BioPAX pathway converted from "Signaling by Receptor Tyrosine Kinases" in the Reactome database. Signaling by Receptor Tyrosine Kinases This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Signaling by EGFR Epidermal Growth Factor Receptor (EGFR) signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT AAMP binds EGFR This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EGFR A0A6I8RLP7 Reactome DB_ID: 10350334 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:A0A6I8RLP7 Xenopus tropicalis NCBI Taxonomy 8364 UniProt A0A6I8RLP7 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 10350334 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=10350334 Reactome R-XTR-179837 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-XTR-179837.1 Reactome http://www.reactome.org AAMP A0A6I8SBZ5 Reactome DB_ID: 10422551 cytosol GENE ONTOLOGY GO:0005829 UniProt:A0A6I8SBZ5 UniProt A0A6I8SBZ5 1 EQUAL 434 EQUAL Reactome Database ID Release 78 10422551 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=10422551 Reactome R-XTR-9674636 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-XTR-9674636.1 EGFR:AAMP Reactome DB_ID: 10422561 1 1 Reactome Database ID Release 78 10422561 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=10422561 Reactome R-XTR-9674862 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-XTR-9674862.1 Reactome Database ID Release 78 10422563 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=10422563 Reactome R-XTR-9674531 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-XTR-9674531.1 AAMP (Angio-associated migratory cell protein) binds to EGFR. The interaction involves the intracellular domain of EGFR. AAMP binding, through and unknown mechanism, promotes EGFR dimerization, trans-autophosphorylation and downstream signaling, leading to activation of ERKs (MAPK1 and MAPK3) and expression of cyclin D1 (CCND1). Downregulation of AAMP inhibits proliferation of a non-small cell lung cancer (NSCLC) cell line and increases its sensitivity to EGFR-targeted chemotherapeutic drugs, and it also inhibits tumorigenesis in a mouse model (Yao et al. 2019).<br>In addition to lung cancer, AAMP overexpression is also linked with poor prognosis in breast cancer, where AAMP level positively correlates with tumor grade. AAMP is overexpressed in breast ductal carcinoma in situ (DCIS) with necrosis (Adeyinka et al. 2002). 12473591 Pubmed 2002 Analysis of gene expression in ductal carcinoma in situ of the breast Adeyinka, Adewale Emberley, Ethan Niu, Yulian Snell, Linda Murphy, Leigh C Sowter, Heidi Wykoff, Charles C Harris, Adrian L Watson, Peter H Clin. Cancer Res. 8:3788-95 31075398 Pubmed 2019 Angio-associated migratory cell protein interacts with epidermal growth factor receptor and enhances proliferation and drug resistance in human non-small cell lung cancer cells Yao, Shun Shi, Feifei Wang, Yingying Sun, Xiaoyang Sun, Wenbo Zhang, Yifeng Liu, Xianfang Liu, Xiangguo Su, Ling Cell. Signal. 61:10-19 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT EGFR binds EGF ligand This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome EGF-like ligands Reactome DB_ID: 10350364 egf EGF F7BYK2 Reactome DB_ID: 10350338 extracellular region GENE ONTOLOGY GO:0005576 UniProt:F7BYK2 egf UniProt F7BYK2 971 EQUAL 1023 EQUAL Reactome Database ID Release 78 10350338 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=10350338 Reactome R-XTR-179863 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-XTR-179863.1 tgfa TGFA(24-98) A0A6I8S5Y9 Reactome DB_ID: 10350342 UniProt:A0A6I8S5Y9 tgfa UniProt A0A6I8S5Y9 24 EQUAL 98 EQUAL Reactome Database ID Release 78 10350342 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=10350342 Reactome R-XTR-9624183 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-XTR-9624183.1 F6VBJ9 AREG(101-187) Reactome DB_ID: 10350346 UniProt:F6VBJ9 UniProt F6VBJ9 101 EQUAL 187 EQUAL Reactome Database ID Release 78 10350346 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=10350346 Reactome R-XTR-9624190 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-XTR-9624190.1 A0A6I8SIL3 EPGN(23-154) Reactome DB_ID: 10350350 UniProt:A0A6I8SIL3 UniProt A0A6I8SIL3 23 EQUAL 154 EQUAL Reactome Database ID Release 78 10350350 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=10350350 Reactome R-XTR-9624187 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-XTR-9624187.1 btc BTC(32-111) F7CD16 Reactome DB_ID: 10350354 UniProt:F7CD16 btc UniProt F7CD16 32 EQUAL 111 EQUAL Reactome Database ID Release 78 10350354 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=10350354 Reactome R-XTR-1233224 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-XTR-1233224.1 ereg EREG(60-108) Q28BU9 Reactome DB_ID: 10350358 UniProt:Q28BU9 ereg UniProt Q28BU9 60 EQUAL 108 EQUAL Reactome Database ID Release 78 10350358 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=10350358 Reactome R-XTR-1233233 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-XTR-1233233.1 hbegf HBEGF(63-148) A0A6I8QCY1 Reactome DB_ID: 10350362 UniProt:A0A6I8QCY1 hbegf UniProt A0A6I8QCY1 63 EQUAL 148 EQUAL Reactome Database ID