BioPAX pathway converted from "Signaling by MST1" in the Reactome database. Signaling by MST1 Inflammatory mediators such as growth factors produced by macrophages play an important role in the inflammatory response occurring during bacterial infection, tissue injury and immune responses. Many growth factors and their receptor-type protein tyrosine kinases (RTKs) play a critical role in inflammation, wound healing and tissue remodelling. The growth factor hepatocyte growth factor-like protein (MST1, also known as macrophage-stimulating protein, MSP) binds to a specific receptor, macrophage-stimulating protein receptor (MST1R, also known as RON, recepteur d'origine nantais). MST1 belongs to the kringle protein family, which includes HGF and plasminogen. It is produced by the liver and circulates in the blood as a biologically-inactive single chain precursor (pro-MST1). Proteolytic cleavage of pro-MST1 into the biologically-active MST1 dimer is necessary for receptor binding. Cleavage occurs during blood coagulation and at inflammatory sites, the resultant MST1 dimer then binds MST1R receptors on local macrophages. MST1R is ubiquitously expressed but mainly in epithelial cells.<br><br>MST1 binding to MST1R promotes receptor homodimerisation which in turn allows autophosphorylation of two tyrosine residues within the catalytic site which regulates kinase activity and allows phosphorylation of the carboxy-terminal binding site of the receptor. The docking site is essential for downstream signaling through direct and indirect binding of SH2 domain-containing adaptor proteins such as GRB2, PI3K, and SRC. MST1/MST1R signaling plays a dual role in regulating inflammation; initially stimulating chemotaxis and phagocytosis (macrophage activation) and then exerts broad inhibitory effects on macrophages, limiting the extent of inflammtory responses (Wang et al. 2002). MST1R is upregulated in many epithelial cancers where it is thought to play a role in the progression of these types of cancer (Kretschmann et al. 2010). Authored: Jassal, Bijay, 2016-01-18 Reviewed: D'Eustachio, Peter, 2016-01-11 Edited: Jassal, Bijay, 2016-01-18 LEFT-TO-RIGHT 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 HPN heterodimer cleaves pro-MST1 to form MST1 dimer Hepsin (HPN, aka TMPRSS1) is a cell surface-expressed chymotrypsin-like serine protease and a member of the family of type II transmembrane serine proteases (TTSP). The HPN zymogen is activated autocatalytically by cleavage at Arg162–Ile163, forming a heterodimeric enzyme (Tsuji et al. 1991, Torres-Rosado et al. 1993). HPN plays an essential role in cell growth and maintenance of cell morphology and is highly upregulated in prostate cancer and promotes tumor progression and metastasis. Located on the cell surface, HPN can activate fibrinolytic enzymes, matrix metalloproteases and latent forms of growth factors such as hepatocyte growth factor-like protein (MST1, aka macrophage stimulatory protein, MSP). MST1 is a plasminogen-related growth factor and ligand for the receptor tyrosine kinase (MST1R, RON). The MST1/MST1R (MSP/RON) signaling system promotes wound healing and invasive tumor growth and suppresses proinflammatory immune response. For MST1 to bind MST1R, the inactive single-chain form (pro-MST1) must be cleaved into the disulfide-linked alpha-beta heterodimer by HPN (Ganesan et al. 2011). The Kunitz-type protease inhibitors 1 and 2 (SPINT1 and 2, aka HAI1 and 2) are inhibitors of HPN activity (Kirchhofer et al. 2005).<br><br>The non-synonymous coding variant in MST1 (R689C) has been associated with genetic susceptibility to both Crohn's disease and ulcerative colitis, two major types of inflammatory bowel disease (IBD). The R689C variant reduces the amount of circulating MST1 thereby reducing MST1R activity and down-regulation of the MST1/MST1R signaling pathway (McGovern et al. 2010, Gorlatova et al. 2011, Kauder et al. 2013). Authored: Jassal, Bijay, 2015-09-28 Reviewed: D'Eustachio, Peter, 2016-01-11 Edited: Jassal, Bijay, 2015-09-28 H2O water Reactome DB_ID: 109276 extracellular region GENE ONTOLOGY GO:0005576 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 78 109276 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109276 Reactome