ID: 10406574 1 2 EQUAL 329 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10387343 1 PolyUb [cytosol] 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: 10388857 Homologues of USP17L2 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity btd [cytosol] USP17L2 [cytosol] LOC101735032 [cytosol] UniProt F7CSJ3 UniProt A0A6I8T1J7 UniProt F7CHL5 GO 0004843 GO molecular function Reactome Database ID Release 77 10406575 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=10406575 Reactome Database ID Release 77 10406577 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=10406577 Reactome R-XTR-9653514 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-XTR-9653514.1 USP17L2, also known as USP17, deubiquitinates RCE1 (RAS-converting enzyme 1), inactivating it. Loss of RCE1 activity after USP17L2-mediated deubiquitination interferes with RAS localization and function and prevents downstream signaling through the RAF MAP kinase cascade (Burrows et al, 2009). inferred by electronic annotation IEA GO IEA 2.1.1.100 ICMT methylates S-Farn RAS proteins ICMT methylates S-Farn RAS 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: 10406492 1 S-farnesyl-L-cysteine (farnesyl group) at 186 (in Homo sapiens) 186 EQUAL 1 EQUAL 186 EQUAL Reactome DB_ID: 71284 1 S-adenosyl-L-methionine [ChEBI:15414] S-adenosyl-L-methionine ChEBI 15414 Reactome DB_ID: 71285 1 S-adenosyl-L-homocysteine [ChEBI:16680] S-adenosyl-L-homocysteine ChEBI 16680 Reactome DB_ID: 10406494 1 S-farnesyl-L-cysteine methyl ester at 186 (in Homo sapiens) 186 EQUAL S-farnesyl-L-cysteine methyl ester 1 EQUAL 186 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10390044 ICMT:Zn2+ [endoplasmic reticulum membrane] ICMT:Zn2+ Reactome DB_ID: 10390042 1 UniProt:F7EBZ7 icmt UniProt F7EBZ7 1 EQUAL 284 EQUAL Reactome DB_ID: 6788653 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome Database ID Release 77 10390044 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=10390044 Reactome R-XTR-6788652 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-XTR-6788652.1 GO 0004671 GO molecular function Reactome Database ID Release 77 10390045 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=10390045 Reactome Database ID Release 77 10406498 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=10406498 Reactome R-XTR-9647977 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-XTR-9647977.1 RAS proteins undergo C-terminal carboxymethylation by isoprenylcysteine methyltransferase (ICMT) (Yang et al, 2011; Dharmaiah et al, 2016; reviewed in Gysin et al, 2011; Ahearn et al, 2018). LIke prenylation, methylation is required for plasma membrane localization and function of RAS proteins, and disruption of ICMT or interference with the methylation reaction inhibits cell growth and KRAS-dependent transformation (Chiu et al, 2004; Michaelson et al, 2005; Bergo et al, 2004; Wahlstrom et al, 2008; Winter-Vann et al, 2003). Consistent with this, a number of small molecule inhibitors of ICMT have been shown to decrease tumor proliferation (Wang et al, 2009; Manu et al, 2017; Sun et al, 2016). 27791178 Pubmed 2016 Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ Dharmaiah, Srisathiyanarayanan Bindu, Lakshman Tran, Timothy H Gillette, William K Frank, Peter H Ghirlando, Rodolfo Nissley, Dwight V Esposito, Dominic McCormick, Frank Stephen, Andrew G Simanshu, Dhirendra K Proc. Natl. Acad. Sci. U.S.A. 113:E6766-E6775 26706195 Pubmed 2016 Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukemia Sun, Wen Tian Xiang, Wei Ng, Bee Ling Asari, Kartini Bunte, Ralph M Casey, Patrick J Wang, Mei Chuah, Charles Exp. Hematol. 44:189-93.e2 20622895 Pubmed 2010 Inhibition of isoprenylcysteine carboxylmethyltransferase induces autophagic-dependent apoptosis and impairs tumor growth Wang, M Hossain, M S Tan, W Coolman, B 周,我 Liu, S Casey, P J Oncogene 29:4959-70 18502828 Pubmed 2008 Inactivating Icmt ameliorates K-RAS-induced myeloproliferative disease Wahlstrom, Annika M Cutts, Briony A Liu, Meng Lindskog, Annika Karlsson, Christin Sjogren, Anna-Karin M Andersson, Karin M E Young, SG Bergo, Martin O Blood 112:1357-65 21779505 Pubmed 2011 Therapeutic strategies for targeting ras proteins Gysin, Stephan Salt, Megan Young, Amy McCormick, Frank Genes Cancer 2:359-72 14660603 Pubmed 2004 Carboxyl methylation of Ras regulates membrane targeting and effector engagement Chiu, Vi K Silletti, Joseph Dinsell, Victoria Wiener, Heidi Loukeris, Kristina Ou, Guoming Philips, Mark R Pillinger, Michael H J. Biol. Chem. 279:7346-52 14966563 Pubmed 2004 Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf Bergo, Martin O Gavino, Bryant J Hong, Christine Beigneux, AP McMahon, Martin Casey, Patrick J Young, SG J. Clin. Invest. 113:539-50 22195972 Pubmed 2011 Mechanism of isoprenylcysteine carboxyl methylation from the crystal structure of the integral membrane methyltransferase ICMT Yang, Jing Kulkarni, Kiran Manolaridis, Ioannis Zhang, Ziguo Dodd, Roger B Mas-Droux, Corine Barford, David Mol. Cell 44:997-1004 12750467 Pubmed 2003 Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate Winter-Vann, Ann M Kamen, Barton A Bergo, Martin O Young, SG Melnyk, Stepan James, S Jill Casey, Patrick J Proc. Natl. Acad. Sci. U.S.A. 100:6529-34 28167504 Pubmed 2017 Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer Manu, Kanjoormana Aryan Chai, Tin Fan Teh, Jing Tsong Zhu, Wan Long Casey, Patrick J Wang, Mei Mol. Cancer Ther. 16:914-923 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 77 10406499 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=10406499 Reactome DB_ID: 10406496 ICMT:Zn2+:Cysmethynil [endoplasmic reticulum membrane] ICMT:Zn2+:Cysmethynil Reactome DB_ID: 10390044 1 Reactome DB_ID: 9656757 1 Cysmethynil [PubChem Compound:6918831] Cysmethynil PubChem Compound 6918831 Reactome Database ID Release 77 10406496 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=10406496 Reactome R-XTR-9656776 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-XTR-9656776.1 mature RAS proteins translocate to plasma membrane mature RAS proteins translocate to plasma membrane 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: 10406505 1 Golgi membrane GO 0000139 S-farnesyl-L-cysteine methyl ester at 186 (in Homo sapiens) 186 EQUAL S-palmitoyl-L-cysteine at 181 (in Homo sapiens) 181 EQUAL S-palmitoyl-L-cysteine [MOD:00115] S-palmitoyl-L-cysteine at 184 (in Homo sapiens) 184 EQUAL 1 EQUAL 186 EQUAL Reactome DB_ID: 10333958 1 plasma membrane GO 0005886 S-farnesyl-L-cysteine methyl ester at 186 (in Homo sapiens) 186 EQUAL S-palmitoyl-L-cysteine at 181 (in Homo sapiens) 181 EQUAL S-palmitoyl-L-cysteine at 184 (in Homo sapiens) 184 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 77 10406507 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=10406507 Reactome R-XTR-9647980 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-XTR-9647980.1 After farnesylation, C-terminal proteolysis, carboxymethylation and palmitoylation, RAS proteins translocate to the plasma membrane (reviewed in Gysin et al, 2011). inferred by electronic annotation IEA GO IEA 3.1.2.22 RAS proteins are depalmitoylated RAS proteins are depalmitoylated 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: 10333958 1 S-farnesyl-L-cysteine methyl ester at 186 (in Homo sapiens) 186 EQUAL S-palmitoyl-L-cysteine at 181 (in Homo sapiens) 181 EQUAL S-palmitoyl-L-cysteine at 184 (in Homo sapiens) 184 EQUAL 1 EQUAL 186 EQUAL Reactome DB_ID: 29356 1 Reactome DB_ID: 8848337 1 hexadecanoate [ChEBI:7896] hexadecanoate ChEBI 7896 Reactome DB_ID: 10406527 1 S-farnesyl-L-cysteine methyl ester at 186 (in Homo sapiens) 186 EQUAL 1 EQUAL 186 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10406521 LYPLA1 dimer, ABHD17A,B,C [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity abhd17c [plasma membrane] abhd17b [plasma membrane] abhd17a [plasma membrane] UniProt Q6GL10 UniProt Q6DEY3 UniProt Q5M904 GO 0008474 GO molecular function Reactome Database ID Release 77 10406528 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=10406528 Reactome Database ID Release 77 10406530 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=10406530 Reactome R-XTR-9647994 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-XTR-9647994.1 RAS proteins undergo a dynamic palmitoylation and depalmitoylation cycle that regulates their association with membranes and thus their localization and function (Hancock et al, 1989; Swarthout et al, 2005; reviewed in Gysin et al, 2011; Lin et al, 2017; Ahearn et al, 2018). Depalmitoylation is catalyzed by the acyl-protein thioesterase LYPLA1, also known as APT1, or by members of the ABHD17 family (Dekker et al, 2010; Lin and Conibear, 2015; reviewed in Lin et al, 2017). 28630138 Pubmed 2017 Targeting the Ras palmitoylation/depalmitoylation cycle in cancer Lin, David Tse Shen Davis, Nicholas G Conibear, Elizabeth Biochem. Soc. Trans. 45:913-921 16000296 Pubmed 2005 DHHC9 and GCP16 constitute a human protein fatty acyltransferase with specificity for H- and N-Ras Swarthout, John T Lobo, Sandra Farh, Lynn Croke, Monica R Greentree, Wendy K Deschenes, Robert J Linder, Maurine E J. Biol. Chem. 280:31141-8 20418879 Pubmed 2010 Small-molecule inhibition of APT1 affects Ras localization and signaling Dekker, Frank J Rocks, Oliver Vartak, Nachiket Menninger, Sascha Hedberg, Christian Balamurugan, Rengarajan Wetzel, Stefan Renner, Steffen Gerauer, Marc Schölermann, Beate Rusch, Marion Kramer, John W Rauh, D Coates, Geoffrey W Brunsveld, Luc Bastiaens, Philippe I H Waldmann, Herbert Nat. Chem. Biol. 6:449-56 26701913 Pubmed 2015 ABHD17 proteins are novel protein depalmitoylases that regulate N-Ras palmitate turnover and subcellular localization Lin, David Tse Shen Conibear, Elizabeth Elife 4:e11306 2661017 Pubmed 1989 All ras proteins are polyisoprenylated but only some are palmitoylated Hancock, John F Magee, Anthony I Childs, Julie E Marshall, Christopher J Cell 57:1167-77 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 77 10406531 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=10406531 Reactome DB_ID: 10406523 Palmostatin B:LYPLA1 dimer, ABHD17A,B,C [cytosol] Palmostatin B:LYPLA1 dimer, ABHD17A,B,C Reactome DB_ID: 9647934 1 Palmostatin B [PubChem Compound:45100481] Palmostatin B PubChem Compound 45100481 Converted from EntitySet in Reactome Reactome DB_ID: 10406521 1 Reactome Database ID Release 77 10406523 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=10406523 Reactome R-XTR-9647947 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-XTR-9647947.1 Palmostatin B binds RAS depalmitoylases Palmostatin B binds RAS depalmitoylases 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: 9647934 1 Converted from EntitySet in Reactome Reactome DB_ID: 10406521 1 Reactome DB_ID: 10406523 1 Reactome Database ID Release 77 10406525 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=10406525 Reactome R-XTR-9647991 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-XTR-9647991.1 Palmostatin B binds to acylthioesterases and inhibits their activity, resulting in RAS proteins that are stably palmitoylated (Dekker et al, 2010; Lin and Conibear, 2015; reviewed in Lin et al, 2017). Although this inhibition might be predicted to promote sustained RAS-dependent signaling, in fact interruption of the palmitoylation-depalmitoylation cycle results in generalized redistribution of RAS proteins to all cellular membranes, impairing function (Dekker et al, 2010). Consistent with this, Inhibition of RAS acyl protein thioesterases has been shown to have some use in restricting the proliferation of NRAS-driven melanomas (Rusch et al, 2011; Hedberg et al, 2011; Xu et al, 2012; Vujic et al, 2016). 22144181 Pubmed 2012 Inhibiting the palmitoylation/depalmitoylation cycle selectively reduces the growth of hematopoietic cells expressing oncogenic Nras Xu, Jin Hedberg, Christian Dekker, Frank J Li, Qing Haigis, Kevin M Hwang, Eugene Waldmann, Herbert Shannon, Kevin Blood 119:1032-5 21905186 Pubmed 2011 Identification of acyl protein thioesterases 1 and 2 as the cellular targets of the Ras-signaling modulators palmostatin B and M Rusch, Marion Zimmermann, Tobias J Bürger, Marco Dekker, Frank J Görmer, Kristina Triola, Gemma Brockmeyer, Andreas Janning, Petra Böttcher, Thomas Sieber, Stephan A Vetter, Ingrid R Hedberg, Christian Waldmann, Herbert Angew. Chem. Int. Ed. Engl. 50:9838-42 26771141 Pubmed 2016 Acyl protein thioesterase 1 and 2 (APT-1, APT-2) inhibitors palmostatin B, ML348 and ML349 have different effects on NRAS mutant melanoma cells Vujic, Igor Sanlorenzo, Martina Esteve-Puig, Rosaura Vujic, Marin Kwong, Andrew Tsumura, Aaron Murphy, Ryan Moy, Adrian Posch, Christian Monshi, Babak Rappersberger, Klemens Ortiz-Urda, Susana Oncotarget 7:7297-306 21905185 Pubmed 2011 Development of highly potent inhibitors of the Ras-targeting human acyl protein thioesterases based on substrate similarity design Hedberg, Christian Dekker, Frank J Rusch, Marion Renner, Steffen Wetzel, Stefan Vartak, Nachiket Gerding-Reimers, Claas Bon, Robin S Bastiaens, Philippe I H Waldmann, Herbert Angew. Chem. Int. Ed. Engl. 50:9832-7 inferred by electronic annotation IEA GO IEA mature p21 RAS binds GDP mature p21 RAS binds GDP 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: 29420 1 GDP [ChEBI:17552] GDP Guanosine 5'-diphosphate Guanosine diphosphate ChEBI 17552 Reactome DB_ID: 10333958 1 S-farnesyl-L-cysteine methyl ester at 186 (in Homo sapiens) 186 EQUAL S-palmitoyl-L-cysteine at 181 (in Homo sapiens) 181 EQUAL S-palmitoyl-L-cysteine at 184 (in Homo sapiens) 184 EQUAL 1 EQUAL 186 EQUAL Reactome DB_ID: 10334974 1 p21 RAS:GDP [plasma membrane] p21 RAS:GDP Reactome DB_ID: 29420 1 Reactome DB_ID: 10333958 1 S-farnesyl-L-cysteine methyl ester at 186 (in Homo sapiens) 186 EQUAL S-palmitoyl-L-cysteine at 181 (in Homo sapiens) 181 EQUAL S-palmitoyl-L-cysteine at 184 (in Homo sapiens) 184 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 77 10334974 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=10334974 Reactome R-XTR-109796 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-XTR-109796.1 Reactome Database ID Release 77 10406559 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=10406559 Reactome R-XTR-9649733 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-XTR-9649733.1 RAS proteins bind GDP with picomolar affinity as part of the RAS:GTP cycle (reviewed in Hennig et al, 2015; Pei et al, 2019; Prior et al, 2012). RAS proteins in the GDP-bound form are inactive. Interaction with guanine nucleotide exchange factors (GEFs) enhances the slow rate of intrinsic GDP dissociation, allowing GTP to bind and activate the protein (reviewed in Henning et al, 2015). 