Release 78 10350362 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=10350362 Reactome R-XTR-1233234 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-XTR-1233234.1 Reactome Database ID Release 78 10350364 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=10350364 Reactome R-XTR-9624194 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-XTR-9624194.1 EGFR:EGF-like ligands Reactome DB_ID: 10350366 1 1 Reactome Database ID Release 78 10350366 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=10350366 Reactome R-XTR-9624419 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-XTR-9624419.1 Reactome Database ID Release 78 10350498 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=10350498 Reactome R-XTR-177942 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-XTR-177942.1 The prototypic receptor tyrosine kinase (RTK) EGFR is composed of 3 major domains; an extracellular domain linked via a single membrane-spanning domain to a cytoplasmic domain. EGF binds to the extracellular domain from where the signal is transmitted to the cytoplasmic domain. 8639530 Pubmed 1996 Activation of epidermal growth factor receptor by epidermal growth factor Sherrill, JM Kyte, J Biochemistry 35:5705-18 INHIBITION Reactome Database ID Release 78 10350499 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=10350499 lrig1 LRIG1 A0A6I8Q496 Reactome DB_ID: 10350496 UniProt:A0A6I8Q496 lrig1 UniProt A0A6I8Q496 35 EQUAL 1093 EQUAL Reactome Database ID Release 78 10350496 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=10350496 Reactome R-XTR-197745 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-XTR-197745.1 LEFT-TO-RIGHT EGFR dimerization This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 EGF-like ligands:EGFR dimer Reactome DB_ID: 10350368 2 Reactome Database ID Release 78 10350368 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=10350368 Reactome R-XTR-9624420 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-XTR-9624420.1 Reactome Database ID Release 78 10350370 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=10350370 Reactome R-XTR-177922 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-XTR-177922.1 EGF and other growth factors induce oligomerization of their specific receptors. Inactive EGFR monomers are in equilibrium with active EGFR dimers and binding of the EGF ligand stabilizes the active dimeric form. LEFT-TO-RIGHT 2.7.10 EGFR autophosphorylation This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 113592 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 additional information MI MI:0361 12 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 12 EGF-like ligands:p-6Y EGFR dimer Reactome DB_ID: 10350407 A0A6I8RLP7 phospho-p-6Y-EGFR Reactome DB_ID: 10350405 992 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 1045 EQUAL 1068 EQUAL 1086 EQUAL 1148 EQUAL 1173 EQUAL 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 10350405 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=10350405 Reactome R-XTR-179803 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-XTR-179803.1 2 2 Reactome Database ID Release 78 10350407 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=10350407 Reactome R-XTR-9624425 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-XTR-9624425.1 ACTIVATION activeUnit: #Protein1 GENE ONTOLOGY GO:0004713 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 10350461 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=10350461 Reactome Database ID Release 78 10350463 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=10350463 Reactome R-XTR-177934 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-XTR-177934.1 The cytoplasmic domain of EGFR contains tyrosine, serine and threonine phosphorylation sites. Dimerization of EGFR activates its intrinsic protein kinase activity and results in autophosphorylation of 6 tyrosine residues in the cytoplasmic tail of EGFR. Tyrosine autophosphorylation is crucial for normal receptor signalling. Five of these tyrosine residues (Y992, Y1068, Y1086, Y1148 and Y1173) serve as specific binding sites for cytosolic target proteins involved in signal transmission, while the tyrosine residue Y1045 is involved in recruitment of CBL ubiquitin ligase and downregulation of EGFR signaling through degradation of activated EGFR. 1688559 Pubmed 1990 Analysis of deletions of the carboxyl terminus of the epidermal growth factor receptor reveals self-phosphorylation at tyrosine 992 and enhanced in vivo tyrosine phosphorylation of cell substrates Walton, GM Chen, WS Rosenfeld, MG Gill, GN J Biol Chem 265:1750-4 2022652 Pubmed 1991 Internalization and down-regulation of the human epidermal growth factor receptor are regulated by the carboxyl-terminal tyrosines Helin, K Beguinot, L J Biol Chem 266:8363-8 2543678 Pubmed 1989 All autophosphorylation sites of epidermal growth factor (EGF) receptor and HER2/neu are located in their carboxyl-terminal tails. Identification of a novel site in EGF receptor. Margolis, BL Lax, I Kris, R Dombalagian, M Honegger, AM Howk, R Givol, D Ullrich, A Schlessinger, J J Biol Chem 264:10667-71 