R-ALL-109276 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-109276.4 Reactome http://www.reactome.org COMPOUND C00001 additional information MI MI:0361 pro-MST1 MST1(19-711) Hepatocyte growth factor-like protein HGFL_HUMAN Reactome DB_ID: 6800227 UniProt:P26927 MST1 MST1 D3F15S2 DNF15S2 HGFL SUBUNIT Dimer of an alpha chain and a beta chain linked by a disulfide bond. Interacts (via beta chain) with MST1R (via SEMA domain).PTM Cleaved after Arg-483, probably by HPN/Hepsin, to yield the active form consisting of two disulfide-linked chains.DISEASE MST1 variant Cys-689 may be associated with inflammatory bowel disease (IBD), a chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is unsure whether Cys-689 itself or a variation in linkage disequilibrium with Cys-689 is responsible for the association with IBD.SIMILARITY Belongs to the peptidase S1 family. Plasminogen subfamily.CAUTION Although related to peptidase S1 family, the active site residues characteristic of serine proteases appear to be absent from this protein, which may therefore lack protease activity. Homo sapiens NCBI Taxonomy 9606 UniProt P26927 19 EQUAL 711 EQUAL Reactome Database ID Release 78 6800227 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800227 Reactome R-HSA-6800227 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800227.1 MST1 dimer Reactome DB_ID: 6800213 HGFL_HUMAN MST1(19-483) MST1 alpha chain Hepatocyte growth factor-like protein Reactome DB_ID: 6800207 19 EQUAL 483 EQUAL Reactome Database ID Release 78 6800207 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800207 Reactome R-HSA-6800207 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800207.1 1 HGFL_HUMAN MST1(484-711) MST1 beta chain Hepatocyte growth factor-like protein Reactome DB_ID: 6800230 484 EQUAL 711 EQUAL Reactome Database ID Release 78 6800230 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800230 Reactome R-HSA-6800230 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800230.1 1 Reactome Database ID Release 78 6800213 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800213 Reactome R-HSA-6800213 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800213.1 ACTIVATION HPN heterodimer HPN(1-162):HPN(163-417) Reactome DB_ID: 8849220 plasma membrane GENE ONTOLOGY GO:0005886 HPN(1-162) Serine protease hepsin ecNumber3.4.21.106/ecNumber HEPS_HUMAN Serine protease hepsin non-catalytic chain Reactome DB_ID: 6800195 UniProt:P05981 HPN HPN TMPRSS1 FUNCTION Serine protease that cleaves extracellular substrates, and contributes to the proteolytic processing of growth factors, such as HGF and MST1/HGFL (PubMed:21875933, PubMed:15839837). Plays a role in cell growth and maintenance of cell morphology (PubMed:8346233, PubMed:21875933). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Mediates the proteolytic cleavage of urinary UMOD that is required for UMOD polymerization (PubMed:26673890).TISSUE SPECIFICITY Detected in liver and kidney.SIMILARITY Belongs to the peptidase S1 family. UniProt P05981 1 EQUAL 162 EQUAL Reactome Database ID Release 78 6800195 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800195 Reactome R-HSA-6800195 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800195.1 1 HEPS_HUMAN HPN(163-417) Serine protease hepsin ecNumber3.4.21.106/ecNumber Serine protease hepsin catalytic chain Reactome DB_ID: 8849219 163 EQUAL 417 EQUAL Reactome Database ID Release 78 8849219 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849219 Reactome R-HSA-8849219 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849219.1 1 Reactome Database ID Release 78 8849220 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8849220 Reactome R-HSA-8849220 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8849220.1 GENE ONTOLOGY GO:0004252 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 6800204 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800204 Reactome Database ID Release 78 6800198 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800198 Reactome R-HSA-6800198 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800198.2 8346233 Pubmed 1993 Hepsin, a putative cell-surface serine protease, is required for mammalian cell growth Torres-Rosado, A O'Shea, K S Tsuji, A Chou, S H Kurachi, K