22589270 Pubmed 2012 A comprehensive survey of Ras mutations in cancer Prior, Ian A Lewis, Paul D Mattos, Carla Cancer Res. 72:2457-67 28778966 Pubmed 2018 Targeting Ras with Macromolecules Pei, Dehua Chen, Kuangyu Liao, Hui Cold Spring Harb Perspect Med 8: 25781681 Pubmed 2015 Ras activation revisited: role of GEF and GAP systems Hennig, Anne Markwart, Robby Esparza-Franco, Manuel A Ladds, Graham Rubio, Ignacio Biol. Chem. 396:831-48 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10410348 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=10410348 Reactome R-XTR-9648002 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-XTR-9648002.1 RAS proteins undergo several processing steps during maturation including farnesylation, carboxy-terminal cleavage and carboxymethylation, among others. These steps are required for their membrane localization and function and ultimately for their ability to activate RAF (reviewed in Gysin et al, 2011; Ahearn et al, 2018). inferred by electronic annotation IEA GO IEA 3.6.5.4 3.6.5.3 3.6.5.2 3.6.5.1 RAS intrinsic GTPase activity hydrolyzes GTP to GDP RAS intrinsic GTPase activity hydrolyzes GTP to GDP 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: 10333960 1 p21 RAS:GTP [plasma membrane] p21 RAS:GTP Reactome DB_ID: 29438 1 GTP [ChEBI:15996] GTP Guanosine 5'-triphosphate ChEBI 15996 Reactome DB_ID: 10333958 1 S-farnesyl-L-cysteine methyl ester at 186 (in Homo sapiens) 186 EQUAL S-palmitoyl-L-cysteine at 181 (in Homo sapiens) 181 EQUAL S-palmitoyl-L-cysteine at 184 (in Homo sapiens) 184 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 77 10333960 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=10333960 Reactome R-XTR-109783 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-XTR-109783.1 Reactome DB_ID: 10334974 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10333960 GO 0003924 GO molecular function Reactome Database ID Release 77 10406562 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=10406562 Reactome Database ID Release 77 10406564 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=10406564 Reactome R-XTR-9649736 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-XTR-9649736.1 RAS蛋白内在的GTPase活性我薄弱n the absence of other effectors (Gibbs et al, 1984; reviewed in Pylayeva-Gupta et al, 2011). Nucleotide attack is mediated by residue Q61 and facilitated by van der Waals bonds contributed by glycine residues at position 12 and 13; these three residues account for the majority of oncogenic and pathogenic mutations found in RAS proteins (reviewed in Prior et al, 2012). GAP proteins stimulate the intrinsic GTPase activity of RAS proteins by inserting an arginine residue into the active site, which contributes to proper positioning of the critical Q61 RAS residue (reviewed in King et al, 2013). 23443682 Pubmed 2013 Nonredundant functions for Ras GTPase-activating proteins in tissue homeostasis King, Philip D Lubeck, Beth A Lapinski, Philip E Sci Signal 6:re1 21993244 Pubmed 2011 RAS oncogenes: weaving a tumorigenic web Pylayeva-Gupta, Yuliya Grabocka, Elda Bar-Sagi, Dafna Nat. Rev. Cancer 11:761-74 6148751 Pubmed 1984 Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules Gibbs, Jackson B Sigal, Irving S Poe, Martin Scolnick, Edward M Proc. Natl. Acad. Sci. U.S.A. 81:5704-8 inferred by electronic annotation IEA GO IEA Intrinsic nucleotide exchange on RAS Intrinsic nucleotide exchange on RAS 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: 29438 1 Reactome DB_ID: 10334974 1 Reactome DB_ID: 29420 1 Reactome DB_ID: 10333960 1 Reactome Database ID Release 77 10406561 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=10406561 Reactome R-XTR-9649735 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-XTR-9649735.1 Inactive RAS:GDP is converted at a low rate to the active GTP-bound state through release of GDP and binding of GTP. This intrinsic GEF activity is weak due to the picomolar affinity of the protein for both nucleotides, but is stimulated by the interaction of RAS proteins with guanine nucleotide exchange factors (Marshall et al, 2012; reviewed in Bourne et al, 1991; Hennig et al, 2015; Pei et al, 2018). 1898771 Pubmed 1991 The GTPase superfamily: conserved structure and molecular mechanism Bourne, Henry R Sanders, David A McCormick, Frank Nature 349:117-27 22750304 Pubmed 2012 Probing the GTPase cycle with real-time NMR: GAP and GEF activities in cell extracts Marshall, Christopher B Meiri, David Smith, Matthew J Mazhab-Jafari, Mohammad T Gasmi-Seabrook, Geneviève M C Rottapel, Robert Stambolic, Vuk Ikura, Mitsuhiko Methods 57:473-85 inferred by electronic annotation IEA GO IEA RAS GEFs promote RAS nucleotide exchange RAS GEFs promote RAS nucleotide exchange 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: 29438 1 Reactome DB_ID: 10334974 1 Reactome DB_ID: 29420 1 Reactome DB_ID: 10333960 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10385106 RAS GEFs [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity rasgef1a [cytosol] rapgef2 [cytosol] rasgrf2 [cytosol] rasgrp4 [cytosol] rasgrp1 [cytosol] UniProt A0JM95 UniProt A0A6I8QG15 UniProt A0A6I8RAX6 UniProt F7E4V9 UniProt A0A6I8PW37 GO 0005085 GO molecular function Reactome Database ID Release 77 10385107 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=10385107 Reactome Database ID Release 77 10385109 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=10385109 Reactome R-XTR-5672965 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-XTR-5672965.1 人类基因组预测编码27 RAS卦nine nucleotide exchange factors (GEFs) that promote the exchange of GDP for GTP on membrane-associated RAS in response to RAS-MAPK pathway activation by growth factors, hormones, cytokines and other stimuli (reviewed in Cherfils and Zeghouf, 2013; Cargnello and Roux, 2011). Nucleotide exchange stimulates a conformational change in RAS to facilitate its interaction with RAF, ultimately promoting the phosphorylation of downstream effectors MAPK3 and MAPK1 (also known as ERK1 and ERK2) (reviewed in Cseh et al, 2014; Vigil et al, 2010). 21372320 Pubmed 2011 Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases Cargnello, Marie Roux, Philippe P Microbiol. Mol. Biol. Rev. 75:50-83 21102635 Pubmed 2010 Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? Vigil, Dominico Cherfils, J Rossman, Kent L Der, CJ Nat. Rev. Cancer 10:842-57 24937142 Pubmed 2014 "RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway Cseh, Botond Doma, Eszter Baccarini, Manuela FEBS Lett. 588:2398-406 23303910 Pubmed 2013 Regulation of small GTPases by GEFs, GAPs, and GDIs Cherfils, J Zeghouf, Mahel Physiol. Rev. 93:269-309 inferred by electronic annotation IEA GO IEA RAS:GTP binds PI3K RAS:GTP binds PI3K 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: 10328366 1 PI3K [cytosol] PI3K Converted from EntitySet in Reactome Reactome DB_ID: 10328354 1 PI3K-regulatory subunit [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity pik3r1 [cytosol] pik3r2 [cytosol] UniProt F6Z0J4 UniProt A0A6I8Q186 Converted from EntitySet in Reactome Reactome DB_ID: 10328364 1 PI3K-catalytic subunit [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity pik3cb [cytosol] pik3ca [cytosol] UniProt A0A6I8PSR5 UniProt F6VXG1 Reactome Database ID Release 77 10328366 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=10328366 Reactome R-XTR-74693 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-XTR-74693.1 Reactome DB_ID: 10333960 1 Reactome DB_ID: 10406603 1 p21 RAS:GTP:PI3K [plasma membrane] p21 RAS:GTP:PI3K Reactome DB_ID: 10328366 1 Reactome DB_ID: 10333960 1 Reactome Database ID Release 77 10406603 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=10406603 Reactome R-XTR-9658249 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-XTR-9658249.1 Reactome Database ID Release 77 10406605 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=10406605 Reactome R-XTR-9658253 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-XTR-9658253.1 GTP-bound RAS interacts with PI3K through a direct interaction with the 110 kDa catalytic subunit (Sjolander et al, 1991; Rodriguez-Viciana et al, 1994; Rodriguex-Viciana et al, 1996; Pacold et al, 2000; reviewed in Gysin et al, 2011; Castellano and Downward, 2011; Martini et al, 2014). Interaction with RAS stimulates the activity of PI3K by promoting a conformational change and/or mediating recruitment to the plasma membrane, among other possible mechanisms (Pacold et al, 2000; Denley et al, 2008; Zhang et al, 2019). The PI3K signaling pathway contributes to RAS-mediated cellular proliferation and survival and through RAC, contributes to cytoskeletal rearrangements and cell motility (reviewed in Vivanco and Sawyers, 2002; Castellano and Downward, 2011; Martini et al, 2014; Nussinov et al, 2015). 11136978 Pubmed 2000 Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma Pacold, Michael E Suire, Sabine Perisic, O Lara-Gonzalez, Samuel Davis, Colin T Walker, Edward H Hawkins, Phillip T Stephens, Len Eccleston, John F Williams, Roger L Cell 103:931-43 26085527 Pubmed 2015 The Key Role of Calmodulin in KRAS-Driven Adenocarcinomas Nussinov, Ruth Muratcioglu, Serena Tsai, Chung-Jung Jang, Hyunbum Gursoy, Attila Keskin, Ozlem Mol. Cancer Res. 13:1265-73 24897931 Pubmed 2014 PI3K/AKT signaling pathway and cancer: an updated review Martini, Miriam De Santis, Maria Chiara Braccini, Laura Gulluni, Federico Hirsch, Emilio Ann. Med. 46:372-83 17998941 Pubmed 2008 Oncogenic signaling of class I PI3K isoforms Denley, A Kang, S Karst, U Vogt, P K Oncogene 27:2561-74 31135801 Pubmed 2019 The structural basis for Ras activation of PI3Kα lipid kinase Zhang, Mingzhen Jang, Hyunbum Nussinov, Ruth Phys Chem Chem Phys 21:12021-12028 21779497 Pubmed 2011 RAS Interaction with PI3K: More Than Just Another Effector Pathway Castellano, Esther Downward, Julian Genes Cancer 2:261-74 8665852 Pubmed 1996 Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation Rodriguez-Viciana, Pablo Warne, Patricia H Vanhaesebroeck, Bart Waterfield, Michael D Downward, Julian EMBO J. 15:2442-51 12094235 Pubmed 2002 The phosphatidylinositol 3-Kinase AKT pathway in human cancer Vivanco, I Sawyers, Charles L Nat. Rev. Cancer 2:489-501 1716764 Pubmed 1991 Association of p21ras with phosphatidylinositol 3-kinase Sjölander, Anita Yamamoto, Kyohei Huber, Brian E Lapetina, Eduardo G Proc. Natl. Acad. Sci. U.S.A. 88:7908-12 8052307 Pubmed 1994 Phosphatidylinositol-3-OH激酶作为直接的圆盾t of Ras Rodriguez-Viciana, Pablo Warne, Patricia H Dhand, Ritu Vanhaesebroeck, Bart Gout, Ivan Fry, Michael J Waterfield, Michael D Downward, Julian Nature 370:527-32 12121613 Pubmed 2002 Activation of phosphoinositide 3-kinase gamma by Ras Suire, Sabine Hawkins, Phillip Stephens, Len Curr. Biol. 12:1068-75 inferred by electronic annotation IEA GO IEA RAS:GTP binds RAL GDS proteins RAS:GTP binds RAL GDS 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 Inactive RAFs bind YWHAB Inactive RAFs bind YWHAB 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: 10385009 1 dephosphorylated inactive RAFS:YWHAB dimer [cytosol] dephosphorylated inactive RAFS:YWHAB dimer Converted from EntitySet in Reactome Reactome DB_ID: 10385007 1 dephosphorylated inactive RAFs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-braf [cytosol] phospho-raf1 [cytosol] Reactome DB_ID: 10328522 1 Reactome Database ID Release 77 10385009 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=10385009 Reactome R-XTR-5672728 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-XTR-5672728.1 Converted from EntitySet in Reactome Reactome DB_ID: 10385007 1 Reactome DB_ID: 10328522 1 Reactome Database ID Release 77 10385011 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=10385011 Reactome R-XTR-5672960 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-XTR-5672960.1 Dephosphorylation of S259 (S365/S214) by PP2A promotes the transient dissociation of 14-3-3 dimers from this site (Ory et al, 2003; Jaumot et al, 2001; Rommel et al, 1996; reviewed in Raabe and Raap, 2003; Matallanas et al, 2011). In the case of RAF1, displacement of 14-3-3 has also been shown to be promoted by a direct interaction between RAF1 and the cell cycle protein prohibitin (PHB; Rajalingam et al, 2005; reviewed in Rajalingam and Rudel, 2005; Chowdhury et al, 2014).
16294014 Pubmed 2005 Ras-Raf signaling needs prohibitin Rajalingam, Krishnaraj Rudel, Thomas Cell Cycle 4:1503-5 16041367 Pubmed 2005 Prohibitin is required for Ras-induced Raf-MEK-ERK activation and epithelial cell migration Rajalingam, Krishnaraj Wunder, Christian Brinkmann, Volker Churin, Yuri Hekman, Mirko Sievers, Claudia Rapp, Ulf R Rudel, Thomas Nat. Cell Biol. 7:837-43 21779496 Pubmed 2011 Raf family kinases: old dogs have learned new tricks Matallanas, David Birtwistle, Marc Romano, David Zebisch, Armin Rauch, Jens von Kriegsheim, Alexander Kolch, Walter Genes Cancer 2:232-60 24347342 Pubmed 2014 Prohibitins role in cellular survival through Ras-Raf-MEK-ERK pathway Chowdhury, Indrajit Thompson, Winston E Thomas, Kelwyn J. Cell. Physiol. 229:998-1004 12932339 Pubmed 2003 Ras signaling: PP2A puts Ksr and Raf in the right place Raabe, Thomas Rapp, Ulf R Curr. Biol. 13:R635-7 8637718 Pubmed 1996 Activated Ras displaces 14-3-3 protein from the amino terminus of c-Raf-1 Rommel, C Radziwill, G Lovri?, J Noeldeke, J Heinicke, T Jones, D Aitken, A Moelling, K Oncogene 12:609-19 inferred by electronic annotation IEA GO IEA "Activator" RAF:YWHAB dimer binds RAS:GTP "Activator" RAF:YWHAB dimer binds RAS:GTP 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: 10333960 1 Reactome DB_ID: 10384970 1 'activator' RAF:YWHAB dimer [cytosol] 'activator' RAF:YWHAB dimer Converted from EntitySet in Reactome Reactome DB_ID: 10384968 1 'activator' RAFs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-braf [cytosol] Reactome DB_ID: 10328522 1 Reactome Database ID Release 77 10384970 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=10384970 Reactome R-XTR-5672710 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-XTR-5672710.1 Reactome DB_ID: 10384972 1 RAS p21:三磷酸鸟苷:“激活”RAF: YWHAB二聚体[plasma membrane] RAS p21:三磷酸鸟苷:“激活”RAF: YWHAB二聚体 Reactome DB_ID: 10333960 1 Reactome DB_ID: 10384970 1 Reactome Database ID Release 77 10384972 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=10384972 Reactome R-XTR-5672729 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-XTR-5672729.1 Reactome Database ID Release 77 10384978 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=10384978 Reactome R-XTR-5672950 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-XTR-5672950.1 Activation of RAS downstream of extracellular signals allows RAS:GTP to recruit BRAF to the plasma membrane, disrupting the pre-existing inactivating interaction between BRAF and the 14-3-3 protein YWHAB (Marais et al, 1997; Yamamori et al, 1995; reviewed in Cseh et al, 2014). BRAF, unique of the three mammalian RAF proteins, is constitutively phosphorylated on the conserved serine residue (445 in BRAF) in the N-terminal acidic motif (NtA). Constitutive negative charge in this region is critical for BRAF to function as an activator of other RAF molecules, allowing signal amplification (Marais et al, 1997; Mason et al, 1999; Wan et al, 2004; Garnett et al, 2005; Hu et al, 2013; reviewed in Cseh et al, 2014). RAS:GTP-bound BRAF heterodimerizes with additional RAF monomers, allowing cis-autophosphorylation in the activation loop of the second RAF protein. Once activated by BRAF in this manner, the 'receiver' kinase monomer is competent to dimerize with and transactivate other monomers in turn (Weber et al, 2001; Garnett et al, 2005; Hu et al, 2013; reviewed in Cseh et al, 2014). Intruigingly, the scaffold protein KSR1 is activated by BRAF in a manner analogous to other RAF monomers and can similarly act as a RAF activator once it is itself activated (Brennan et al, 2011; Ory et al, 2003; reviewed in Raabe and Rapp, 2003; Cseh et al, 2014).