LEFT-TO-RIGHT 2.7.10 Phosphorylation of EGFR by SRC kinase This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 12 12 ACTIVATION src SRC-1 A0A6I8QGM2 Reactome DB_ID: 10350479 UniProt:A0A6I8QGM2 src UniProt A0A6I8QGM2 2 EQUAL 536 EQUAL Reactome Database ID Release 78 10350479 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=10350479 Reactome R-XTR-65043 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-XTR-65043.1 Reactome Database ID Release 78 10350480 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=10350480 Reactome Database ID Release 78 10350482 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=10350482 Reactome R-XTR-177937 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-XTR-177937.1 Besides autophosphorylation, EGFR can become tyrosine-phosphorylated by the action of the proto-oncogene tyrosine-protein kinase, c-src. This Src homology 2 (SH2) domain-containing protein is one of many such proteins which bind to phosphorylated sites on EGFR to affect signal transmission into the cell. 8845374 Pubmed 1995 In vitro phosphorylation of the epidermal growth factor receptor autophosphorylation domain by c-src: identification of phosphorylation sites and c-src SH2 domain binding sites Lombardo, CR Consler, TG Kassel, DB Biochemistry 34:16456-66 EGFR interacts with phospholipase C-gamma This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Phospholipase C-gamma1 binds to the activated EGF receptor This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PLCG1 A0A6I8S1M1 Reactome DB_ID: 10355874 UniProt:A0A6I8S1M1 UniProt A0A6I8S1M1 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 10355874 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=10355874 Reactome R-XTR-202320 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-XTR-202320.1 EGF-like ligands:p-6Y-EGFR:PLCG1 Reactome DB_ID: 10357900 1 1 Reactome Database ID Release 78 10357900 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=10357900 Reactome R-XTR-212717 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-XTR-212717.1 Reactome Database ID Release 78 10357902 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=10357902 Reactome R-XTR-212706 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-XTR-212706.1 Inactive phospholipase C-gamma1 (PLCG1) binds to activated epidermal growth factor receptor (EGFR). 2153914 Pubmed 1990 Tyrosine kinase activity is essential for the association of phospholipase C-gamma with the epidermal growth factor receptor Margolis, B Bellot, F Honegger, AM Ullrich, A Schlessinger, J Zilberstein, A Mol Cell Biol 10:435-41 2472219 Pubmed 1989 Phospholipase C-gamma is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro Meisenhelder, J Suh, PG Rhee, SG Hunter, Tony Cell 57:1109-22 LEFT-TO-RIGHT 2.7.10 EGFR activates PLC-gamma1 by phosphorylation This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 4 4 EGF-like ligand:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1 Reactome DB_ID: 10357904 1 A0A6I8S1M1 phospho-p-4Y-PLCG1 Reactome DB_ID: 10355960 472 EQUAL 771 EQUAL 783 EQUAL 1253 EQUAL 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 10355960 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=10355960 Reactome R-XTR-167679 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-XTR-167679.1 1 Reactome Database ID Release 78 10357904 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=10357904 Reactome R-XTR-212703 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-XTR-212703.1 ACTIVATION activeUnit: #Protein12 Reactome Database ID Release 78 10357905 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=10357905 Reactome Database ID Release 78 10357907 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=10357907 Reactome R-XTR-212710 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-XTR-212710.1 EGFR phosphorylates PLC-gamma1, thus activating it. 1689311 Pubmed 1990 Identification of two epidermal growth factor-sensitive tyrosine phosphorylation sites of phospholipase C-gamma in intact HSC-1 cells Wahl, MI Nishibe, S Kim, JW Kim, H Rhee, SG Carpenter, G J Biol Chem 265:3944-8 LEFT-TO-RIGHT Active PLC-gamma1 dissociates from EGFR This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome Database ID Release 78 10357909 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=10357909 Reactome R-XTR-212713 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-XTR-212713.1 Once activated PLC-gamma1 dissociates from EGFR, it can hydrolyze PIP2. 10579907 Pubmed 1999 Phospholipase C-gamma as a signal-transducing element Carpenter, G Ji, Q Exp Cell Res 253:15-24 Reactome Database ID Release 78 10425284 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=10425284 Reactome R-XTR-212718 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-XTR-212718.1 GENE ONTOLOGY GO:0007165 gene ontology term for cellular process MI MI:0359 Activated epidermal growth factor receptors (EGFR) can stimulate phosphatidylinositol (PI) turnover. Activated EGFR can activate phospholipase C-gamma1 (PLC-gamma1, i.e. PLCG1) which hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 is instrumental in the release of calcium from intracellular stores and DAG is involved in protein kinase C activation. 