Proc. Natl. Acad. Sci. U.S.A. 90:7181-5 20228799 Pubmed 2010 Genome-wide association identifies multiple ulcerative colitis susceptibility loci McGovern, Dermot P B Gardet, Agnès Törkvist, Leif Goyette, P Essers, Jonah Taylor, Kent D Neale, Benjamin M Ong, Rick T H Lagacé, Caroline Li, Chun Green, Todd Stevens, Christine R Beauchamp, Claudine Fleshner, Phillip R Carlson, Marie D'Amato, Mauro Halfvarson, Jonas Hibberd, Martin L Lördal, Mikael Padyukov, Leonid Andriulli, Angelo Colombo, Elisabetta Latiano, Anna Palmieri, Orazio Bernard, Edmond-Jean Deslandres, Colette Hommes, Daan W de Jong, Dirk J Stokkers, Pieter C Weersma, Rinse K Nat. Genet. 42:332-7 15792801 Pubmed 2005 Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2 Kirchhofer, Daniel Peek, Mark Lipari, Michael T Billeci, Karen Fan, Bin Moran, Paul FEBS Lett. 579:1945-50 21875933 Pubmed 2011 Proteolytic activation of pro-macrophage-stimulating protein by hepsin Ganesan, Rajkumar Kolumam, Ganesh A Lin, S Jack Xie, Ming-Hong Santell, Lydia Wu, Thomas D Lazarus, Robert A Chaudhuri, Amitabha Kirchhofer, Daniel Mol. Cancer Res. 9:1175-86 22087277 Pubmed 2011 Protein characterization of a candidate mechanism SNP for Crohn's disease: the macrophage stimulating protein R689C substitution Gorlatova, Natalia Chao, Kinlin Pal, Lipika R Araj, Rawan Hanna Galkin, Andrey Turko, Illarion Moult, John Herzberg, Osnat PLoS ONE 6:e27269 1885621 Pubmed 1991 Hepsin, a cell membrane-associated protease. Characterization, tissue distribution, and gene localization Tsuji, A Torres-Rosado, A Arai, T Le Beau, M M Lemons, R S Chou, S H Kurachi, K J. Biol. Chem. 266:16948-53 24409221 Pubmed 2013 Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele Kauder, Steven E Santell, Lydia Mai, Elaine Wright, Lilyan Y Luis, Elizabeth N'Diaye, Elsa N Lutman, Jeff Ratti, Navneet Sa, Susan M Maun, Henry R Stefanich, Eric Gonzalez, Lino C Graham, Robert R Diehl, Lauri Faubion, William A Keir, Mary E Young, Judy Chaudhuri, Amitabha Lazarus, Robert A Egen, Jackson G PLoS ONE 8:e83958 INHIBITION Reactome Database ID Release 78 6800236 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800236 Reactome R-HSA-6800236 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800236.1 Converted from EntitySet in Reactome SPINT1,2 Reactome DB_ID: 6800235 SPINT1 Kunitz-type protease inhibitor 1 SPIT1_HUMAN Reactome DB_ID: 6800232 UniProt:O43278 SPINT1 SPINT1 HAI1 UNQ223/PRO256 FUNCTION Inhibitor of HGF activator. Also acts as an inhibitor of matriptase (ST14).SUBUNIT Interacts with HGFAC.DOMAIN This inhibitor contains two inhibitory domains. UniProt O43278 36 EQUAL 529 EQUAL Reactome Database ID Release 78 6800232 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800232 Reactome R-HSA-6800232 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800232.1 SPINT2 Kunitz-type protease inhibitor 2 SPIT2_HUMAN Reactome DB_ID: 6800233 UniProt:O43291 SPINT2 SPINT2 HAI2 KOP FUNCTION Inhibitor of HGF activator. Also inhibits plasmin, plasma and tissue kallikrein, and factor XIa.TISSUE SPECIFICITY Expressed in placenta, kidney, pancreas, prostate, testis, thymus, and trachea.DOMAIN This inhibitor contains two inhibitory domains. UniProt O43291 28 EQUAL 252 EQUAL Reactome Database ID Release 78 6800233 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800233 Reactome R-HSA-6800233 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800233.1 Reactome Database ID Release 78 6800235 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800235 Reactome R-HSA-6800235 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800235.1 LEFT-TO-RIGHT MST1 binds MST1R The receptor tyrosine kinase macrophage stimulating 1 receptor (MST1R, aka recepteur d'origine nantais, RON) is the cell surface receptor for macrophage stimulating protein 1 (MST1, aka MSP) (Wang et al. 1997). Like their ligands, MST1R (and MET) is a cleaved disulfide-linked heterodimer, the mature receptor consisting of alpha and beta chains. The MST1/MST1R pathway is involved in several important biological processes, including macrophage activity, wound healing, and epithelial cell behaviour (Kretschmann et al. 2010). MST1 binding to MST1R promotes receptor dimerisation followed by receptor autophosphorylation. Authored: Jassal, Bijay, 2015-09-29 Reviewed: D'Eustachio, Peter, 2016-01-11 Edited: Jassal, Bijay, 2015-09-29 MST1R dimer Reactome DB_ID: 6800307 RON_HUMAN MST1R (25-304) Macrophage-stimulating protein receptor MST1R alpha chain Reactome DB_ID: 6800303 UniProt:Q04912 MST1R MST1R PTK8 RON FUNCTION Receptor tyrosine kinase that transduces signals from the extracellular matrix into the cytoplasm by binding to MST1 ligand. Regulates many physiological processes including cell survival, migration and differentiation. Ligand binding at the cell surface induces autophosphorylation of RON on its intracellular domain that provides docking sites for downstream signaling molecules. Following activation by ligand, interacts with the PI3-kinase subunit PIK3R1, PLCG1 or the adapter GAB1. Recruitment of these downstream effectors by RON leads to the activation of several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLCgamma-PKC. RON signaling activates the wound healing response by promoting epithelial cell migration, proliferation as well as survival at the wound site. Plays also a role in the innate immune response by regulating the migration and phagocytic activity of macrophages. Alternatively, RON can also promote signals such as cell migration and proliferation in response to growth factors other than MST1 ligand.ACTIVITY REGULATION In its inactive state, the C-terminal tail interacts with the catalytic domain and inhibits the kinase activity. Upon ligand binding, the C-terminal tail is displaced and becomes phosphorylated, thus increasing the kinase activity.SUBUNIT Heterodimer of an alpha chain and a beta chain which are disulfide linked. Binds PLXNB1. Associates with and is negatively regulated by HYAL2. Interacts when phosphorylated with downstream effectors including PIK3R1, PCLG1, GRB2 and GAB1. Interacts with integrin beta1/ITGB1 in a ligand-independent fashion.TISSUE SPECIFICITY Expressed in colon, skin, lung and bone marrow.PTM Proteolytic processing yields the two subunits.PTM Autophosphorylated in response to ligand binding on Tyr-1238 and Tyr-1239 in the kinase domain leading to further phosphorylation of Tyr-1353 and Tyr-1360 in the C-terminal multifunctional docking site.PTM Ubiquitinated. Ubiquitination by CBL regulates the receptor stability and activity through proteasomal degradation.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. UniProt Q04912 25 EQUAL 304 EQUAL Reactome Database ID Release 78 6800303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800303 Reactome R-HSA-6800303 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800303.1 1 RON_HUMAN MST1R (310-1400) Macrophage-stimulating protein receptor MST1R beta chain Reactome DB_ID: 6800308 310 EQUAL 1400 EQUAL Reactome Database ID Release 78 6800308 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800308 Reactome R-HSA-6800308 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800308.1 1 Reactome Database ID Release 78 6800307 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800307 Reactome R-HSA-6800307 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800307.1 MST1 dimer:MST1R dimer Reactome DB_ID: 6800284 1 1 Reactome Database ID Release 78 6800284 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800284 Reactome R-HSA-6800284 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800284.1 Reactome Database ID Release 78 6800315 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800315 Reactome R-HSA-6800315 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800315.1 9202013 Pubmed 1997 Macrophage stimulating protein (MSP) binds to its receptor via the MSP beta chain Wang, M H Julian, F M Breathnach, R Godowski, P J Takehara, T Yoshikawa, W Hagiya, M Leonard, E J J. Biol. Chem. 272:16999-7004 20545605 Pubmed 2010 The macrophage stimulating protein/Ron pathway as a potential therapeutic target to impede multiple mechanisms involved in breast cancer progression Kretschmann, Kelsi L Eyob, Henok Buys, Saundra S Welm, Alana L Curr Drug Targets 11:1157-68 LEFT-TO-RIGHT MST1R dimer dimerises MST1 dimer:MST1R dimer binds MST1R dimer The receptor tyrosine kinase macrophage stimulating 1 receptor (MST1R, aka recepteur d'origine nantais, RON) is the cell surface receptor for macrophage stimulating