Although this pathway shows PP2A-mediated dephosphorylation of RAF and transient displacement of 14-3-3 proteins as preceding RAS and plasma membrane binding of RAF proteins, the order and dependency of these events is not clear. Both membrane binding and 14-3-3 displacement also appear to be facilitated by an interaction between RAF and the cell cycle protein Prohibitin (PHB; Rajalingam et al, 2005; reviewed in Rajalingam and Rudel, 2005; Chowdhury et al, 2014). 16364920 Pubmed 2005 Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization Garnett, Mathew J Rana, Sareena Paterson, Hugh Barford, David Marais R Mol. Cell 20:963-9 10205168 Pubmed 1999 Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation Mason, Clive S Springer, Caroline J Cooper, Robert G Superti-Furga, Giulio Marshall, Christopher J Marais R EMBO J. 18:2137-48 9020159 Pubmed 1997 Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases Marais R Light, Yvonne Paterson, Hugh F Mason, Clive S Marshall, Christopher J J. Biol. Chem. 272:4378-83 23993095 Pubmed 2013 Allosteric activation of functionally asymmetric RAF kinase dimers Hu, Jiancheng Stites, Edward C Yu, Haiyang Germino, Elizabeth A Meharena, Hiruy S Stork, Philip J S Kornev, Alexandr P Taylor, Susan S Shaw, Andrey S Cell 154:1036-46 15035987 Pubmed 2004 Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF Wan, Paul T C Garnett, Mathew J Roe, S Mark 李,Sharlene Niculescu-Duvaz, Dan Good, Valerie M Jones, C Michael Marshall, Christopher J Springer, Caroline J Barford, David Marais R Cell 116:855-67 7744815 Pubmed 1995 Purification of a Ras-dependent mitogen-activated protein kinase kinase kinase from bovine brain cytosol and its identification as a complex of B-Raf and 14-3-3 proteins Yamamori, Bunpei Kuroda, Shinya Shimizu, Kazuya Fukui, Koji Ohtsuka, Toshihisa Takai, Yoshimi J. Biol. Chem. 270:11723-6 11325826 Pubmed 2001 Active Ras induces heterodimerization of cRaf and BRaf Weber, Christoph K Slupsky, Joseph R Kalmes, H Andreas Rapp, Ulf R Cancer Res. 61:3595-8 21441910 Pubmed 2011 A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK Brennan, Damian F Dar, Arvin C Hertz, Nicholas T Chao, William C H Burlingame, Alma L Shokat, Kevan M Barford, David Nature 472:366-9 inferred by electronic annotation IEA GO IEA ACTIVATION Reactome Database ID Release 77 10384979 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=10384979 Reactome DB_ID: 10384976 UniProt:Q6P850 phb UniProt Q6P850 1 EQUAL 272 EQUAL RAS:GTP:'activator' RAF homo/heterodimerizes with other RAF monomers RAS:GTP:'activator' RAF homo/heterodimerizes with other RAF monomers 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: 10384972 1 Converted from EntitySet in Reactome Reactome DB_ID: 10385111 1 dephosphorylated "receiver" RAF/KSR1 [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-braf [cytosol] phospho-raf1 [cytosol] Reactome DB_ID: 10385113 1 p21 RAS:GTP:homo/heterodimerized RAF complex [plasma membrane] p21 RAS:GTP:homo/heterodimerized RAF complex Reactome DB_ID: 10384972 1 Converted from EntitySet in Reactome Reactome DB_ID: 10385111 1 Reactome Database ID Release 77 10385113 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=10385113 Reactome R-XTR-5672733 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-XTR-5672733.1 Reactome Database ID Release 77 10385115 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=10385115 Reactome R-XTR-5672966 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-XTR-5672966.1 RAF activation depends on the formation of a side-by-side asymmetric homo- or heterodimer (formed from either 2 RAF monomers or a RAF monomer and KSR1) (Weber et al, 2001; Garnett et al, 2005; Rushworth et al, 2006; Rajakulendran et al, 2009; Hu et al, 2013). Dimerization is mediated by cluster of basic residues in the kinase domain, and mutation of these critical residues abrogates RAF activation (Rajakulendran et al, 2009). Dimerization is required for the 'activator' monomer to induce an allosteric change in the 'receiver' monomer that, in conjunction with activation loop phosphorylation, activates the kinase activity of the receiver (Hu et al, 2013). BRAF, by virtue of its constitutive negative charge in the NtA region, is uniquely able to function as an activator RAF without further modification, while RAF1, ARAF and KSR1 can function as activators only after being phosphorylated in the NtA region downstream of RAF pathway activation (Hu et al, 2013; Leicht et al, 2013; reviewed in Cseh et al, 2014). Homo and heterodimerization of RAF monomers may be promoted by association with MAP3K11, which interacts with BRAF and RAF1 in vitro and in vivo and which is required for RAF activation (Chadee et al, 2004a, Chadee et al, 2004b; Chadee et al, 2006). 15258589 Pubmed 2004 MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation Chadee, Deborah N Kyriakis, John M Nat. Cell Biol. 6:770-6 23360980 Pubmed 2013 MEK-1 activates C-Raf through a Ras-independent mechanism Leicht, Deborah T Balan, Vitaly Zhu, Jun Kaplun, Alexander Bronisz, Agnieszka Rana, Ajay Tzivion, Guri Biochim. Biophys. Acta 1833:976-86 19727074 Pubmed 2009 A dimerization-dependent mechanism drives RAF catalytic activation Rajakulendran, T Sahmi, M Lefrancois, M Sicheri, F Therrien, M Nature 461:542-5 16508002 Pubmed 2006 Regulation and role of Raf-1/B-Raf heterodimerization Rushworth, Linda K Hindley, Alison D O'Neill, Eric Kolch, Walter Mol. Cell. Biol. 26:2262-72 15467451 Pubmed 2004 A novel role for mixed lineage kinase 3 (MLK3) in B-Raf activation and cell proliferation Chadee, Deborah N Kyriakis, John M Cell Cycle 3:1227-9 16537381 Pubmed 2006 Mixed-lineage kinase 3 regulates B-Raf through maintenance of the B-Raf/Raf-1 complex and inhibition by the NF2 tumor suppressor protein Chadee, Deborah N Xu, Dazhong Hung, Gene Andalibi, Ali Lim, David J Luo, Zhijun Gutmann, David H Kyriakis, John M Proc. Natl. Acad. Sci. U.S.A. 103:4463-8 inferred by electronic annotation IEA GO IEA 2.7.11 MARK3 phosphorylates KSR1 MARK3 phosphorylates KSR1 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 2 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 10384941 1 KSR1:MARK3 [cytosol] KSR1:MARK3 Reactome DB_ID: 10384939 1 UniProt:A0A6I8Q0M1 mark3 UniProt A0A6I8Q0M1 1 EQUAL 753 EQUAL Reactome DB_ID: 10384935 1 UniProt:A0A6I8SEI5 ksr1 UniProt A0A6I8SEI5 1 EQUAL 923 EQUAL Reactome Database ID Release 77 10384941 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=10384941 Reactome R-XTR-5672689 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-XTR-5672689.1 Reactome DB_ID: 29370 2 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 Reactome DB_ID: 10384947 1 p-S311,S406 KSR1:MARK3 [cytosol] p-S311,S406 KSR1:MARK3 Reactome DB_ID: 10384945 1 O-phospho-L-serine at 311 (in Homo sapiens) 311 EQUAL O-phospho-L-serine [MOD:00046] O-phospho-L-serine at 406 (in Homo sapiens) 406 EQUAL 1 EQUAL 923 EQUAL Reactome DB_ID: 10384939 1 1 EQUAL 753 EQUAL Reactome Database ID Release 77 10384947 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=10384947 Reactome R-XTR-5672695 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-XTR-5672695.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10384941 GO 0004674 GO molecular function Reactome Database ID Release 77 10384948 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=10384948 Reactome Database ID Release 77 10384950 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=10384950 Reactome R-XTR-5672948 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-XTR-5672948.1 KSR1 (RAS的激酶抑制因子1)最初是我的dentified in Drosophila and C. elegans as a suppressor of activated RAS, and is one of a number of scaffolding proteins that bring RAS-RAF-MAPK members together to promote pathway activation (Therrien et al, 1995; Kornfeld et al, 1995; Sundaram et al, 1995; reviewed in Zhang et al, 2013). Consistent with its role as a scaffolding protein, KSR1 interacts with all of the kinases of the MAPK pathway. Interaction with the MEK proteins MAP2K1 and MAP2K2 is constitutive, while pathway activation promotes heterodimerization with activated RAF proteins and subsequent interaction with ERK/MAPK proteins (Rajakulendran et al, 2009; Therrien et al, 1996; McKay et al, 2009; Hu et al, 2011; Hu et al, 2013; Brennan et al, 2011; note, however, that for simplicity MAP2K/MEK proteins are not depicted as part of this reaction).
Like the RAF proteins, KSR1 is maintained in an inactive state in quiescent cells by interaction with 14-3-3 dimers; this interaction is promoted by phosphorylation of KSR1 residues S311 and S406 by the MAP/microtubule affinity-regulating kinase 3 (MARK3), which is constitutively bound to KSR1 (Muller et al, 2001). 21441104 Pubmed 2011 Mutation that blocks ATP binding creates a pseudokinase stabilizing the scaffolding function of kinase suppressor of Ras, CRAF and BRAF Hu, Jiancheng Yu, Haiyang Kornev, Alexandr P Zhao, Jianping Filbert, Erin L Taylor, Susan S Shaw, Andrey S Proc. Natl. Acad. Sci. U.S.A. 108:6067-72 8946910 Pubmed 1996 KSR modulates signal propagation within the MAPK cascade Therrien, Marc Michaud, Neil R Rubin, Gerald M Morrison, Deborah K Genes Dev. 10:2684-95 8521513 Pubmed 1995 The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction Sundaram, M Han, Min Cell 83:889-901 8521514 Pubmed 1995 The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans Kornfeld, Kerry Hom, Dennis B Horvitz, H Robert Cell 83:903-13 8521512 Pubmed 1995 KSR, a novel protein kinase required for RAS signal transduction Therrien, Marc Chang, Henry C Solomon, Noah M Karim, Felix D Wassarman, David A Rubin, Gerald M Cell 83:879-88 23863182 Pubmed 2013 The dual function of KSR1: a pseudokinase and beyond Zhang, Hua Koo, Chuay Yeng Stebbing, Justin Giamas, Georgios Biochem. Soc. Trans. 41:1078-82 19541618 Pubmed 2009 Signaling dynamics of the KSR1 scaffold complex McKay, Melissa M Ritt, Daniel A Morrison, Deborah K Proc. Natl. Acad. Sci. U.S.A. 106:11022-7 11741534 Pubmed 2001 C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1 Muller, J Ory, Stephane Copeland, T Piwnica-Worms, H Morrison, Deborah K Mol Cell 8:983-93 inferred by electronic annotation IEA GO IEA p-S311,S406 KSR1:MARK3 binds YWHAB dimer p-S311,S406 KSR1:MARK3 binds YWHAB dimer 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: 10384947 1 Reactome DB_ID: 10328522 1 Reactome DB_ID: 10384993 1 p-S311,S406 KSR1:MARK3:YWHAB dimer [cytosol] p-S311,S406 KSR1:MARK3:YWHAB dimer Reactome DB_ID: 10384947 1 Reactome DB_ID: 10328522 1 Reactome Database ID Release 77 10384993 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=10384993 Reactome R-XTR-5672696 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-XTR-5672696.1 Reactome Database ID Release 77 10384995 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=10384995 Reactome R-XTR-5672954 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-XTR-5672954.1 MARK3-mediated phosphorylation of S311 and particularly S406 promotes the binding of 14-3-3 dimers, sequestering KSR1 in the cytosol in quiescent cells (Cacace et al, 1999; Muller et al, 2000; Muller et al, 2001; reviewed in Raabe and Raap, 2003). Mutation of S406 abrogates 14-3-3 binding and results in constitutive plasma membrane localization of KSR1 (Muller et al, 2001). 10891492 Pubmed 2000 Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling Muller, J Cacace, AM Lyons, WE McGill, CB Morrison, Deborah K Mol Cell Biol 20:5529-39 9858547 Pubmed 1999 Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14-3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression Cacace, AM Michaud, NR Therrien, M Mathes, K Copeland, T Rubin, GM Morrison, Deborah K Mol Cell Biol 19:229-40 inferred by electronic annotation IEA GO IEA YWHAB dimer dissociates from KSR1:MARK3 YWHAB dimer dissociates from KSR1:MARK3 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: 10385001 1 p-S311 KSR1: MARK3:YWHAB dimer [plasma membrane] p-S311 KSR1: MARK3:YWHAB dimer Reactome DB_ID: 10384999 1 p-S311 KSR1: MARK3[cytosol] p-S311 KSR1: MARK3 Reactome DB_ID: 10384939 1 1 EQUAL 753 EQUAL Reactome DB_ID: 10384997 1 O-phospho-L-serine at 311 (in Homo sapiens) 311 EQUAL 1 EQUAL 923 EQUAL Reactome Database ID Release 77 10384999 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=10384999 Reactome R-XTR-5672691 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-XTR-5672691.1 Reactome DB_ID: 10328522 1 Reactome Database ID Release 77 10385001 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=10385001 Reactome R-XTR-5672692 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-XTR-5672692.1 Reactome DB_ID: 10384999 1 Reactome DB_ID: 10328522 1 Reactome Database ID Release 77 10385003 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=10385003 Reactome R-XTR-5672958 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-XTR-5672958.1 Dephosphorylation of KSR1 S406 by PP2A promotes the dissociation of 14-3-3 from this site, exposing both the CR1 region that is required for membrane localization of KSR1 and the MAPK-binding FxFP motif (Ory et al, 2003; Muller et al, 2001; reviewed in Raabe and Raap, 2003). inferred by electronic annotation IEA GO IEA 2.7.12.1 Phosphorylation of RAF Phosphorylation of RAF 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: 10385113 1 Reactome DB_ID: 113592 4 Reactome DB_ID: 10385129 1 p21 RAS:GTP:activated RAF homo/heterodimer complexes [plasma membrane] p21 RAS:GTP:activated RAF homo/heterodimer complexes Reactome DB_ID: 10385127 1 p21 RAS:GTP:'activator' RAFs:YWHAB dimer [plasma membrane] p21 RAS:GTP:'activator' RAFs:YWHAB dimer Converted from EntitySet in Reactome Reactome DB_ID: 10384968 1 Reactome DB_ID: 10333960 1 Reactome DB_ID: 10328522 1 Reactome Database ID Release 77 10385127 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=10385127 Reactome R-XTR-5672715 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-XTR-5672715.1 Converted from EntitySet in Reactome Reactome DB_ID: 10385125 1 activated RAF/KSR1 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-raf1 [plasma membrane] Reactome Database ID Release 77 10385129 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=10385129 Reactome R-XTR-5672718 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-XTR-5672718.1 Reactome DB_ID: 29370 4 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10385133 RAF activating kinases [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004712 GO molecular function Reactome Database ID Release 77 10385134 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=10385134 Reactome Database ID Release 77 10385136 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=10385136 Reactome R-XTR-5672969 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-XTR-5672969.1 皇家空军的下游二聚和变构活动vation, RAF monomers and KSR1 undergo a series of activating phosphorylations in both the activation loop (AL) and, in the case of ARAF, RAF1 and KSR1, in the NtA . Phosphorylation of the activation loop residues (T491, S494 in RAF1, T452, T455 in ARAF and T599, S602 in BRAF) contributes to full kinase activity, although this may be less critical for ARAF, and RAFs in general, than for other kinases due to their regulation by 14-3-3 binding (Zhu et al, 2005; Zhang et al, 2000; Baljuls et al, 2008, reviewed in Matallanas et al, 2011; Udell et al, 2011). AL phosphorylation may occur through cis-autophosphorylation within the RAF dimer, although phosphorylation by other kinases is also possible (Hu et al, 2013; reviewed in Matallanas et al, 2011).