1501243 Pubmed 1992 Epidermal growth factor receptor: elements of intracellular communication Hernández-Sotomayor, SM Carpenter, G J Membr Biol 128:81-9 GRB2 events in EGFR signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT GRB2-1 binds SOS1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> SOS1 A0A6I8RRS5 Reactome DB_ID: 10343808 UniProt:A0A6I8RRS5 UniProt A0A6I8RRS5 1 EQUAL 1333 EQUAL Reactome Database ID Release 78 10343808 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=10343808 Reactome R-XTR-64847 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-XTR-64847.1 grb2 GRB2-1 Q66II3 Reactome DB_ID: 10343804 UniProt:Q66II3 grb2 UniProt Q66II3 1 EQUAL 217 EQUAL Reactome Database ID Release 78 10343804 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=10343804 Reactome R-XTR-74686 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-XTR-74686.1 GRB2-1:SOS1 Reactome DB_ID: 10343810 1 1 Reactome Database ID Release 78 10343810 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=10343810 Reactome R-XTR-109797 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-XTR-109797.1 Reactome Database ID Release 78 10345497 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=10345497 Reactome R-XTR-109813 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-XTR-109813.1 In the cytoplasm of unstimulated cells, SOS1 is found in a complex with GRB2. The interaction occurs between the carboxy terminal domain of SOS1 and the Src homology 3 (SH3) domains of GRB2. 8479541 Pubmed 1993 Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Li, N Batzer, A Daly, R Yajnik, V Skolnik, E Margolis, B Schlessinger, J Nature 363:85-8 LEFT-TO-RIGHT GRB2:SOS1 complex binds to EGF:EGFR complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EGF-like ligands:p-6Y-EGFR:GRB2:SOS1 Reactome DB_ID: 10350486 1 1 Reactome Database ID Release 78 10350486 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=10350486 Reactome R-XTR-179820 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-XTR-179820.1 Reactome Database ID Release 78 10350501 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=10350501 Reactome R-XTR-177943 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-XTR-177943.1 Cytoplasmic target proteins containing the SH2 domain can bind to activated EGFR. One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain. GRB2 can bind at either Y1068 and/or Y1086 tyrosine autophosphorylation sites on the receptor. 7527043 Pubmed 1994 Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells Okutani, T Okabayashi, Y Kido, Y Sugimoto, Y Sakaguchi, K Matuoka, K Takenawa, T Kasuga, M J Biol Chem 269:31310-4 7518560 Pubmed 1994 Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor Batzer, AG Rotin, D Urena, JM Skolnik, EY Schlessinger, J Mol Cell Biol 14:5192-201 LEFT-TO-RIGHT SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:GRB2:SOS1) This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> GTP Guanosine 5'-triphosphate GTP)(4-) Reactome DB_ID: 29438 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI CHEBI:37565 Reactome Database ID Release 78 29438 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=29438 Reactome R-ALL-29438 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-29438.4 COMPOUND C00044 p21 RAS:GDP Reactome DB_ID: 10350484 A0A6I8S624 S-Farn-Me-2xPalmS HRAS Reactome DB_ID: 10349459 UniProt:A0A6I8S624 UniProt A0A6I8S624 186 EQUAL S-farnesyl-L-cysteine methyl ester MOD MOD:01116 181 EQUAL S-palmitoyl-L-cysteine MOD MOD:00115 184 EQUAL 1 EQUAL 186 EQUAL Reactome Database ID Release 78 10349459 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=10349459 Reactome R-XTR-9647912 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-XTR-9647912.1 1 GDP Guanosine 5'-diphosphate Guanosine diphosphate GDP(3-) Reactome DB_ID: 29420 GDP(3-) [ChEBI:58189] GDP(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate(3-) GDP guanosine 5'-diphosphate trianion guanosine 5'-diphosphate GDP trianion ChEBI CHEBI:58189 Reactome Database ID Release 78 29420 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=29420 Reactome R-ALL-29420 3 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-29420.3 COMPOUND C00035 1 Reactome Database ID Release 78 10350484 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=10350484 Reactome R-XTR-109796 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-XTR-109796.1 p21 RAS:GTP Reactome DB_ID: 10349461 1 1 Reactome Database ID Release 78 10349461 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=10349461 Reactome R-XTR-109783 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-XTR-109783.1 ACTIVATION activeUnit: #Protein16 GENE ONTOLOGY GO:0005085 Reactome Database ID Release 78 10350487 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=10350487 Reactome Database ID Release 78 10350489 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=10350489 Reactome R-XTR-177938 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-XTR-177938.1 The guanine nucleotide exchange factor SOS1 interacts with EGFR through the adaptor protein, GRB2. Upon formation of this complex, SOS activates RAS by promoting GDP release and GTP binding. 