protein 1 (MST1, aka MSP). Once ligand binding takes place, MST1R can undergo homodimerisation (Miller & Leonard 1998, Chao et al. 2014). Authored: Jassal, Bijay, 2016-01-19 Reviewed: D'Eustachio, Peter, 2016-01-11 Edited: Jassal, Bijay, 2016-01-19 MST1 dimer:2xMST1R dimer Reactome DB_ID: 8852534 1 2 Reactome Database ID Release 78 8852534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852534 Reactome R-HSA-8852534 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852534.2 Reactome Database ID Release 78 8852522 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852522 Reactome R-HSA-8852522 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852522.1 25193665 Pubmed 2014 Structural basis for the binding specificity of human Recepteur d'Origine Nantais (RON) receptor tyrosine kinase to macrophage-stimulating protein Chao, Kinlin L Gorlatova, Natalia V Eisenstein, Edward Herzberg, Osnat J. Biol. Chem. 289:29948-60 9657372 Pubmed 1998 Mode of receptor binding and activation by plasminogen-related growth factors Miller, M Leonard, E J FEBS Lett. 429:1-3 LEFT-TO-RIGHT 2.7.10.1 MST1R autophosphorylates In response to ligand binding and receptor dimerisation, macrophage-stimulating protein receptor (MST1R aka RON) autophosphorylates on Tyr-1238 and Tyr-1239 in the kinase domain. This leads to further phosphorylation of Tyr-1353 and Tyr-1360 in the C-terminal multifunctional docking site (Yokoyama et al. 2005, Wang et al. 2010). Authored: Jassal, Bijay, 2016-01-19 Reviewed: D'Eustachio, Peter, 2016-01-11 Edited: Jassal, Bijay, 2016-01-19 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 cytosol GENE ONTOLOGY GO:0005829 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 78 113592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592 Reactome R-ALL-113592 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.5 COMPOUND C00002 8 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 29370 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 78 29370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370 Reactome R-ALL-29370 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.5 COMPOUND C00008 8 MST1 dimer:2x p-4Y-MST1R dimer Reactome DB_ID: 8852547 p-4Y-MST1R dimer Reactome DB_ID: 8852548 1 RON_HUMAN p-Y1238,1239,1353,1360-MST1R (310-1400) Macrophage-stimulating protein receptor MST1R beta chain Reactome DB_ID: 8852533 1238 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1239 EQUAL 1353 EQUAL 1360 EQUAL 310 EQUAL 1400 EQUAL Reactome Database ID Release 78 8852533 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852533 Reactome R-HSA-8852533 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852533.1 1 Reactome Database ID Release 78 8852548 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852548 Reactome R-HSA-8852548 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852548.1 2 1 Reactome Database ID Release 78 8852547 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852547 Reactome R-HSA-8852547 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852547.1 ACTIVATION activeUnit: #Complex7 GENE ONTOLOGY GO:0004714 Reactome Database ID Release 78 8852554 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852554 Reactome Database ID Release 78 8852552 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852552 Reactome R-HSA-8852552 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852552.1 15632155 Pubmed 2005 The C terminus of RON tyrosine kinase plays an autoinhibitory role Yokoyama, Noriko Ischenko, Irene Hayman, Michael J Miller, WT J. Biol. Chem. 280:8893-900 20726546 Pubmed 2010 The crystal structure of a constitutively active mutant RON kinase suggests an intramolecular autophosphorylation hypothesis Wang, J Steinbacher, S Augustin, Martin Schreiner, Patrick Epstein, David Mulvihill, Mark J Crew, Andrew P Biochemistry 49:7972-4 Reactome Database ID Release 78 8852405 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8852405 Reactome R-HSA-8852405 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8852405.1 12472665 Pubmed 2002 Macrophage-stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities Wang, M-H Zhou, Y-Q Chen, Y-Q Scand. J. Immunol. 56:545-53 GENE ONTOLOGY GO:0048012 gene ontology term for cellular process MI MI:0359