Phosphorylation in the RAF NtA region is required for full kinase activity, for interaction with MAP2K substrates and for the ability of activated RAF to act as an allosteric activator of other RAF monomers (Marais et al, 1995; Diaz et al, 1997; Xiang et al, 2002; Edin et al, 2005; Hu et al, 2013; Mason et al, 1999). Phosphorylation of these residues (S338 and Y441 in RAF1, S299 and Y302 in ARAF and Y602 in KSR1) may be mediated by a kinase of the SRC, JAK or PAK family kinases, by MAP2K kinases, calmodulin kinase CaMKII or through autophosphorylation by RAF itself (Marais et al, 1995; Xia et al, 1996; King et al, 1998; Sun et al, 2000; Tran et al, 2003; Tran et al, 2005; Salzano et al. 2012, Hu et al, 2013; reviewed in Matallanas et al, 2011). The phosphorylated NtA of RAF1 is also the binding site for the negative regulator PEPB1, also known as RKIP. PEBP1 binding to RAF1 prevents phosphorylation of the MAP2K substrates (Park et al, 2006; Rath et al, 2008; reviewed in Shin et al, 2009). 18294816 Pubmed 2008 The RKIP (Raf-1 Kinase Inhibitor Protein) conserved pocket binds to the phosphorylated N-region of Raf-1 and inhibits the Raf-1-mediated activated phosphorylation of MEK Rath, Oliver Park, Sungdae Tang, Hui-hui Banfield, Mark J Brady, R Leo 李,Yie Chia Dignam, John D Sedivy, John M Kolch, Walter Yeung, Kam C Cell. Signal. 20:935-41 19158341 Pubmed 2009 Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway Shin, Sung-Young Rath, Oliver Choo, Sang-Mok Fee, Frances McFerran, Brian Kolch, Walter Cho, Kwang-Hyun J. Cell. Sci. 122:425-35 18662992 Pubmed 2008 Positive regulation of A-RAF by phosphorylation of isoform-specific hinge segment and identification of novel phosphorylation sites Baljuls, Angela Schmitz, Werner Mueller, Thomas Zahedi, René P Sickmann, Albert Hekman, Mirko Rapp, Ulf R J. Biol. Chem. 283:27239-54 8876196 Pubmed 1996 The cytokine-activated tyrosine kinase JAK2 activates Raf-1 in a p21ras-dependent manner Xia, Kai Mukhopadhyay, Nishit K Inhorn, Roger C Barber, Dwayne L Rose, Paul E 李,Robert S Narsimhan, Radha P D'Andrea, Alan D Griffin, James D Roberts, Thomas M Proc. Natl. Acad. Sci. U.S.A. 93:11681-6 12244094 Pubmed 2002 Phosphorylation of 338SSYY341 regulates specific interaction between Raf-1 and MEK1 Xiang, Xiaoqin Zang, Mengwei Waelde, Christine A Wen, Rong Luo, Zhijun J. Biol. Chem. 277:44996-5003 10712905 Pubmed 2000 Regulation of the protein kinase Raf-1 by oncogenic Ras through phosphatidylinositol 3-kinase, Cdc42/Rac and Pak Sun, Huaiyu King, Alastair J Diaz, H Bruce Marshall, Mark S Curr. Biol. 10:281-4 17097642 Pubmed 2006 Regulation of RKIP binding to the N-region of the Raf-1 kinase Park, Sungdae Rath, Oliver Beach, Sandy Xiang, Xiaoqin Kelly, Sharon M Luo, Zhijun Kolch, Walter Yeung, Kam C FEBS Lett. 580:6405-12 15899852 Pubmed 2005 Raf-1 serine 338 phosphorylation plays a key role in adhesion-dependent activation of extracellular signal-regulated kinase by epidermal growth factor Edin, Matthew L Juliano, Rudy L Mol. Cell. Biol. 25:4466-75 11032810 Pubmed 2000 Activation of B-Raf kinase requires phosphorylation of the conserved residues Thr598 and Ser601 Zhang, Bao-Hong Guan, KL EMBO J. 19:5429-39 16093354 Pubmed 2005 Identification of Raf-1 S471 as a novel phosphorylation site critical for Raf-1 and B-Raf kinase activities and for MEK binding Zhu, Jun Balan, Vitaly Bronisz, Agnieszka Balan, Karina Sun, Hengrui Leicht, Deborah T Luo, Zhijun Qin, J Avruch, Joseph Tzivion, Guri Mol. Biol. Cell 16:4733-44 7542586 Pubmed 1995 Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation Marais R Light, Y Paterson, H F Marshall, Chris J EMBO J. 14:3136-45 9234708 Pubmed 1997 Phosphorylation of Raf-1 serine 338-serine 339 is an essential regulatory event for Ras-dependent activation and biological signaling Diaz, Bruce Barnard, Darlene Filson, Adele MacDonald, Susan King, Alastair Marshall, Mark Mol. Cell. Biol. 17:4509-16 22592532 Pubmed 2012 钙/ calmodulin-dependent蛋白激酶二世(CaMKII) phosphorylates Raf-1 at serine 338 and mediates Ras-stimulated Raf-1 activation Salzano, Marcella Rusciano, Maria Rosaria Russo, Eleonora Bifulco, Maurizio Postiglione, Loredana Vitale, Mario Cell Cycle 11:2100-6 9823899 Pubmed 1998 The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338 King, Alastair J Sun, Huaiyu Diaz, Bruce Barnard, Darlene Miao, Wenyan Bagrodia, Shubha Marshall, Mark S Nature 396:180-3 inferred by electronic annotation IEA GO IEA Raf dimer inhibitors bind RAF heterodimers Raf dimer inhibitors bind RAF heterodimers 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: 10385113 1 Converted from EntitySet in Reactome Reactome DB_ID: 9657579 1 RAF dimer inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TAK-632 [cytosol] LY3009120 [cytosol] TAK-580 [cytosol] Guide to Pharmacology 10387 Guide to Pharmacology 8943 Guide to Pharmacology 9977 Reactome DB_ID: 10385184 1 p21RAS:GTP:homo/heterodimerized RAF complex:RAF dimer inhibitors [plasma membrane] p21RAS:GTP:homo/heterodimerized RAF complex:RAF dimer inhibitors Reactome DB_ID: 10385113 1 Converted from EntitySet in Reactome Reactome DB_ID: 9657579 1 Reactome Database ID Release 77 10385184 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=10385184 Reactome R-XTR-9653109 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-XTR-9653109.1 Reactome Database ID Release 77 10406572 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=10406572 Reactome R-XTR-9653108 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-XTR-9653108.1 LY3009120, TAK-580 and TAK-632 are pan-RAF inhibitors that binds to all 3 RAF isoforms as well as to RAF dimers to inhibit phosphorylation of MAP2K and MAPK proteins (Nakamura et al, 2013; Okaniwa et al, 2013; Sun et al, 2017; Peng et al, 2015; Henry et al, 2015; Vakana et al, 2017). Because they inhibit the kinase activity of RAF homo- and heterodimers, treatment with pan-RAF dimer inhibitors generates minimal paradoxical RAF activation and inhibits cellular proliferation in a number of tumor models (Peng et al, 2015; Henry et al, 2015, Vakana et al, 2017; reviewed in Karoulia et al, 2017; Agianian and Gavathiotis, 2018; ). 28984291 Pubmed 2017 New perspectives for targeting RAF kinase in human cancer Karoulia, Zoi Gavathiotis, Evripidis Poulikakos, Poulikos I Nat. Rev. Cancer 17:676-691 23906342 Pubmed 2013 Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives Okaniwa, Masanori Hirose, Masaaki Arita, Takeo Yabuki, Masato Nakamura, Akito Takagi, Terufumi Kawamoto, Tomohiro Uchiyama, Noriko Sumita, Akihiko Tsutsumi, Shunichirou Tottori, Tsuneaki Inui, Yoshitaka Sang, Bi-Ching Yano, Jason Aertgeerts, Kathleen Yoshida, Sei Ishikawa, Tomoyasu J. Med. Chem. 56:6478-94 25965804 Pubmed 2015 Discovery of 1-(3,3-dimethylbutyl)-3-(2-fluoro-4-methyl-5-(7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells Henry, James R Kaufman, Michael D Peng, Sheng-Bin Ahn, Yu Mi Caldwell, Timothy M Vogeti, Lakshminarayana Telikepalli, Hanumaiah Lu, Wei-Ping Hood, Molly M Rutkoski, Thomas J Smith, Bryan D Vogeti, Subha Miller, David Wise, Scott C Chun, Lawrence Zhang, Xiaoyi Zhang, Youyan Kays, Lisa Hipskind, Philip A Wrobleski, Aaron D Lobb, Karen L Clay, Julia M Cohen, Jeffrey D Walgren, Jennie L McCann, Denis Patel, Phenil Clawson, David K Guo, Sherry Manglicmot, Danalyn Groshong, Chris Logan, Cheyenne Starling, James J Flynn, Daniel L J. Med. Chem. 58:4165-79 29461827 Pubmed 2018 Current Insights of BRAF Inhibitors in Cancer Agianian, Bogos Gavathiotis, Evripidis J. Med. Chem. 61:5775-5793 27999210 Pubmed 2017 LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer Vakana, Eliza Pratt, Susan Blosser, Wayne Dowless, Michele Simpson, Nicholas Yuan, Xiu-Juan Jaken, Susan Manro, Jason Stephens, Jennifer Zhang, Youyan Huber, Lysiane Peng, Sheng-Bin Stancato, Louis F Oncotarget 8:9251-9266 26343583 Pubmed 2015 Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers Peng, Sheng-Bin Henry, James R Kaufman, Michael D Lu, Wei-Ping Smith, Bryan D Vogeti, Subha Rutkoski, Thomas J Wise, Scott Chun, Lawrence Zhang, Youyan Van Horn, Robert D Yin, Tinggui Zhang, Xiaoyi Yadav, Vipin Chen, Shih-Hsun Gong, Xueqian Ma, Xiwen Webster, Yue Buchanan, Sean Mochalkin, Igor Huber, Lysiane Kays, Lisa Donoho, Gregory P Walgren, Jennie McCann, Denis Patel, Phenil Conti, Ilaria Plowman, Gregory D Starling, James J Flynn, Daniel L Cancer Cell 28:384-98 28082416 Pubmed 2017 A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas Sun, Yu Alberta, John A Pilarz, Catherine Calligaris, David Chadwick, Emily J Ramkissoon, Shakti H Ramkissoon, Lori A Garcia, Veronica Matia Mazzola, Emanuele Goumnerova, Liliana Kane, Michael Yao, Zhan Kieran, Mark W Ligon, Keith L Hahn, WC Garraway, Levi A Rosen, N Gray, Nathanael S Agar, Nathalie Y Buhrlage, Sara J Segal, Rosalind A Stiles, Charles D Neuro-oncology 19:774-785 24121489 Pubmed 2013 Antitumor activity of the selective pan-RAF inhibitor TAK-632 in BRAF inhibitor-resistant melanoma Nakamura, Akito Arita, Takeo Tsuchiya, Shuntarou Donelan, Jill Chouitar, Jouhara Carideo, Elizabeth Galvin, Katherine Okaniwa, Masanori Ishikawa, Tomoyasu Yoshida, Sei Cancer Res. 73:7043-55 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10409868 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=10409868 Reactome R-XTR-5673000 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-XTR-5673000.1 哺乳动物有三个皇家空军亚型,A, B和C,are activated downstream of RAS and stimulate the MAPK pathway. Although CRAF (also known as RAF-1) was the first identified and remains perhaps the best studied, BRAF is most similar to the RAF expressed in other organisms. Notably, MAPK (ERK) activation is more compromised in BRAF-deficient cells than in CRAF or ARAF deficient cells (Bonner et al, 1985; Mikula et al, 2001, Huser et al, 2001, Mercer et al, 2002; reviewed in Leicht et al, 2007; Matallanas et al, 2011; Cseh et al, 2014). Consistent with its important role in MAPK pathway activation, mutations in the BRAF gene, but not in those for A- or CRAF, are associated with cancer development (Davies et al, 2002; reviewed in Leicht et al, 2007). ARAF and CRAF may have arisen through gene duplication events, and may play additional roles in MAPK-independent signaling (Hindley and Kolch, 2002; Murakami and Morrison, 2001).
Despite divergences in function, all mammalian RAF proteins share three conserved regions (CRs) and each interacts with RAS and MEK proteins, although with different affinities. The N-terminal CR1 contains a RAS-binding domain (RBD) and a cysteine-rich domain (CRD) that mediate interactions with RAS and the phospholipid membrane. CR2 contains inhibitory phosphorylation sites that impact RAS binding and RAF activation, while the C-terminal CR3 contains the bi-lobed kinase domain with its activation loop, and an adjacent upstream "N-terminal acidic motif" -S(S/G)YY in C- and A-RAF,respectively, and SSDD in B-RAF - that is required for RAF activation (Tran et al, 2005; Dhillon et al, 2002; Chong et al, 2001; Cutler et al, 1998; Chong et al, 2003; reviewed in Matallanas et al, 2011).

Regulation of RAF activity involves multiple phosphorylation and dephosphorylation events, intramolecular conformational changes, homo- and heterodimerization between RAF monomers and changes to protein binding partners, including scaffolding proteins which bring pathway members together (reviewed in Matallanas et al, 2011; Cseh et al, 2014). The details of this regulation are not completely known and differ slightly from one RAF isoform to another. Briefly, in the inactive state, RAF phosphorylation on conserved serine residues in CR2 promote an interaction with 14-3-3 dimers, maintaining the kinase in a closed conformation. Upon RAS activation, these sites are dephosphorylated, allowing the RAF CRD and RBD to bind RAS and phospholipids, facilitating membrane recruitment. RAF activation requires homo- or heterodimerization, which promotes autophosphorylation in the activation loop of the receiving monomer. Of the three isoforms, only BRAF is able to initiate this allosteric activation of other RAF monomers (Hu et al, 2013; Heidorn et al, 2010; Garnett et al, 2005). This activity depends on negative charge in the N-terminal acidic region (NtA; S(S/G)YY or SSDD) adjacent to the kinase domain. In BRAF, this region carries permanent negative charge due to the presence of the two aspartate residues in place of the tyrosine residues of A- and CRAF. In addition, unique to BRAF, one of the serine residues of the NtA is constitutively phosphorylated. In A- and CRAF, residues in this region are subject to phosphorylation by activated MEK downstream of RAF activation, establishing a positive feedback loop and allowing activated A- and CRAF monomers to act as transactivators in turn (Hu et al, 2013; reviewed in Cseh et al, 2014). RAF signaling is terminated through dephosphorylation of the NtA region and phosphorylation of the residues that mediate the inhibitory interaction with 14-3-3, promoting a return to the inactive state (reviewed in Matallanas et al, 2011; Cseh et al, 2014).
2993863 Pubmed 1985 Structure and biological activity of human homologs of the raf/mil oncogene Bonner, Tom I Kerby, Stephen B Sutrave, Pramod Gunnell, Mark A Mark, George Rapp, Ulf R Mol. Cell. Biol. 5:1400-7 11296227 Pubmed 2001 MEK kinase activity is not necessary for Raf-1 function Hüser, Martin Luckett, Jeni Chiloeches, Antonio Mercer, Kathryn Iwobi, Mabel Giblett, Susan Sun, Xiao-Ming Brown, Jane Marais R Pritchard, Catrin EMBO J. 20:1940-51 11447113 Pubmed 2001 Positive and negative regulation of Raf kinase activity and function by phosphorylation Chong, Huria 李,Jeeyong Guan, KL EMBO J. 20:3716-27 11821947 Pubmed 2002 ERK signalling and oncogene transformation are not impaired in cells lacking A-Raf Mercer, Kathryn Chiloeches, Antonio Hüser, Martin Kiernan, Michelle Marais R Pritchard, Catrin Oncogene 21:347-55 20141835 Pubmed 2010 Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF Heidorn, Sonja J Milagre, Carla Whittaker, Steven Nourry, Arnaud Niculescu-Duvas, Ion Dhomen, Nathalie Hussain, Jahan Reis-Filho, JS Springer, Caroline J Pritchard, Catrin Marais R Cell 140:209-21 11296228 Pubmed 2001 Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene Mikula, Mario Schreiber, Martin Husak, Zvenislava Kucerova, Lucia Rüth, Jochen Wieser, Rotraud Zatloukal, Kurt Beug, Hartmut Wagner, Erwin F Baccarini, Manuela EMBO J. 20:1952-62 17555829 Pubmed 2007 Raf kinases: function, regulation and role in human cancer Leicht, Deborah T Balan, Vitaly Kaplun, Alexander Singh-Gupta, Vinita Kaplun, Ludmila Dobson, Melissa Tzivion, Guri Biochim. Biophys. Acta 1773:1196-212 11950876 Pubmed 2002 Extracellular signal regulated kinase (ERK)/mitogen activated protein kinase (MAPK)-independent functions of Raf kinases Hindley, Alison Kolch, Walter J. Cell. Sci. 115:1575-81 12865432 Pubmed 2003 Regulation of Raf through phosphorylation and N terminus-C terminus interaction Chong, Huira Guan, KL J. Biol. Chem. 278:36269-76 12068308 Pubmed 2002 Mutations of the BRAF gene in human cancer Davies, H Bignell, Graham R Cox, Charles Stephens, Philip Edkins, S Clegg, Sheila Teague, J Woffendin, Hayley Garnett, Mathew J Bottomley, William Davis, Neil Dicks, E Ewing, Rebecca Floyd, Yvonne Gray, K Hall, Sarah Hawes, Rachel Hughes, Jaime Kosmidou, Vivian Menzies, A Mould, Catherine Parker, A Stevens, C Watt, Stephen Hooper, Steven Wilson, Rebecca Jayatilake, Hiran Gusterson, Barry A Cooper, C Shipley, J Hargrave, Darren Pritchard-Jones, Katherine Maitland, Norman Chenevix-Trench, G Riggins, GJ Bigner, Darell D Palmieri, Giuseppe Cossu, Antonio Flanagan, Adrienne 尼克尔森Andrew Ho, Judy W C Leung, SY Yuen, ST Weber, Barbara L Seigler, Hilliard F Darrow, Timothy L Paterson, Hugh Marais R Marshall, Christopher J Wooster, R Stratton, MR Futreal, P Andrew Nature 417:949-54 11579234 Pubmed 2001 Raf-1 without MEK? Murakami, Monica S Morrison, Deborah K Sci. STKE 2001:pe30 11782426 Pubmed 2002 Regulation of Raf-1 activation and signalling by dephosphorylation Dhillon, Amardeep S Meikle, Sharon Yazici, Zihni Eulitz, Manfred Kolch, Walter EMBO J. 21:64-71 inferred by electronic annotation IEA GO IEA MAP2K and MAPK activation MAP2K and MAPK activation 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 MAP2Ks and MAPKs bind to the activated RAF complex MAP2Ks and MAPKs bind to the activated RAF 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: 10385129 1 Reactome DB_ID: 10385152 1 MAP2K1 dimer [cytosol] MAP2K1 dimer Reactome DB_ID: 10330654 2 UniProt:F6YYZ1 map2k1 UniProt F6YYZ1 2 EQUAL 393 EQUAL Reactome Database ID Release 77 10385152 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=10385152 Reactome R-XTR-5672683 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-XTR-5672683.1 Reactome DB_ID: 10348109 1 UniProt:A0A6I8RA44 mapk1 UniProt A0A6I8RA44 2 EQUAL 360 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10385150 1 RAF/MAPK scaffolds [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10385154 1 activated RAF:scaffold:MAP2K:MAPK complex [plasma membrane] activated RAF:scaffold:MAP2K:MAPK complex Reactome DB_ID: 10385129 1 Reactome DB_ID: 10385152 1 Reactome DB_ID: 10348109 1 2 EQUAL 360 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10385150 1 Reactome Database ID Release 77 10385154 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=10385154 Reactome R-XTR-5672720 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-XTR-5672720.1 Reactome Database ID Release 77 10385164 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=10385164 Reactome R-XTR-5672972 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-XTR-5672972.1 英国皇家空军激酶限制底物特异性and have as their primary substrates the two MAP2K proteins MAP2K1 and MAP2K2 (also known as MEK1 and 2). MAP2K1 knockout is embryonic lethal in mice, while MAP2K2 knockouts have no apparent abnormalities, suggesting that MAP2K1 can compensate for MAP2K2 in vivo (Giroux et al, 1999; Belanger et al, 2003). MAP2K proteins exist as stable homo- and heterodimers independent of growth factor stimulation and are generally recruited to activated RAF proteins in conjunction with a scaffolding protein and the MAP2K substrates, MAPK1 and 3 (also known as ERK1 and 2) (Ohren et al, 2004; Catalanotti et al, 2009; Catling et al, 1995; reviewed in Matallanas et al, 2011; Roskoski et al, 2012a; Roskoski et al, 2012b).