8493579 Pubmed 1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2 Chardin, P Camonis, JH Gale, NW Van Aelst, L Schlessinger, J Wigler, Michael H Bar-Sagi, Dafna Science 260:1338-43 Reactome Database ID Release 78 10424398 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=10424398 Reactome R-XTR-179812 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-XTR-179812.1 Autophosphorylated EGFR tyrosine residues are docking sites for many downstream effectors in EGFR signaling. The adaptor protein GRB2 binds to phosphotyrosine residues in the C-tail of EGFR through its SH2 domain. GRB2 is constitutively associated with SOS, a guanine nucleotide exchange factor of RAS. GRB2 binding to phosphorylated EGFR results in the recruitment of SOS to the plasma membrane where it comes in proximity to RAS. This mechanism has been seen to be the model for RAS activation. 11706405 Pubmed 2001 GRB2: a pivotal protein in signal transduction Tari, AM Lopez-Berestein, G Semin Oncol 28:142-7 11498013 Pubmed 2001 Internalization of the epidermal growth factor receptor: role in signalling Sorkin, A Biochem Soc Trans 29:480-4 SHC1 events in EGFR signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT SHC1 binds to the phosphorylated EGF receptor:ligand complex This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> SHC1 F6WD85 Reactome DB_ID: 10343869 UniProt:F6WD85 UniProt F6WD85 1 EQUAL 583 EQUAL Reactome Database ID Release 78 10343869 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=10343869 Reactome R-XTR-74680 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-XTR-74680.1 EGF-like ligands:p-6Y EGFR:SHC1 Reactome DB_ID: 10350422 1 1 Reactome Database ID Release 78 10350422 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=10350422 Reactome R-XTR-9624427 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-XTR-9624427.1 Reactome Database ID Release 78 10350424 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=10350424 Reactome R-XTR-177925 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-XTR-177925.1 SHC1 (Src homology 2 domain-containing) transforming protein can bind to either phosphorylated tyrosine 1148 (p-Y1148) and/or tyrosine 1173 (p-Y1173) sites on the EGF receptor. The N-terminal phosphotyrosine binding domain (PBD) of SHC1, also known as the phosphotyrosine interaction (PI) domain, binds to phosphorylated p-Y1148 of EGFR, which is part of the NPXpY motif. The SH2 domain of SHC1 binds to p-Y1173 of EGFR (Batzer et al. 1995, Songyang et al. 1995, Sakaguchi et al. 1998). 7542744 Pubmed 1995 The phosphotyrosine interaction domain of Shc binds an LXNPXY motif on the epidermal growth factor receptor Batzer, A G Blaikie, P Nelson, K Schlessinger, J Margolis, B Mol. Cell. Biol. 15:4403-9 9544989 Pubmed 1998 Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells Sakaguchi, K Okabayashi, Y Kido, Y Kimura, S Matsumura, Y Inushima, K Kasuga, M Mol Endocrinol 12:536-43 7541030 Pubmed 1995 The phosphotyrosine interaction domain of SHC recognizes tyrosine-phosphorylated NPXY motif Songyang, Z Margolis, B Chaudhuri, M Shoelson, S E Cantley, Lewis C J. Biol. Chem. 270:14863-6 LEFT-TO-RIGHT 2.7.10.1 SHC1 phosphorylation by phosphorylated EGFR This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 2 EGF-like ligands:p-6Y-EGFR:p-Y349,350-SHC1 Reactome DB_ID: 10350457 1 F6WD85 phospho-p-Y349,Y350-SHC1 Reactome DB_ID: 10350455 349 EQUAL 350 EQUAL 1 EQUAL 583 EQUAL Reactome Database ID Release 78 10350455 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=10350455 Reactome R-XTR-180276 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-XTR-180276.1 1 Reactome Database ID Release 78 10350457 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=10350457 Reactome R-XTR-180337 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-XTR-180337.1 ACTIVATION activeUnit: #Protein1 GENE ONTOLOGY GO:0004714 Reactome Database ID Release 78 10350458 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=10350458 Reactome Database ID Release 78 10350460 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=10350460 Reactome R-XTR-177933 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-XTR-177933.1 Once bound to EGFR, SHC1 is phosphorylated on two tyrosines (Y349, Y350). 7535773 Pubmed 1995 Growth hormone-promoted tyrosyl phosphorylation of SHC proteins and SHC association with Grb2 VanderKuur, J Allevato, G Billestrup, N Norstedt, G Carter-Su, C J Biol Chem 270:7587-93 8036006 Pubmed 1994 Potent SHC tyrosine phosphorylation by epidermal growth factor at low receptor density or in the absence of receptor autophosphorylation sites Soler, C Alvarez, CV Beguinot, L Carpenter, G Oncogene 9:2207-15 LEFT-TO-RIGHT GRB2:SOS1 binds to phosphorylated SHC1 in complex with EGFR This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EGF-like ligands:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1 Reactome DB_ID: 10350475 1 1 Reactome Database ID Release 78 10350475 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=10350475 Reactome R-XTR-180331 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-XTR-180331.1 Reactome Database ID Release 78 10350477 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=10350477 Reactome R-XTR-177936 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-XTR-177936.1 The tyrosine sites on SHC1 become possible binding sites for the GRB2:SOS1 complex. LEFT-TO-RIGHT SOS1-mediated nucleotide exchange of RAS (EGF:EGFR:SHC1:GRB2:SOS1) This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ACTIVATION activeUnit: #Protein16 Reactome Database ID Release 78 10350504 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=10350504 Reactome Database ID Release 78 10350506 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=10350506 Reactome R-XTR-177945 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-XTR-177945.1 Son of sevenless homolog 1 (SOS1) is the guanine nucleotide exchange factor (GEF) for rat sarcoma (RAS) protein. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP). Reactome Database ID Release 78 10424930 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=10424930 Reactome R-XTR-180336 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-XTR-180336.1 GRB2 can bind EGFR directly or through another SH2-containing protein, SHC1. This association leads to RAS activation. 8755247 Pubmed 1996 Not all Shc's roads lead to Ras Bonfini, L Migliaccio, E Pelicci, G Lanfrancone, L Pelicci, PG Trends Biochem Sci 21:257-61 GAB1 signalosome This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT 2.7.10 GAB1 phosphorylation by EGFR kinase This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 5 EGF-like ligands:p-6Y-EGFR:GRB2:GAB1 Reactome DB_ID: 10350443 1 Ghost homologue of GRB2:GAB1,GRB2:GAB1:PIP3 Reactome DB_ID: 10350441 Reactome Database ID Release 78 10350441 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=10350441 Reactome R-XTR-9038397 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-XTR-9038397.1 1 Reactome Database ID Release 78 10350443 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=10350443 Reactome R-XTR-180348 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-XTR-180348.1 EGF-like ligands:p-6Y-EGFR:GRB2:p-5Y-GAB1 Reactome DB_ID: 10350409 Ghost homologue of GRB2:p-5Y-GAB1,GRB2:p-5Y-GAB1:PIP3 Reactome DB_ID: 10350397 Reactome Database ID Release 78 10350397 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=10350397 Reactome R-XTR-9038398 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-XTR-9038398.1 1 1 Reactome Database ID Release 78 10350409 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=10350409 Reactome R-XTR-180286 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-XTR-180286.1 5 ACTIVATION activeUnit: #Protein21 Reactome Database ID Release 78 10350449 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=10350449 Converted from EntitySet in Reactome Phosphorylated EGFR dimer Reactome DB_ID: 10350448 A0A6I8RLP7 phospho-p-Y1086,Y1101-EGFR Reactome DB_ID: 10350446 1101 EQUAL 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 10350446 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=10350446 Reactome R-XTR-179868 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-XTR-179868.1 Reactome Database ID Release 78 10350448 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=10350448 Reactome R-XTR-180285 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-XTR-180285.1 Reactome Database ID Release 78 10350451 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=10350451 Reactome R-XTR-177930 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-XTR-177930.1 EGFR kinase phosphorylates the phosphorylation sites tyrosine 627 and 659 on GAB1 15231819 Pubmed 2004 Ligand regulates epidermal growth factor receptor kinase specificity: activation increases preference for GAB1 and SHC versus autophosphorylation sites Fan, YX Wong, L Deb, TB Johnson, GR J Biol Chem 279:38143-50 9890893 Pubmed 1999 Identification of tyrosine phosphorylation sites in human Gab-1 protein by EGF receptor kinase in vitro Lehr, S Kotzka, J Herkner, A Klein, E Siethoff, C Knebel, B Noelle, V Bruning, JC Klein, HW Meyer, HE Krone, W Muller-Wieland, D Biochemistry 38:151-9 LEFT-TO-RIGHT PI3K binds to EGF:EGFR:GRB2:GAB1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PIK3CA:PIK3R1 Reactome DB_ID: 10350435 PIK3R1 F6Z0J4 Reactome DB_ID: 10343830 UniProt:F6Z0J4 UniProt F6Z0J4 1 EQUAL 724 EQUAL Reactome Database ID Release 78 10343830 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=10343830 Reactome R-XTR-74789 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-XTR-74789.1 1 pik3ca PIK3CA F6VXG1 Reactome DB_ID: 10343840 UniProt:F6VXG1 pik3ca UniProt F6VXG1 1 EQUAL 1068 EQUAL Reactome Database ID Release 78 10343840 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=10343840 Reactome R-XTR-74787 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-XTR-74787.1 1 Reactome Database ID Release 78 10350435 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=10350435 Reactome R-XTR-1806218 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-XTR-1806218.1 