Scaffolding proteins promote signaling by providing a docking platform that colocalizes components of the signaling cascade, and provide specificity by controlling the spatial and temporal regulation of the pathway (reviewed in Brown and Sacks, 2009; Matallanas et al, 2011). KSR1 and 2, CNKSR1 and 2, IQGAP1 and the beta arrestins are among the known MAPK scaffold proteins that act at the plasma membrane upon MAPK pathway activation; in addition, paxillin localizes MAPK pathway components to focal adhesion sites in the plasma membrane (Roy et al, 2005; Ren et al, 2007; DeFea et al, 2000; Togho et al, 2003; Ishibe et al, 2003; reviewed in Claperon and Therrien, 2007; Brown and Sacks, 2009; Matallanas et al, 2011). Although this reaction depicts these scaffolding proteins acting equivalently, the details of how they promote pathway activation vary. For instance, KSR1 and 2 are constitutively bound to MAP2K dimers but recruit MAPKs only upon pathway stimulation, while IQGAP1 associates constitutively with both MAP2K and MAPK proteins in unstimulated cells and shows increased interaction with MAP2K1 upon pathway activation by EGF (Stewart et al, 1999; Cacace et al, 2000; Muller et al, 2000; Roy et al, 2004; Roy et al, 2005; reviewed in Brown and Sacks, 2009). Scaffolding complexes may be particularly important for the phosphorylation of cytosolic MAPK targets (reviewed in Casar et al, 2009). 17496912 Pubmed 2007 KSR and CNK: two scaffolds regulating RAS-mediated RAF activation Claperon, A Therrien, M Oncogene 26:3143-58 16135787 Pubmed 2005 IQGAP1 is a scaffold for mitogen-activated protein kinase signaling Roy, Monideepa Li, Zhigang Sacks, David B Mol. Cell. Biol. 25:7940-52 12473660 Pubmed 2003 The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation Tohgo, A Choy, Eric W Gesty-Palmer, Diane Pierce, Kristen L Laporte, Stephane Oakley, Robert H Caron, Marc G Lefkowitz, Robert J Luttrell, Louis M J. Biol. Chem. 278:6258-67 12832465 Pubmed 2003 Mek2 is dispensable for mouse growth and development Bélanger, Louis-François Roy, Sophie Tremblay, Michel Brott, Barbara Steff, Ann-Muriel Mourad, Walid Hugo, Patrice Erikson, Raymond Charron, Jean Mol. Cell. Biol. 23:4778-87 14636584 Pubmed 2003 Phosphorylation-dependent paxillin-ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis Ishibe, Shuta Joly, Dominique Zhu, Xiaolei Cantley, Lloyd G Mol. Cell 12:1275-85 19219045 Pubmed 2009 A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal Catalanotti, Federica Reyes, Gloria Jesenberger, Veronika Galabova-Kovacs, Gergana de Matos Simoes, Ricardo Carugo, Oliviero Baccarini, Manuela Nat. Struct. Mol. Biol. 16:294-303 10209122 Pubmed 1999 Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta Giroux, S Tremblay, M Bernard, D Cardin-Girard, J F Aubry, S Larouche, L Rousseau, S Huot, J Landry, J Jeannotte, L Charron, J Curr. Biol. 9:369-72 14970219 Pubmed 2004 IQGAP1 binds ERK2 and modulates its activity Roy, Monideepa Li, Zhigang Sacks, David B J. Biol. Chem. 279:17329-37 19279408 Pubmed 2009 ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task Casar, Berta Pinto, Adán Crespo, Piero Cell Cycle 8:1007-13 22177953 Pubmed 2012 MEK1/2 dual-specificity protein kinases: structure and regulation Roskoski, Robert Jr Biochem. Biophys. Res. Commun. 417:5-10 7565670 Pubmed 1995 A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function. Catling, AD Schaeffer, HJ Reuter, CW Reddy, GR Weber, MJ Mol Cell Biol 15:5214-25 19091303 Pubmed 2009 Protein scaffolds in MAP kinase signalling Brown, Matthew D Sacks, David B Cell. Signal. 21:462-9 17563371 Pubmed 2007 IQGAP1 modulates activation of B-Raf Ren, Jian-Guo Li, Zhigang Sacks, David B Proc. Natl. Acad. Sci. U.S.A. 104:10465-9 10409742 Pubmed 1999 Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization Stewart, Scott Sundaram, M Zhang, Yanping 李,Jeeyong Han, Min Guan, Kun Liang Mol. Cell. Biol. 19:5523-34 22569528 Pubmed 2012 ERK1/2地图激酶:结构、功能和regulation Roskoski, Robert Jr Pharmacol. Res. 66:105-43 10725339 Pubmed 2000 beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2 DeFea, K A Zalevsky, J Thoma, M S Déry, O Mullins, R D Bunnett, N W J. Cell Biol. 148:1267-81 15543157 Pubmed 2004 Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition Ohren, Jeffrey F Chen, Huifen Pavlovsky, Alexander Whitehead, Christopher Zhang, Erli Kuffa, Peter Yan, Chunhong McConnell, Patrick Spessard, Cindy Banotai, Craig Mueller, WT Delaney, Amy Omer, Charles Sebolt-Leopold, Judith Dudley, David T Leung, Iris K Flamme, Cathlin Warmus, Joseph Kaufman, Michael Barrett, Stephen Tecle, Haile Hasemann, Charles A Nat. Struct. Mol. Biol. 11:1192-7 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 77 10385165 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=10385165 Reactome DB_ID: 10385162 p21 RAS:GTP:activated RAF1 homo/heterodimer:PEBP1 [plasma membrane] p21 RAS:GTP:activated RAF1 homo/heterodimer:PEBP1 Reactome DB_ID: 10385156 1 p21RAS:GTP:activated RAF1 homo/heterodimer [plasma membrane] p21RAS:GTP:activated RAF1 homo/heterodimer Converted from EntitySet in Reactome Reactome DB_ID: 10384968 1 Reactome DB_ID: 10333960 1 Reactome DB_ID: 10328522 1 Reactome DB_ID: 10385117 1 UniProt:L7N3R3 raf1 O-phospho-L-serine at 621 (in Homo sapiens) 621 EQUAL O4'-phospho-L-tyrosine at 341 (in Homo sapiens) 341 EQUAL O4'-phospho-L-tyrosine [MOD:00048] O-phospho-L-serine at 338 (in Homo sapiens) 338 EQUAL O-phospho-L-threonine at 491 (in Homo sapiens) 491 EQUAL O-phospho-L-threonine [MOD:00047] O-phospho-L-serine at 494 (in Homo sapiens) 494 EQUAL 1 EQUAL 648 EQUAL Reactome Database ID Release 77 10385156 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=10385156 Reactome R-XTR-5675414 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-XTR-5675414.1 Reactome DB_ID: 10385160 1 UniProt:F6Y4G1 pebp1.2 UniProt F6Y4G1 2 EQUAL 187 EQUAL Reactome Database ID Release 77 10385162 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=10385162 Reactome R-XTR-5675413 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-XTR-5675413.1 Dual mechanism MAP2K inhibitors bind MAP2Ks Dual mechanism MAP2K inhibitors bind MAP2Ks 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: 10385154 1 Converted from EntitySet in Reactome Reactome DB_ID: 9657567 1 dual mechanism MAP2K1/2 inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity trametinib [cytosol] Guide to Pharmacology 6495 Reactome DB_ID: 10385174 1 activated RAF:scaffold:MAP2K:MAPK complex:dual mechanism MAP2K inhibitors [plasma membrane] activated RAF:scaffold:MAP2K:MAPK complex:dual mechanism MAP2K inhibitors Reactome DB_ID: 10385154 1 Converted from EntitySet in Reactome Reactome DB_ID: 9657567 1 Reactome Database ID Release 77 10385174 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=10385174 Reactome R-XTR-9657583 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-XTR-9657583.1 Reactome Database ID Release 77 10406589 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=10406589 Reactome R-XTR-9657599 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-XTR-9657599.1 Although mutations in MAP2K proteins are infrequent in human cancers, the position of these kinases downstream of RAS and RAF make them good candidates for therapeutic targeting. Dual mechanism inhibitors such as trametinib bind to non-phosphorylated MAP2K proteins, inhibiting their MAPK-directed kinase activity as well as preventing their phosphorylation by RAF proteins (Hatzivassiliou et al, 2013; Lito et al, 2014; Ishii et al, 2013; reviewed in Samatar and Poulikakos, 2014). 25435214 Pubmed 2014 Targeting RAS-ERK signalling in cancer: promises and challenges Samatar, Ahmed A Poulikakos, Poulikos I Nat Rev Drug Discov 13:928-42 23934108 Pubmed 2013 Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers Hatzivassiliou, Georgia Haling, Jacob R Chen, Huifen Song, Kyung Price, Steve Heald, Robert Hewitt, Joanne F M Zak, Mark Peck, Ariana Orr, Christine Merchant, Mark Hoeflich, Klaus P Chan, Jocelyn Luoh, Shiuh-Ming Anderson, Daniel J Ludlam, Mary J C Wiesmann, C Ultsch, Mark Friedman, Lori S Malek, Shiva Belvin, Marcia Nature 501:232-6 24746704 Pubmed 2014 Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors Lito, Piro Saborowski, Anna Yue, Jingyin Solomon, Martha Joseph, Eric Gadal, Sunyana Saborowski, Michael Kastenhuber, Edward Fellmann, Christof Ohara, Kazuhiro Morikami, Kenji Miura, Takaaki Lukacs, Christine Ishii, Nobuya Lowe, S Rosen, N Cancer Cell 25:697-710 23667175 Pubmed 2013 Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity Ishii, Nobuya Harada, Naoki Joseph, Eric W Ohara, Kazuhiro Miura, Takaaki Sakamoto, Hiroshi Matsuda, Yutaka Tomii, Yasushi Tachibana-Kondo, Yukako Iikura, Hitoshi Aoki, Toshihiro Shimma, Nobuo Arisawa, Mikio Sowa, Yoshihiro Poulikakos, Poulikos I Rosen, N Aoki, Yuko Sakai, Toshiyuki Cancer Res. 73:4050-4060 inferred by electronic annotation IEA GO IEA 2.7.11 RAF phosphorylates MAP2K dimer RAF phosphorylates MAP2K dimer 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: 10385154 1 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 10385167 1 activated RAF:scaffold:p-2S MAP2K:MAPK complex [plasma membrane] activated RAF:scaffold:p-2S MAP2K:MAPK complex Reactome DB_ID: 10385129 1 Reactome DB_ID: 10385131 1 p-S218,S222 MAP2K1 dimer [cytosol] p-S218,S222 MAP2K1 dimer Reactome DB_ID: 10330027 2 O-phospho-L-serine at 218 (in Homo sapiens) 218 EQUAL O-phospho-L-serine at 222 (in Homo sapiens) 222 EQUAL 2 EQUAL 393 EQUAL Reactome Database ID Release 77 10385131 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=10385131 Reactome R-XTR-5672703 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-XTR-5672703.1 Reactome DB_ID: 10348109 1 2 EQUAL 360 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 10385150 1 Reactome Database ID Release 77 10385167 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=10385167 Reactome R-XTR-5672723 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-XTR-5672723.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10385154 Reactome Database ID Release 77 10385182 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=10385182 Reactome Database ID Release 77 10385186 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=10385186 Reactome R-XTR-5672978 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-XTR-5672978.1 Activated RAF phosphorylates the MEK kinases MAP2K1 and MAP2K2 on 2 serine residues in the MAP2K activation loop (S218 and S222 in MAP2K1 and S222 and S226 in MAP2K2 (Zheng and Guan, 1994; Alessi et al, 1994; Catling et al, 1995; Papin et al, 1995; Seger et al, 1994; reviewed in Roskoski, 2012a). Although all three RAF kinases can phosphorylate MAP2K1 and MAP2K2, BRAF appears to be the primary activator in vivo (Marais et al, 1997; Jaiswal et al, 1994; Pritchard et al, 1995; reviewed in Welbrock et al, 2004) 8051079 Pubmed 1994 Cytoplasmic localization of the mitogen-activated protein kinase activator MEK Zheng, CF Guan, K L J. Biol. Chem. 269:19947-52 7565795 Pubmed 1995 Conditionally oncogenic forms of the A-Raf and B-Raf protein kinases display different biological and biochemical properties in NIH 3T3 cells Pritchard, Catrin A Samuels, Michael L Bosch, Elizabeth McMahon, Martin Mol. Cell. Biol. 15:6430-42 7929275 Pubmed 1994 Overexpression of mitogen-activated protein kinase kinase (MAPKK) and its mutants in NIH 3T3 cells. Evidence that MAPKK involvement in cellular proliferation is regulated by phosphorylation of serine residues in its kinase subdomains VII and VIII. Seger, R Seger, D Reszka, AA Munar, ES Eldar-Finkelman, H Dobrowolska, G Jensen, AM Campbell, JS Fischer, EH Krebs, EG J Biol Chem 269:25699-709 8157000 Pubmed 1994 Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1 Alessi, DR Saito, Yuji Campbell, David G Cohen, P Sithanandam, Gunamani Rapp, Ulf Ashworth, A Marshall, Chris J Cowley, Sally EMBO J. 13:1610-9 7935411 Pubmed 1994 The mitogen-activated protein kinase cascade is activated by B-Raf in response to nerve growth factor through interaction with p21ras Jaiswal, Rama K Moodie, Shonna A Wolfman, Alan Landreth, Gary E Mol. Cell. Biol. 14:6944-53 7731720 Pubmed 1995 B-Raf protein isoforms interact with and phosphorylate Mek-1 on serine residues 218 and 222. Papin, C Eychène, A Brunet, A Pagès, G Pouysségur, Jacques Calothy, G Barnier, JV Oncogene 10:1647-51 inferred by electronic annotation IEA GO IEA INHIBITION Reactome Database ID Release 77 10385180 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=10385180 Reactome DB_ID: 10385174 INHIBITION Reactome Database ID Release 77 10385187 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=10385187 Reactome DB_ID: 10385184 Single mechanism MAP2K inhibitors bind phosphorylated MAP2Ks Single mechanism MAP2K inhibitors bind phosphorylated MAP2Ks 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: 10385167 1 Converted from EntitySet in Reactome Reactome DB_ID: 9657574 1 single mechanism MAP2K1/2 inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity cobimetinib [cytosol] binimetinib [cytosol] Guide to Pharmacology 7626 Guide to Pharmacology 7921 Reactome DB_ID: 10385172 1 activated RAF:scaffold:p-2S MAP2K:MAPK:single mechanism MAP2K inhibitors [plasma membrane] activated RAF:scaffold:p-2S MAP2K:MAPK:single mechanism MAP2K inhibitors Reactome DB_ID: 10385167 1 Converted from EntitySet in Reactome Reactome DB_ID: 9657574 1 Reactome Database ID Release 77 10385172 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=10385172 Reactome R-XTR-9657587 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-XTR-9657587.1 Reactome Database ID Release 77 10406593 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=10406593 Reactome R-XTR-9657606 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-XTR-9657606.1 Single mechanism MAP2K inhibitors bind to phosphorylated forms of MAP2K 1 and 2 and prevent their phosphorylation of MAPK proteins (Hatzivassiliou et al, 2013; reviewed in Samatar and Poulikakos, 2014). inferred by electronic annotation IEA GO IEA Dual mechanism MAPK inhibitors bind MAPKs Dual mechanism MAPK inhibitors bind MAPKs 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: 10385167 1 Reactome DB_ID: 113592 2 Reactome DB_ID: 29370 2 Reactome DB_ID: 10385169 1 activated RAF:scaffold:p-2S MAP2K:p-2T MAPK complex [plasma membrane] activated RAF:scaffold:p-2S MAP2K:p-2T MAPK complex Reactome DB_ID: 10385129 1 Reactome DB_ID: 10385131 1 Converted from EntitySet in Reactome Reactome DB_ID: 10385150 1 Reactome DB_ID: 10330474 1 O-phospho-L-threonine at 185 (in Homo sapiens) 185 EQUAL O4'-phospho-L-tyrosine at 187 (in Homo sapiens) 187 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 77 10385169 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=10385169 Reactome R-XTR-5672724 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-XTR-5672724.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10385167 Reactome Database ID Release 77 10385170 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=10385170 Reactome Database ID Release 77 10385178 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=10385178 Reactome R-XTR-5672973 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-XTR-5672973.1 Activated MAP2K phosphorylates MAPK on threonine and tyrosine residues in the activation loop (residues T202 and Y204 in MAPK3, residues T185 and Y187 in MAPK1) (Ray et al, 1988; reviewed in Roskoski, 2012b). MAPK3 and MAPK1 are 84% identical and appear to be stimulated in parallel by all known activators of the MAPK pathway (Lefloch et al, 2009; reviewed in Lloyd, 2006). 16879721 Pubmed 2006 Distinct functions for ERKs? Lloyd, Alison C J. Biol. 5:13 3287375 Pubmed 1988 Insulin-stimulated microtubule-associated protein kinase is phosphorylated on tyrosine and threonine in vivo Ray, L Bryan Sturgill, Thomas W Proc. Natl. Acad. Sci. U.S.A. 85:3753-7 19242111 Pubmed 2009 Total ERK1/2 activity regulates cell proliferation Lefloch, Renaud Pouysségur, Jacques Lenormand, Philippe Cell Cycle 8:705-11 inferred by electronic annotation IEA GO IEA INHIBITION Reactome DB_ID: 10385174 INHIBITION Reactome Database ID Release 77 10385179 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=10385179 Reactome DB_ID: 10385172 INHIBITION Reactome Database ID Release 77 10385181 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=10385181 Reactome DB_ID: 10385176 Dissociation of RAS:RAF complex Dissociation of RAS:RAF 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: 10385169 1 Reactome DB_ID: 10385131 1 Reactome DB_ID: 10385189 1 p21RAS:GTP:activated RAF homo/heterodimers [plasma membrane] p21RAS:GTP:activated RAF homo/heterodimers Converted from EntitySet in Reactome Reactome DB_ID: 10384968 1 Converted from EntitySet in Reactome Reactome DB_ID: 10385125 1 Reactome DB_ID: 10333960 1 Reactome DB_ID: 10328522 1 Reactome Database ID Release 77 10385189 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=10385189 Reactome R-XTR-5672712 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-XTR-5672712.1 Converted from EntitySet in Reactome Reactome DB_ID: 10385150 1 Reactome DB_ID: 10330474 1 O-phospho-L-threonine at 185 (in Homo sapiens) 185 EQUAL O4'-phospho-L-tyrosine at 187 (in Homo sapiens) 187 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 77 10385191 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=10385191 Reactome R-XTR-5672980 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-XTR-5672980.1 离解或traff管理的机制icking of activated MAPK signaling complexes at the plasma membrane are not fully worked out. Some active complexes may be endocytosed and targeted to other cellular locations, for example the Golgi complex (Lorentzen et al, 2010). Activated RAF monomers may dissociate and homo- or heterodimerize with additional inactive RAF monomers and in this way amplify the signal (reviewed in Matallanas et al, 2011; Cseh et al, 2014).