EGF-like ligands:p-6Y-EGFR:GRB2:p-5Y-GAB1:PI3K Reactome DB_ID: 10350437 1 1 Reactome Database ID Release 78 10350437 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=10350437 Reactome R-XTR-179791 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-XTR-179791.1 Reactome Database ID Release 78 10350439 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=10350439 Reactome R-XTR-177927 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-XTR-177927.1 The Src homology 2 (SH2) domain of the phosphatidylinositol 3-kinase (PIK3) regulatory subunit (PIK3R1, i.e. PI3Kp85) binds to GAB1 in a phosphorylation-independent manner. GAB1 serves as a docking protein which recruits a number of downstream signalling proteins. PIK3R1 can bind to either GAB1 or phosphorylated GAB1(Rodrigues et al. 2000, Onishi-Haraikawa et al. 2001). In unstimulated cells, PI3K class IA exists as an inactive heterodimer of a p85 regulatory subunit (encoded by PIK3R1, PIK3R2 or PIK3R3) and a p110 catalytic subunit (encoded by PIK3CA, PIK3CB or PIK3CD). Binding of the iSH2 domain of the p85 regulatory subunit to the ABD and C2 domains of the p110 catalytic subunit both stabilizes p110 and inhibits its catalytic activity. This inhibition is relieved when the SH2 domains of p85 bind phosphorylated tyrosines on activated RTKs or their adaptor proteins. Binding to membrane-associated receptors brings activated PI3K in proximity to its membrane-localized substrate, PIP2 (Mandelker et al. 2009, Burke et al. 2011). 10648629 Pubmed 2000 A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling Rodrigues, GA Falasca, M Zhang, Z Ong, SH Schlessinger, J Mol Cell Biol 20:1448-59 19805105 Pubmed 2009 A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane Mandelker, Diana Gabelli, Sandra B Schmidt-Kittler, Oleg Zhu, Jiuxiang Cheong, Ian Huang, Chuan-Hsiang Kinzler, KW Vogelstein, B Amzel, L Mario Proc. Natl. Acad. Sci. U.S.A. 106:16996-7001 21827948 Pubmed 2011 Dynamics of the phosphoinositide 3-kinase p110? interaction with p85? and membranes reveals aspects of regulation distinct from p110? Burke, John E Vadas, Oscar Berndt, Alex Finegan, Tara Perisic, O Williams, RL Structure 19:1127-37 11606067 Pubmed 2001 Unique phosphorylation mechanism of Gab1 using PI 3-kinase as an adaptor protein Onishi-Haraikawa, Y Funaki, M Gotoh, N Shibuya, M Inukai, K Katagiri, H Fukushima, Y Anai, M Ogihara, T Sakoda, H Ono, H Kikuchi, M Oka, Y Asano, T Biochem Biophys Res Commun 288:476-82 LEFT-TO-RIGHT 2.7.1.153 PI3K converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3) This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PIP2 PI(4,5)P2 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate Phosphatidylinositol-4,5-bisphosphate 1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate Reactome DB_ID: 179856 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate [ChEBI:18348] 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate PIP2 ChEBI CHEBI:18348 Reactome Database ID Release 78 179856 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=179856 Reactome R-ALL-179856 3 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-179856.3 COMPOUND C04637 PIP3 PI(3,4,5)P3 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate Phosphatidylinositol-3,4,5-trisphosphate Reactome DB_ID: 179838 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate [ChEBI:16618] 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate PIP3 ChEBI CHEBI:16618 Reactome Database ID Release 78 179838 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=179838 Reactome R-ALL-179838 3 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-179838.3 COMPOUND C05981 ACTIVATION activeUnit: #Protein24 GENE ONTOLOGY GO:0046934 Reactome Database ID Release 78 10350490 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=10350490 Reactome Database ID Release 78 10350492 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=10350492 Reactome R-XTR-177939 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-XTR-177939.1 The kinase activity of PIK3 mediates the phosphorylation of PIP2 to form PIP3 LEFT-TO-RIGHT Activation of SHP2 through the binding to phospho-Gab1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PTPN11 A0A6I8SAV8 Reactome DB_ID: 10350395 UniProt:A0A6I8SAV8 UniProt A0A6I8SAV8 1 EQUAL 597 EQUAL Reactome Database ID Release 78 10350395 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=10350395 Reactome R-XTR-162563 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-XTR-162563.1 EGF-like ligands:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2 Reactome DB_ID: 10350411 1 1 Reactome Database ID Release 78 10350411 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=10350411 Reactome R-XTR-180269 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-XTR-180269.1 Reactome Database ID Release 78 10350503 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=10350503 Reactome R-XTR-177944 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-XTR-177944.1 The SH2 domains repress phosphatase activity of SHP2. Binding of these domains to phosphotyrosine-containing proteins relieves this autoinhibition, possibly by inducing a conformational change in the enzyme. 