Ultimately, active RAF complexes are subject to PP5- and PP2A-mediated dephosphorylation, which promotes a return to the inactive state. Hydrolysis of RAS-bound GTP by the intrinsic GTPase activity, stimulated by association with RAS GAP proteins, ultimately promotes dissociation of RAS from RAF allowing a return to the quiescent state (reviewed in Wellbrock et al, 2004; Matallanas et al, 2011). 20858867 Pubmed 2010 Regulation of Ras localization by acylation enables a mode of intracellular signal propagation Lorentzen, Anna Kinkhabwala, Ali Rocks, Oliver Vartak, Nachiket Bastiaens, Philippe I H Sci Signal 3:ra68 15520807 Pubmed 2004 The RAF proteins take centre stage Wellbrock, C Karasarides, M Marais R Nat Rev Mol Cell Biol 5:875-85 inferred by electronic annotation IEA GO IEA Single mechanism MAPK inhibitors bind phosphorylated MAPK Single mechanism MAPK inhibitors bind phosphorylated MAPK 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: 10385169 1 Converted from EntitySet in Reactome Reactome DB_ID: 9657577 1 single mechanism MAPK inhibitors [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 10406595 1 activated RAF:scaffold:p-2S MAP2K:p-2T MAPK:single mechanism MAPK inhibitors [plasma membrane] activated RAF:scaffold:p-2S MAP2K:p-2T MAPK:single mechanism MAPK inhibitors Reactome DB_ID: 10385169 1 Converted from EntitySet in Reactome Reactome DB_ID: 9657577 1 Reactome Database ID Release 77 10406595 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=10406595 Reactome R-XTR-9657592 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-XTR-9657592.1 Reactome Database ID Release 77 10406597 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=10406597 Reactome R-XTR-9657608 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-XTR-9657608.1 Single mechanism MAPK inhibitors such as ulixertinib and ravoxertinib bind to the activated forms of MAPK proteins and inhibit their intrinsic target-directed kinase activity (Germann et al, 2017; Blake et al, 2016; reviewed in Samatar and Poulikakos, 2014). 27227380 Pubmed 2016 Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development Blake, James F Burkard, Michael Chan, Jocelyn Chen, Huifen Chou, Kang-Jye Diaz, Dolores Dudley, Danette A Gaudino, John J Gould, Stephen E Grina, Jonas Hunsaker, Thomas Liu, Lichuan Martinson, Matthew Moreno, David Mueller, Lars Orr, Christine Pacheco, Patricia Qin, Ann Rasor, Kevin Ren, Li Robarge, Kirk Shahidi-Latham, Sheerin Stults, Jeffrey Sullivan, Francis Wang, Weiru Yin, Jianping Zhou, Aihe Belvin, Marcia Merchant, Mark Moffat, John Schwarz, Jacob B J. Med. Chem. 59:5650-60 28939558 Pubmed 2017 Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib) Germann, Ursula A Furey, Brinley F Markland, William Hoover, Russell R Aronov, Alex M Roix, Jeffrey J Hale, Michael Boucher, Diane M Sorrell, David A Martinez-Botella, Gabriel Fitzgibbon, Matthew Shapiro, Paul Wick, Michael J Samadani, Ramin Meshaw, Kathryn Groover, Anna DeCrescenzo, Gary Namchuk, Mark Emery, Caroline M Saha, Saurabh Welsch, Dean J Mol. Cancer Ther. 16:2351-2363 inferred by electronic annotation IEA GO IEA WDR83:LAMTOR2:LAMTOR3 binds MAPK components WDR83:LAMTOR2:LAMTOR3 binds MAPK components 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: 10385209 1 activated RAF homo/heterodimer [cytosol] activated RAF homo/heterodimer Converted from EntitySet in Reactome Reactome DB_ID: 10385207 2 activated RAF monomer [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity phospho-braf [cytosol] phospho-raf1 [cytosol] Reactome Database ID Release 77 10385209 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=10385209 Reactome R-XTR-5674136 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-XTR-5674136.1 Reactome DB_ID: 10385205 1 endosome membrane GO 0010008 WDR83:LAMTOR2:LAMTOR3 [endosome membrane] WDR83:LAMTOR2:LAMTOR3 Reactome DB_ID: 10385199 1 UniProt:Q5XGI5 wdr83 UniProt Q5XGI5 1 EQUAL 315 EQUAL Reactome DB_ID: 10385201 1 UniProt:F7DKR6 lamtor2 UniProt F7DKR6 1 EQUAL 125 EQUAL Reactome DB_ID: 10385203 1 UniProt:B4F6Y3 lamtor3 UniProt B4F6Y3 1 EQUAL 124 EQUAL Reactome Database ID Release 77 10385205 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=10385205 Reactome R-XTR-5674133 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-XTR-5674133.1 Reactome DB_ID: 10385152 1 Reactome DB_ID: 10348109 1 2 EQUAL 360 EQUAL Reactome DB_ID: 10385211 1 WDR83:LAMTOR2:LAMTOR3:activated RAF:MAP2K:MAPK complex [endosome membrane] WDR83:LAMTOR2:LAMTOR3:activated RAF:MAP2K:MAPK complex Reactome DB_ID: 10385209 1 Reactome DB_ID: 10385205 1 Reactome DB_ID: 10385152 1 Reactome DB_ID: 10348109 1 2 EQUAL 360 EQUAL Reactome Database ID Release 77 10385211 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=10385211 Reactome R-XTR-5674138 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-XTR-5674138.1 Reactome Database ID Release 77 10385217 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=10385217 Reactome R-XTR-5674132 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-XTR-5674132.1 LAMTOR3 (also known as MEK partner 1, MP1) exists in an obligatory complex with LAMTOR2 (p14) at the endosomal membrane where they act as a scaffold and promote MAPK activation (Schaeffer et al, 1998; Teis et al, 2002; Teis et al, 2006; Sharma et al, 2005). The LAMTOR2/LAMTOR3 complex may also be part of a larger molecular weight complex at the endosome that includes the MAPK organizer protein MORG1 (Vomastek et al, 2004; Sharma et al, 2005; reviewed in Matallanas et al, 2011). 17178906 Pubmed 2006 p14-MP1-MEK1 signaling regulates endosomal traffic and cellular proliferation during tissue homeostasis Teis, David Taub, Nicole Kurzbauer, Robert Hilber, Diana de Araujo, Mariana E Erlacher, Miriam Offterdinger, Martin Villunger, Andreas Geley, Stephan Bohn, Georg Klein, Christoph Hess, Michael W Huber, Lukas A J. Cell Biol. 175:861-8 9733512 Pubmed 1998 MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade Schaeffer, Hans J Catling, Andrew D Eblen, Scott T Collier, Lara S Krauss, Anke Weber, Michael J Science 281:1668-71 12479806 Pubmed 2002 Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction Teis, David Wunderlich, Winfried Huber, Lukas A Dev. Cell 3:803-14 15118098 Pubmed 2004 Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists Vomastek, Tomás Schaeffer, Hans-Joerg Tarcsafalvi, Adel Smolkin, Mark E Bissonette, Eric A Weber, Michael J Proc. Natl. Acad. Sci. U.S.A. 101:6981-6 15547943 Pubmed 2005 MEK partner 1 (MP1): regulation of oligomerization in MAP kinase signaling 沙玛,Charu Vomastek, Tomás Tarcsafalvi, Adel Catling, Andrew D Schaeffer, Hans-Joerg Eblen, Scott T Weber, Michael J J. Cell. Biochem. 94:708-19 inferred by electronic annotation IEA GO IEA MAP2Ks and MAPKs are phosphorylated at the endosome membrane MAP2Ks and MAPKs are phosphorylated at the endosome membrane 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: 10385211 1 Reactome DB_ID: 113592 4 Reactome DB_ID: 29370 4 Reactome DB_ID: 10385213 1 WDR83:LAMTOR2:LAMTOR3:activated RAF:p-2S MAP2K:p-T,Y MAPK complex [endosome membrane] WDR83:LAMTOR2:LAMTOR3:activated RAF:p-2S MAP2K:p-T,Y MAPK complex Reactome DB_ID: 10385209 1 Reactome DB_ID: 10385131 1 Reactome DB_ID: 10385205 1 Reactome DB_ID: 10330474 1 O-phospho-L-threonine at 185 (in Homo sapiens) 185 EQUAL O4'-phospho-L-tyrosine at 187 (in Homo sapiens) 187 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 77 10385213 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=10385213 Reactome R-XTR-5674131 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-XTR-5674131.1 Reactome Database ID Release 77 10385215 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=10385215 Reactome R-XTR-5674130 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-XTR-5674130.1 Interaction of MAPK pathway components with LAMTOR2, 3 and MORG1 facilitates pathway activation in response to varied stimuli, resulting in the phosphorylation of MAP2K and MAPK proteins at conserved sites in their activation loops (Schaeffer et al, 1998; Teis et al, 2002; Teis et al, 2006; Vomastek et al, 2004; Sharma et al, 2005; reviewed in Matallanas et al, 2011). inferred by electronic annotation IEA GO IEA IL17RD binds p-2S MAP2Ks and MAPKs IL17RD binds p-2S MAP2Ks and MAPKs 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: 10385229 1 UniProt:F6ZRR0 il17rd UniProt F6ZRR0 17 EQUAL 739 EQUAL Reactome DB_ID: 10385131 1 Reactome DB_ID: 10348109 1 2 EQUAL 360 EQUAL Reactome DB_ID: 10385231 1 IL17RD:p-2S MAP2Ks:MAPKs [Golgi membrane] IL17RD:p-2S MAP2Ks:MAPKs Reactome DB_ID: 10385229 1 17 EQUAL 739 EQUAL Reactome DB_ID: 10385131 1 Reactome DB_ID: 10348109 1 2 EQUAL 360 EQUAL Reactome Database ID Release 77 10385231 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=10385231 Reactome R-XTR-5674360 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-XTR-5674360.1 Reactome Database ID Release 77 10385233 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=10385233 Reactome R-XTR-5674366 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-XTR-5674366.1 IL17RD, also known as SEF (similar expression to FGF), was identified as a negative regulator of nuclear MAPK signaling (Tsang et al, 2002; Furthauer et al, 2002). IL17RD is a spatial regulator of MAPK signaling that binds activated MAP2K dimers at the Golgi membrane and prevents the dissociation and translocation of phosphorylated MAPK into the nucleus. In this way, IL17RD restricts activation of nuclear MAPK targets while not affecting activation of cytosolic ones (Torii et al, 2004; reviewed in Phillips, 2004; Matallanas et al, 2011). 11802164 Pubmed 2002 Identification of Sef, a novel modulator of FGF signalling Tsang, M Friesel, R Kudoh, Tetsuhiro Dawid, Igor B Nat. Cell Biol. 4:165-9 11802165 Pubmed 2002 Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling Fürthauer, Maximilian Lin, Wei Ang, Siew-Lan Thisse, Bernard Thisse, Christine Nat. Cell Biol. 4:170-4 15260967 Pubmed 2004 Sef: a MEK/ERK catcher on the Golgi Philips, Mark R Mol. Cell 15:168-9 15239952 Pubmed 2004 Sef is a spatial regulator for Ras/MAP kinase signaling Torii, S Kusakabe, M Yamamoto, T Maekawa, M Nishida, E Dev Cell 7:33-44 inferred by electronic annotation IEA GO IEA 2.7.12.1 MAP2Ks phosphorylate MAPK at the Golgi membrane MAP2Ks phosphorylate MAPK at the Golgi membrane 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 2 Reactome DB_ID: 10385231 1 Reactome DB_ID: 10385235 1 IL17RD:p-2S MAP2Ks:p-T,Y MAPKs [Golgi membrane] IL17RD:p-2S MAP2Ks:p-T,Y MAPKs Reactome DB_ID: 10385229 1 17 EQUAL 739 EQUAL Reactome DB_ID: 10385131 1 Reactome DB_ID: 10330474 1 O-phospho-L-threonine at 185 (in Homo sapiens) 185 EQUAL O4'-phospho-L-tyrosine at 187 (in Homo sapiens) 187 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 77 10385235 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=10385235 Reactome R-XTR-5674362 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-XTR-5674362.1 Reactome DB_ID: 29370 2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10385231 Reactome Database ID Release 77 10385236 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=10385236 Reactome Database ID Release 77 10385238 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=10385238 Reactome R-XTR-5674373 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-XTR-5674373.1 Activated MAP2Ks in complex with IL17RD phosphorylate MAPKs at the Golgi membrane. IL17RD prevents the dissociation of phosphorylated MAPK from the complex at the Golgi as assessed by coimmunoprecipitation, preventing MAPK nuclear translocation and activation of nuclear targets (Torii et al, 2004; reviewed in Philips, 2004; Brown and Sacks, 2009). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10409870 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=10409870 Reactome R-XTR-5674135 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-XTR-5674135.1 Activated RAF proteins are restricted substrate kinases whose primary downstream targets are the two MAP2K proteins, MAPK2K1 and MAP2K2 (also known as MEK1 and MEK2) (reviewed in Roskoski, 2010, Roskoski, 2012a). Phosphorylation of the MAPK2K activation loop primes them to phosphorylate the primary effector of the activated MAPK pathway, the two MAPK proteins MAPK3 and MAPK1 (also known as ERK1 and 2). Unlike their upstream counterparts, MAPK3 and MAPK1 catalyze the phosphorylation of hundreds of cytoplasmic and nuclear targets including transcription factors and regulatory molecules (reviewed in Roskoski, 2012b). Activation of MAP2K and MAPK proteins downstream of activated RAF generally occurs in the context of a higher order scaffolding complex that regulates the specificity and localization of the pathway (reviewed in Brown and Sacks, 2009; Matallanas et al, 2011). 20674547 Pubmed 2010 RAF protein-serine/threonine kinases: structure and regulation Roskoski, Robert Jr Biochem. Biophys. Res. Commun. 399:313-7 inferred by electronic annotation IEA GO IEA p-T,Y MAPKs dimerize p-T,Y MAPKs dimerize 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: 10330474 2 O-phospho-L-threonine at 185 (in Homo sapiens) 185 EQUAL O4'-phospho-L-tyrosine at 187 (in Homo sapiens) 187 EQUAL 2 EQUAL 360 EQUAL Reactome DB_ID: 10362972 1 p-T185,Y187 MAPK1 dimer [cytosol] p-T185,Y187 MAPK1 dimer Reactome DB_ID: 10330474 2 O-phospho-L-threonine at 185 (in Homo sapiens) 185 EQUAL O4'-phospho-L-tyrosine at 187 (in Homo sapiens) 187 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 77 10362972 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=10362972 Reactome R-XTR-109855 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-XTR-109855.1 Reactome Database ID Release 77 10385240 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=10385240 Reactome R-XTR-5674385 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-XTR-5674385.1 磷酸化MAPK单体可以使二聚,属lly into MAPK1 and MAPK3 homodimers, as the heterodimer is unstable- but the physiological significance of dimerization is unclear (Khokhlatchev et al, 1998; reviewed Rosokoski, 2012b). MAPKs have both cytosolic and nuclear targets and dimerization may be particularly important for MAPK-dependent phosphorylation of cytosolic targets. Phosphorylation of cytosolic MAPK targets appears to happen predominantly in the context of larger scaffolding complexes, and since the scaffolds and cytosolic MAPK substrates contact the same hydrophobic surface of MAPK, dimerization is necessary to allow assembly of a functional complex (Casar et al, 2008; Lidke et al, 2010; reviewed in Casar et al, 2009). Consistent with this, disrupting either MAPK dimerization or the MAPK interaction with the scaffolding protein abrogated proliferation and transformation (Casar et al, 2008). Note that, for simplicity in this diagram, dimerization is shown as happening between free cytosolic monomers of activated MAPK rather than in the context of the scaffolding complex.
Although predominantly cytoplasmic in resting cells, a proportion of activated MAPK translocates to the nucleus upon stimulation where it activates nuclear targets. Despite early studies to the suggesting that dimerization was required for nuclear translocation, a few recent papers have challenged this notion (Lenormand et al, 1993; Chen et al, 1992; Khokhlatchev et al, 1998; Casar et al, 2008; Lidke et al, 2010; Burack and Shaw, 2005; reviewed in Roskoski, 2012b). 9604935 Pubmed 1998 Phosphorylation of the MAP kinase ERK2 promotes its homodimerization and nuclear translocation Khokhlatchev, AV Canagarajah, B Wilsbacher, J Robinson, M Atkinson, M Goldsmith, E Cobb, MH Cell 93:605-15 19920141 Pubmed 2010 ERK nuclear translocation is dimerization-independent but controlled by the rate of phosphorylation Lidke, Diane S Huang, Fang Post, Janine N Rieger, Bernd Wilsbacher, Julie Thomas, JL Pouysségur, Jacques Jovin, Thomas M Lenormand, Philippe J. Biol. Chem. 285:3092-102 8394845 Pubmed 1993 Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts Lenormand, Phillipe Sardet, Claude 页,胃肠道lles L'Allemain, Gilles Brunet, Anne Pouysségur, Jacques J. Cell Biol. 122:1079-88 1545823 Pubmed 1992 Nuclear localization and regulation of erk- and rsk-encoded protein kinases Chen, Rey-Huei Sarnecki, Charlyn Blenis,John Mol. Cell. Biol. 12:915-27 15546878 Pubmed 2005 Live Cell Imaging of ERK and MEK: simple binding equilibrium explains the regulated nucleocytoplasmic distribution of ERK Burack, W Richard Shaw, Andrey S J. Biol. Chem. 280:3832-7 18775330 Pubmed 2008 ERK活化的二聚体的重要作用cytoplasmic but not nuclear substrates by ERK-scaffold complexes Casar, Berta Pinto, Adán Crespo, Piero Mol. Cell 31:708-21 inferred by electronic annotation IEA GO IEA Phosphorylated MAPKs translocate into the nucleus Phosphorylated MAPKs translocate into the nucleus 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: 10385242 1 Reactome DB_ID: 10385248 1 1 EQUAL 130 EQUAL Reactome DB_ID: 10385250 1 Reactome Database ID Release 77 10385273 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=10385273 Reactome R-XTR-5675206 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-XTR-5675206.1 PEA15 is a cytoplasmic anchor that binds directly to activated MAPKs prevents their translocation into the nucleus (Formstecher et al, 2001; Whitehurst et al, 2004; Hill et al, 2002; Chou et al, 2003). PEA15 also protects phosphorylated MAPKs in the cytoplasm from inactivating dephosphorylation (Mace et al, 2013). In this way, binding of PEA15 promotes phosphorylation of cytoplasmic MAPK targets at the expense of nuclear ones. 14506247 Pubmed 2003 PEA-15 binding to ERK1/2 MAPKs is required for its modulation of integrin activation Chou, Fan-Li Hill, Justine M Hsieh, Jyh-Cheng Pouysségur, Jacques Brunet, Anne Glading, Angela Uberall, Florian Ramos, Joe W Werner, Milton H Ginsberg, Mark H J. Biol. Chem. 278:52587-97 14707138 Pubmed 2004 The death effector domain protein PEA-15 prevents nuclear entry of ERK2 by inhibiting required interactions Whitehurst, Angelique W Robinson, Fred L Moore, Mary Shannon Cobb, Melanie H J. Biol. Chem. 279:12840-7 23575685 Pubmed 2013 ERK2结构绑定到PEA-15揭示了一个探讨ism for rapid release of activated MAPK Mace, Peter D Wallez, Yann Egger, Michael F Dobaczewska, Ma?gorzata K Robinson, H Pasquale, Elena B Riedl, Stefan J Nat Commun 4:1681 11702783 Pubmed 2001 PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase Formstecher, Etienne Ramos, Joe W Fauquet, Mireille Calderwood, David A Hsieh, Jyh-Cheng Canton, Brigitte Nguyen, Xuan-Thao Barnier, Jean-Vianney Camonis, J Ginsberg, Mark H Chneiweiss, Herve Dev. Cell 1:239-50 inferred by electronic annotation IEA GO IEA Negative regulation of MAPK pathway Negative regulation of MAPK pathway 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 PAQR3 binds inactive RAFs PAQR3 binds inactive RAFs 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: 10384987 1 Reactome DB_ID: 10385221 1 UniProt:F6XNG4 paqr3 UniProt F6XNG4 1 EQUAL 311 EQUAL Reactome DB_ID: 10385223 1 PAQR3:inactive RAFs [Golgi membrane] PAQR3:inactive RAFs Converted from EntitySet in Reactome Reactome DB_ID: 10384987 1 Reactome DB_ID: 10385221 1 1 EQUAL 311 EQUAL Reactome Database ID Release 77 10385223 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=10385223 Reactome R-XTR-5674139 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-XTR-5674139.1 Reactome Database ID Release 77 10385225 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=10385225 Reactome R-XTR-5674140 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-XTR-5674140.1 PAQR3, also known as RKTG (Raf kinase trapping to Golgi) is a multi-pass transmembrane protein that binds to RAF1 and BRAF and sequesters them in the Golgi. This inhibits the interaction of RAF with activated RAS and the plasma membrane and inhibits RAF signaling (Feng et al, 2007; Fan et al, 2008; Luo et al, 2008). 18515281 Pubmed 2008 RKTG sequesters B-Raf to the Golgi apparatus and inhibits the proliferation and tumorigenicity of human malignant melanoma cells Fan, Fengjuan Feng, Lin He, Jing Wang, Xiao Jiang, Xiaomeng Zhang, Yixuan Wang, Zhenzhen Chen, Yan Carcinogenesis 29:1157-63 17724343 Pubmed 2007 Spatial regulation of Raf kinase signaling by RKTG Feng, Lin Xie, Xiaoduo Ding, Qiurong Luo, Xiaolin He, Jing Fan, Fengjuan Liu, Weizhong Wang, Zhenzhen Chen, Yan Proc. Natl. Acad. Sci. U.S.A. 104:14348-53 18547165 Pubmed 2008 Characterization of the topology and functional domains of RKTG Luo, Xiaolin Feng, Lin Jiang, Xiaomeng Xiao, Fei Wang, Zhenzhen Feng, Gen-Sheng Chen, Yan Biochem. J. 414:399-406 inferred by electronic annotation IEA GO IEA Negative feedback regulation of MAPK pathway Negative feedback regulation of MAPK pathway 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 2.7.11 Activated MAPK phosphorylates RAF1 Activated MAPK phosphorylates RAF1 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 6 Reactome DB_ID: 10385117 1 O-phospho-L-serine at 621 (in Homo sapiens) 621 EQUAL O4'-phospho-L-tyrosine at 341 (in Homo sapiens) 341 EQUAL O-phospho-L-serine at 338 (in Homo sapiens) 338 EQUAL O-phospho-L-threonine at 491 (in Homo sapiens) 491 EQUAL O-phospho-L-serine at 494 (in Homo sapiens) 494 EQUAL 1 EQUAL 648 EQUAL Reactome DB_ID: 29370 6 Reactome DB_ID: 10385260 1 O-phospho-L-serine at 621 (in Homo sapiens) 621 EQUAL O4'-phospho-L-tyrosine at 341 (in Homo sapiens) 341 EQUAL O-phospho-L-serine at 338 (in Homo sapiens) 338 EQUAL O-phospho-L-threonine at 491 (in Homo sapiens) 491 EQUAL O-phospho-L-serine at 494 (in Homo sapiens) 494 EQUAL O-phospho-L-serine at 29 (in Homo sapiens) 29 EQUAL O-phospho-L-serine at 43 (in Homo sapiens) 43 EQUAL O-phospho-L-serine 259(智人) 259 EQUAL O-phospho-L-serine at 296 (in Homo sapiens) 296 EQUAL O-phospho-L-serine at 301 (in Homo sapiens) 301 EQUAL O-phospho-L-serine at 642 (in Homo sapiens) 642 EQUAL 1 EQUAL 648 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10385242 Reactome Database ID Release 77 10385261 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=10385261 Reactome Database ID Release 77 10385263 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=10385263 Reactome R-XTR-5675194 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-XTR-5675194.1 RAF1 is phosphorylated by activated MAPK at 6 serine residues (S29, S43, S289, S296, S301 and S642). MAPK-dependent hyperphosphorylation of RAF1 abrogates the ability of activated RAF1 to interact with RAS and is coincident with inactivation of RAF1. RAF1 proteins containing mutation of these phosphorylation sites persist at the plasma membrane, show sustained S338 phosphorylation and persistent activation relative to WT RAF1 protein. In wild type cells, PP2A and the prolyl-isomerase PIN1 contribute to the dephosphorylation of hyperphosphorylated RAF1, allowing subsequent cycles of activation to occur (Dougherty et al, 2005; reviewed in Roskoski, 2010) 15664191 Pubmed 2005 Regulation of Raf-1 by direct feedback phosphorylation Dougherty, Michele K Müller, Jürgen Ritt, Daniel A Zhou, Ming Zhou, Xiao Zhen Copeland, Terry D Conrads, Thomas P Veenstra, TD Lu, Kun Ping Morrison, Deborah K Mol. Cell 17:215-24 inferred by electronic annotation IEA GO IEA 2.7.11 Activated MAPKs phosphorylate BRAF Activated MAPKs phosphorylate BRAF 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: 10385119 1 UniProt:A0A6I8QZC5 braf O-phospho-L-serine at 445 (in Homo sapiens) 445 EQUAL O-phospho-L-serine at 729 (in Homo sapiens) 729 EQUAL O-phospho-L-threonine at 599 (in Homo sapiens) 599 EQUAL O-phospho-L-serine at 602 (in Homo sapiens) 602 EQUAL 2 EQUAL 766 EQUAL Reactome DB_ID: 113592 4 Reactome DB_ID: 10385269 1 O-phospho-L-serine at 445 (in Homo sapiens) 445 EQUAL O-phospho-L-serine at 729 (in Homo sapiens) 729 EQUAL O-phospho-L-threonine at 599 (in Homo sapiens) 599 EQUAL O-phospho-L-serine at 602 (in Homo sapiens) 602 EQUAL O-phospho-L-serine at 151 (in Homo sapiens) 151 EQUAL O-phospho-L-serine at 750 (in Homo sapiens) 750 EQUAL O-phospho-L-serine at 753 (in Homo sapiens) 753 EQUAL O-phospho-L-threonine at 401 (in Homo sapiens) 401 EQUAL 2 EQUAL 766 EQUAL Reactome DB_ID: 29370 4 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10385242 Reactome Database ID Release 77 10385271 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=10385271 Reactome R-XTR-5675198 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-XTR-5675198.1 BRAF is subject to MAPK-dependent phosphorylation that limits its activity. Phosphorylation of S151 inhibits binding of BRAF to activated RAS, while phosphorylation of T401, S750 and S753 abrogates heterodimerization with RAF1 (Ritt et al, 2010; Rushworth et al, 2006; Brummer et al, 2003). 19933846 Pubmed 2010 Impact of feedback phosphorylation and Raf heterodimerization on normal and mutant B-Raf signaling Ritt, Daniel A Monson, Daniel M Specht, Suzanne I Morrison, Deborah K Mol. Cell. Biol. 30:806-19 14654779 Pubmed 2003 Identification of novel ERK-mediated feedback phosphorylation sites at the C-terminus of B-Raf Brummer, Tilman Naegele, Heike Reth, Michael Misawa, Yukiko Oncogene 22:8823-34 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10409874 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=10409874 Reactome R-XTR-5674499 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-XTR-5674499.1 MAPK pathway activation is limited by a number of negative feedback loops established by MAPK-dependent phosphorylations. Known substrates of activated MAPK proteins that lie upstream in the RAF/MAPK pathway include SOS, RAF1, BRAF, and MAP2K1 (Buday et al, 1995; Dong et al, 1996; Dougherty et al, 2005; Sturm et al, 2010; Fritsche-Guenther et al, 2011; Rushworth et al, 2006; Brummer et al, 2003; Ritt et al, 2010; Catalanotti et al, 2009) 21177493 Pubmed 2010 The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier Sturm, Oliver E Orton, Richard Grindlay, Joan Birtwistle, Marc Vyshemirsky, Vladislav Gilbert, David Calder, Muffy Pitt, Andrew Kholodenko, Boris Kolch, Walter Sci Signal 3:ra90 21613978 Pubmed 2011 Strong negative feedback from Erk to Raf confers robustness to MAPK signalling Fritsche-Guenther, Raphaela Witzel, Franziska Sieber, Anja Herr, Ricarda Schmidt, Nadine Braun, Sandra Brummer, Tilman Sers, Christine Blüthgen, Nils Mol. Syst. Biol. 7:489 8626428 Pubmed 1996 SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways Dong Chen, D C 水域,史蒂文B Holt, Kathleen H Pessin, JE J. Biol. Chem. 271:6328-32 7478553 Pubmed 1995 Downregulation of the Ras activation pathway by MAP kinase phosphorylation of Sos Buday, L Warne, P H Downward, J Oncogene 11:1327-31 inferred by electronic annotation IEA GO IEA PEBP1 binds activated RAF1 PEBP1 binds activated RAF1 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: 10385156 1 Reactome DB_ID: 10385160 1 2 EQUAL 187 EQUAL Reactome DB_ID: 10385162 1 Reactome Database ID Release 77 10385296 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=10385296 Reactome R-XTR-5675417 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-XTR-5675417.1 PEBP1, also known as RKIP (Raf kinase inhibitor protein), is a negative regulator of RAF1 that binds to the phosphorylated NtA region and prevents activation of MAP2K substrates (Yeung et al, 1999; Yeung et al, 2000; Rath et al, 2008; Park et al, 2006; reviewed in Lorenz et al, 2014). Relief of this PEBP1 repression of RAF1 activity is stimulated by phosphorylation of PEBP1, which promotes it dissociation from RAF1. Candidate kinases for phosphorylation of PEBP1 include PKC and the MAPKs themselves, which would establish a positive feedback loop stimulating MAPK pathway activity (Corbit et al, 2003; Cho et al, 2003; Shin et al, 2009). 10490027 Pubmed 1999 Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP Yeung, K Seitz, T Li, S Janosch, P McFerran, B Kaiser, C Fee, F Katsanakis, KD Rose, DW Mischak, H Sedivy, JM Kolch, W Nature 401:173-7 25597358 Pubmed 2014 RKIP: a governor of intracellular signaling Lorenz, Kristina Schmid, Evelyn Deiss, Katharina Crit Rev Oncog 19:489-96 10757792 Pubmed 2000 Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein Yeung, Kam Janosch, Petra McFerran, Brian Rose, David W Mischak, H Sedivy, John M Kolch, Walter Mol. Cell. Biol. 20:3079-85 inferred by electronic annotation IEA GO IEA 3.1.3.16 PP5 dephosphorylates RAF1 S338 PP5 dephosphorylates RAF1 S338 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: 10385156 1 Reactome DB_ID: 29356 1 Reactome DB_ID: 10385300 1 p21RAS:三磷酸鸟苷:脱去磷酸RAF1 homo /异质二聚体[plasma membrane] p21RAS:三磷酸鸟苷:脱去磷酸RAF1 homo /异质二聚体 Converted from EntitySet in Reactome Reactome DB_ID: 10384968 1 Reactome DB_ID: 10333960 1 Reactome DB_ID: 10385298 1 O-phospho-L-serine at 621 (in Homo sapiens) 621 EQUAL O4'-phospho-L-tyrosine at 341 (in Homo sapiens) 341 EQUAL O-phospho-L-threonine at 491 (in Homo sapiens) 491 EQUAL O-phospho-L-serine at 494 (in Homo sapiens) 494 EQUAL 1 EQUAL 648 EQUAL Reactome DB_ID: 10328522 1 Reactome Database ID Release 77 10385300 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=10385300 Reactome R-XTR-5675430 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-XTR-5675430.1 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 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10385308 UniProt:A0A6I8R3J3 ppp5c UniProt A0A6I8R3J3 2 EQUAL 499 EQUAL GO 0004722 GO molecular function Reactome Database ID Release 77 10385309 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=10385309 Reactome Database ID Release 77 10385311 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=10385311 Reactome R-XTR-5675433 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-XTR-5675433.1 PPP5C dephosphorylates S338 in the NtA region of RAF1, which reduces the catalytic activity of RAF1 towards MAP2K proteins (von Kriegsheim et al, 2006; reviewed in Matallanas et al, 2011). 16892053 Pubmed 2006 Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5 von Kriegsheim, Alex Pitt, Andrew Grindlay, G Joan Kolch, Walter Dhillon, Amardeep S Nat. Cell Biol. 8:1011-6 inferred by electronic annotation IEA GO IEA 3.1.3 Cytosolic DUSPs dephosphorylate MAPKs Cytosolic DUSPs dephosphorylate MAPKs 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: 10385242 1 Reactome DB_ID: 29356 1 Converted from EntitySet in Reactome Reactome DB_ID: 10385279 1 MAPK monomers and dimers [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity mapk1 [cytosol] Reactome DB_ID: 29372 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 10385291 cytosolic MAPK DUSPs [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity dusp9 [cytosol] dusp6 [cytosol] UniProt F7EIM1 UniProt Q28E94 GO 0008138 GO molecular function Reactome Database ID Release 77 10385292 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=10385292 Reactome Database ID Release 77 10385294 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=10385294 Reactome r -额外的5675376 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-XTR-5675376.1 MAPKs are inactivated by dephosphorylation of the activation loop T and Y residues by dual-specificity MAPK phosphatases (DUSPs) (reviewed in Roskoski, 2012b). Cytosolic MAPKs are dephosphorylated by the MAPK-specific class II DUSPs 6,7 and 9, but may also be dephosphorylated by cytosolic forms of class III DUSPs 8, 10 and 16, which preferentially dephosphorylate p38 and JNK MAP kinases (reviewed in Bermudez et al, 2010; Kandoh and Nishida, 2007). 20463170 Pubmed 2010 The dual-specificity MAP kinase phosphatases: critical roles in development and cancer Bermudez, O Pagès, G Gimond, C Am. J. Physiol., Cell Physiol. 299:C189-202 17208316 Pubmed 2007 Regulation of MAP kinases by MAP kinase phosphatases Kondoh, Kunio Nishida, E Biochim. Biophys. Acta 1773:1227-37 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10409872 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=10409872 Reactome R-XTR-5675221 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-XTR-5675221.1 The duration and extent of activated MAPK signaling is regulated at many levels through mechanisms that include phosphorylation and dephosphorylation, changes to protein interacting partners and subcellular localization (reviewed in Matallanas et al, 2011).

Activated RAF proteins are subject to MAPK-dependent phosphorylation that promotes the subsequent dephosphorylation of the activation loop and NtA region, terminating RAF kinase activity. This dephosphorylation, catalyzed by PP2A and PP5, primes the RAF proteins for PKA or AKT-mediated phosphorylation of residues S259 and S621, restoring the 14-3-3 binding sites and returning the RAF proteins to the inactive state (von Kriegsheim et al, 2006; Dougherty et al, 2005; reviewed in Matallanas et al, 2011). The phosphorylated RAF1 NtA is also subject to additional regulation through binding to the PEBP1 protein, which promotes its dissociation from MAP2K substrates (Shin et al, 2009).

Activated MAPK proteins also phosphorylate T292 of MAP2K1; this phosphorylation limits the activity of MAP2K1, and indirectly affects MAP2K2 activity through by modulating the activity of the MAP2K heterodimer (Catalanotti et al, 2009; reviewed in Matallanas et al, 2011).

Dephosphorylation of MAPKs by the dual specificity MAPK phosphatases (DUSPs) plays a key role in limiting the extent of pathway activation (Owens et al, 2007; reviewed in Roskoski, 2012b). Class I DUSPs are localized in the nucleus and are induced by activation of the MAPK pathway, establishing a negative feedback loop, while class II DUSPs dephosphorylate cytoplasmic MAPKs (reviewed in Rososki, 2012b).
MAPK signaling is also regulated by the RAS GAP-mediated stimulation of intrinsic RAS GTPase activity which returns RAS to the inactive, GDP bound state (reviewed in King et al, 2013). 17496916 Pubmed 2007 Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases Owens, D M Keyse, S M Oncogene 26:3203-13 inferred by electronic annotation IEA GO IEA Regulation of RAS by GAPs Regulation of RAS by GAPs 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 RAS GAPs bind RAS:GTP RAS GAPs bind RAS:GTP 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: 10384311 1 Converted from EntitySet in Reactome Reactome DB_ID: 10384309 1 Reactome DB_ID: 10334974 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10384311 Reactome Database ID Release 77 10384312 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=10384312 Reactome Database ID Release 77 10384314 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=10384314 Reactome R-XTR-5658231 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-XTR-5658231.1 The intrinsic GTPase activity of RAS proteins is stimulated by the GAP proteins, of which there are at least 10 in the human genome (reviewed in King et al, 2013). inferred by electronic annotation IEA GO IEA SPRED dimer binds NF1 SPRED dimer binds NF1 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: 10325172 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity mrpl3 [cytosol] ubc [cytosol] UniProt Q28I48 UniProt A0A6I8RD22 Reactome DB_ID: 10384307 1 Reactome DB_ID: 10384319 1 SPRED dimer:ub-NF1 [plasma membrane] SPRED dimer:ub-NF1 Converted from EntitySet in Reactome Reactome DB_ID: 10384301 1 Reactome DB_ID: 10384317 1 ubiquitinylated lysine at unknown position 2 EQUAL 2839 EQUAL Reactome Database ID Release 77 10384319 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=10384319 Reactome R-XTR-5658420 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-XTR-5658420.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 10384321 KBTBD7:CUL3:RBX1 [cytosol] KBTBD7:CUL3:RBX1 Reactome DB_ID: 10358232 1 UniProt:F6TU96 kbtbd7 UniProt F6TU96 1 EQUAL 684 EQUAL Reactome DB_ID: 10357938 1 UniProt:A0A6I8S0I4 rbx1 UniProt A0A6I8S0I4 2 EQUAL 108 EQUAL Reactome DB_ID: 10358264 1 UniProt:A4IHP4 cul3 UniProt A4IHP4 1 EQUAL 768 EQUAL Reactome Database ID Release 77 10384321 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=10384321 Reactome R-XTR-5658416 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-XTR-5658416.1 GO 0061630 GO molecular function Reactome Database ID Release 77 10384322 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=10384322 Reactome Database ID Release 77 10384324 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=10384324 Reactome R-XTR-5658424 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-XTR-5658424.1 NF1水平由蛋白酶体degradati控制on in response to stimulation by some growth factors (Cichowski et al, 2003). Ubiquitination is mediated by the CUL3:RBX1 RING E3 ligase complex in conjunction with the BTB adaptor protein KBTBD7 (Hollstein et al, 2013). After its initial rapid degradation, NF1 protein levels are re-established shortly after growth factor treatment, allowing appropriate termination of RAS MAPK signaling (Cichowski et al, 2003). Aberrant destabilization of NF1 by CUL3:KBTBD7-mediated proteasomal degradation has been identified in cases of glioblastoma and depends on activation of PKC alpha (Cichowski et al, 2003; McGillicuddy et al, 2009; Hollstein et al, 2013). 19573811 Pubmed 2009 Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis McGillicuddy, Lauren T Fromm, Jody A Hollstein, Pablo E Kubek, Sara Beroukhim, R De Raedt, Thomas Johnson, Bryan W Williams, Sybil M G Nghiemphu, P Liau, LM Cloughesy, Tim F Mischel, Paul S Parret, Annabel Seiler, Jeanette Moldenhauer, Gerd Scheffzek, Klaus Stemmer-Rachamimov, Anat O Sawyers, Charles L Brennan, Cameron Messiaen, Ludwine Mellinghoff, Ingo K Cichowski, Karen 癌细胞16:44-54 12600938 Pubmed 2003 Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor suppressor Cichowski, Karen Santiago, Sabrina Jardim, Melanie Johnson, Bryan W Jacks, Tyler Genes Dev. 17:449-54 23661552 Pubmed 2013 Identifying the Ubiquitin Ligase complex that regulates the NF1 tumor suppressor and Ras Hollstein, Pablo E Cichowski, Karen Cancer Discov 3:880-93 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10409852 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=10409852 Reactome R-XTR-5658442 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-XTR-5658442.1 The intrinsic GTPase activity of RAS proteins is stimulated by the GAP proteins, of which there are at least 10 in the human genome (reviewed in King et al, 2013). inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10409854 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=10409854 Reactome R-XTR-5673001 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-XTR-5673001.1 GO 0000165 GO biological process 苏RAS-RAF-MEK-ERK通路调节过程ch as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011). 17496923 Pubmed 2007 Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer Roberts, P J Der, Channing J Oncogene 26:3291-310 22535895 Pubmed 2012 Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update Kyriakis, John M Avruch, Joseph Physiol. Rev. 92:689-737 21388974 Pubmed 2011 BRAFV600E: implications for carcinogenesis and molecular therapy Cantwell-Dorris, Emma R O'Leary, John J Sheils, Orla M Mol. Cancer Ther. 10:385-94 17496910 Pubmed 2007 Integrating signals from RTKs to ERK/MAPK McKay, MM Morrison, Deborah K Oncogene 26:3113-21 21167873 Pubmed 2011 The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation Plotnikov, Alexander Zehorai, Eldar Procaccia, Shiri Seger, Rony Biochim. Biophys. Acta 1813:1619-33 17496919 Pubmed 2007 MAP kinases and the control of nuclear events Turjanski, A G Vaqué, J P Gutkind, J S Oncogene 26:3240-53 inferred by electronic annotation IEA GO IEA RAF-independent MAPK1/3 activation RAF-independent MAPK1/3 activation 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 MAPK3 (ERK1) activation MAPK3 (ERK1) activation 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 2.7.11 Inactivation of MAP2K1 by CDK1 Inactivation of MAP2K1 by CDK1 This event has been computationally inferred from an event that has been demonstrated in another species.

In response to stimuli the cell surface receptors transmit signals inducing MAP3 kinases, e.g., TPL2, MEKK1, which in turn phosphorylate MAP2Ks (MEK1/2). MAP2K then phosphorylate and activate the MAPK1/3 (ERK1 and ERK2 MAPKs). Activated MAPK1/3 phosphorylate and regulate the activities of an ever growing pool of substrates that are estimated to comprise over 160 proteins (Yoon and Seger 2006). The majority of ERK substrates are nuclear proteins, but others are found in the cytoplasm and other organelles. Activated MAPK1/3 can translocate to the nucleus, where they phosphorylate and regulate various transcription factors, such as Ets family transcription factors (e.g., ELK1), ultimately leading to changes in gene expression (Zuber J et al. 2000). 17112607 Pubmed 2007 The MEK/ERK cascade: from signaling specificity to diverse functions Shaul, Yoav D Seger, Rony Biochim. Biophys. Acta 1773:1213-26 25378393 Pubmed 2014 Tumor progression locus 2-dependent oxidative burst drives phosphorylation of extracellular signal-regulated kinase during TLR3 and 9 signaling Kuriakose, Teneema Rada, Balazs Watford, Wendy T J. Biol. Chem. 289:36089-100 16393692 Pubmed 2006 The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions Yoon, S Seger, R Growth Factors 24:21-44 16377629 Pubmed 2006 HER-2/neu represses the metastasis suppressor RECK via ERK and Sp transcription factors to promote cell invasion Hsu, Ming-Chuan Chang, Hui-Chiu Hung, Wen-Chun J. Biol. Chem. 281:4718-25 23954936 Pubmed 2013 Mitogen-activated protein kinases in innate immunity Arthur, J Simon C Ley, Steven C Nat. Rev. Immunol. 13:679-92 21135874 Pubmed 2011 Regulation and function of TPL-2, an I?B kinase-regulated MAP kinase kinase kinase Gantke, Thorsten Sriskantharajah, Srividya Ley, Steven C Cell Res. 21:131-45 15659800 Pubmed 2004 Regulation of tumor cell motility by ERK mitogen-activated protein kinases Viala, Emmanuel Pouysségur, Jacques Ann. N. Y. Acad. Sci. 1030:208-18 10655059 Pubmed 2000 A genome-wide survey of RAS transformation targets Zuber, J Tchernitsa, O I Hinzmann, B Schmitz, A C Grips, M Hellriegel, M Sers, C Rosenthal, A Schäfer, R Nat. Genet. 24:144-52 19520853 Pubmed 2009 A non-canonical MEK/ERK signaling pathway regulates autophagy via regulating Beclin 1 Wang, Jianrong Whiteman, Mary W Lian, Huiqin Wang, Guangxin Singh, Amit Huang, Dongyang Denmark, Ted J. Biol. Chem. 284:21412-24 18199641 Pubmed 2008 Epstein-Barr virus-encoded LMP1 regulates epithelial cell motility and invasion via the ERK-MAPK pathway Dawson, Christopher W Laverick, Louise Morris, Mhairi A Tramoutanis, Giorgos Young, Lawrence S J. Virol. 82:3654-64 inferred by electronic annotation IEA GO IEA Reactome Database ID Release 77 10407876 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=10407876 Reactome R-XTR-5684996 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-XTR-5684996.1 The extracellular signal regulated kinases (ERKs) 1 and 2, also known as MAPK3 and MAPK1, are phosphorylated by the MAP2Ks 1 and 2 in response to a wide range of extracellular stimuli to promote differentiation, proliferation, cell motility, cell survivial, metabolism and transcription, among others (reviewed in Roskoski, 2012b; McKay and Morrison, 2007; Raman et al, 2007). In the classical pathway, MAPK1/3 activation is triggered by the GEF-mediated activation of RAS at the plasma membrane, leading to the activation of the RAF MAP3Ks (reviewed in McKay and Morrison, 2007; Matallanas et al, 2011; Wellbrock et al, 2004). However, many physiological and pathological stimuli have been found to activate MAPK1/3 independently of RAF and RAS, acting instead through MAP3Ks such as MOS, TPL2 and AMPK (Dawson et al, 2008; Wang et al, 2009; Kuriakose et al, 2014; Awane et al, 1999). Activated MAPK1/3 phosphorylate numerous targets in both the nucleus and cytoplasm (reviewed in Yoon and Seger, 2006; Roskoski 2012b). 10228009 Pubmed 1999 NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells Awane, M Andres, P G Li, D J Reinecker, H C J. Immunol. 162:5337-44 17496909 Pubmed 2007 Differential regulation and properties of MAPKs Raman, M Chen, W Cobb, MH Oncogene 26:3100-12 inferred by electronic annotation IEA GO IEA