11323411 Pubmed 2001 Phosphotyrosines 627 and 659 of Gab1 constitute a bisphosphoryl tyrosine-based activation motif (BTAM) conferring binding and activation of SHP2 Cunnick, JM Mei, L Doupnik, CA Wu, J J Biol Chem 276:24380-7 14701753 Pubmed 2004 Distinct domains in the SHP-2 phosphatase differentially regulate epidermal growth factor receptor/NF-kappaB activation through Gab1 in glioblastoma cells Kapoor, GS Zhan, Y Johnson, GR O'Rourke, DM Mol Cell Biol 24:823-36 LEFT-TO-RIGHT Dephosphorylation of Gab1 by SHP2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> H2O water Reactome DB_ID: 29356 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 78 29356 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=29356 Reactome R-ALL-29356 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-29356.5 COMPOUND C00001 3 EGF-like ligands:p-6Y-EGFR:GRB2:p-Y627,659-GAB1:SHP2 Reactome DB_ID: 10350418 1 Ghost homologue of GRB2:p-Y627,Y659-GAB1,GRB2:p-Y627,Y659-GAB1:PIP3 Reactome DB_ID: 10350416 Reactome Database ID Release 78 10350416 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=10350416 Reactome R-XTR-9038479 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-XTR-9038479.1 1 1 Reactome Database ID Release 78 10350418 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=10350418 Reactome R-XTR-180503 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-XTR-180503.1 Pi Orthophosphate hydrogenphosphate Phosphate Inorganic Phosphate Reactome DB_ID: 29372 hydrogenphosphate [ChEBI:43474] hydrogenphosphate hydrogen phosphate phosphate [PO3(OH)](2-) INORGANIC PHOSPHATE GROUP HYDROGENPHOSPHATE ION HPO4(2-) [P(OH)O3](2-) ChEBI CHEBI:43474 Reactome Database ID Release 78 29372 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=29372 Reactome R-ALL-29372 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-29372.4 COMPOUND C00009 3 ACTIVATION activeUnit: #Protein25 GENE ONTOLOGY GO:0004726 Reactome Database ID Release 78 10350412 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=10350412 Reactome Database ID Release 78 10350420 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=10350420 Reactome R-XTR-177924 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-XTR-177924.1 Phosphorylated GAB1 can bind PI3 kinase by its regulatory alpha subunit. SHP2 dephosphorylation of the tyrosine residues 447, 472 and 589 on GAB1 means PI3 kinase can no longer bind to the complex in the plasma membrane and cannot be activated. 10734310 Pubmed 2000 Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis Gual, P Giordano, S Williams, TA Rocchi, S Van Obberghen, E Comoglio, PM Oncogene 19:1509-18 LEFT-TO-RIGHT SHP2 dephosphorylates Tyr 992 on EGFR This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EGF-like ligands:p-5Y-EGFR:GRB2:p-5Y-GAB1:SHP2 Reactome DB_ID: 10350471 1 EGF-like ligands:Phospho-EGFR (-Y992) dimer Reactome DB_ID: 10350469 EGF-like ligands:Phospho-EGFR (- Y992) Reactome DB_ID: 10350467 A0A6I8RLP7 phospho-p-4Y-EGFR Reactome DB_ID: 10350465 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 10350465 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=10350465 Reactome R-XTR-180287 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-XTR-180287.1 1 1 Reactome Database ID Release 78 10350467 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=10350467 Reactome R-XTR-180277 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-XTR-180277.1 2 Reactome Database ID Release 78 10350469 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=10350469 Reactome R-XTR-180343 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-XTR-180343.1 1 1 Reactome Database ID Release 78 10350471 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=10350471 Reactome R-XTR-180326 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-XTR-180326.1 ACTIVATION activeUnit: #Protein25 Reactome Database ID Release 78 10350473 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=10350473 Reactome R-XTR-177935 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-XTR-177935.1 The tyrosine-protein phosphatase SHP2 is a positive effector of EGFR signalling. SHP2 inhibits the tyrosine-dependent translocation of RasGAP (catalyses Ras inactivation) to the plasma membrane, thereby keeping it away from Ras-GTP (its substrate). This inhibition is achieved by the dephosphorylation of a RasGAP binding site on the EGF receptor. 14560030 Pubmed 2003 Molecular mechanism for a role of SHP2 in epidermal growth factor receptor signaling Agazie, YM Hayman, MJ Mol Cell Biol 23:7875-86 LEFT-TO-RIGHT Dephosphorylation of PAG by SHP2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> F6YY63 phospho-pag1 p-Y317-PAG1 Reactome DB_ID: 10350429 UniProt:F6YY63 pag1 UniProt F6YY63 317 EQUAL 1 EQUAL 432 EQUAL Reactome Database ID Release 78 10350429 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=10350429 Reactome R-XTR-180494 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-XTR-180494.1 pag1 PAG1 F6YY63 Reactome DB_ID: 10350431 1 EQUAL 432 EQUAL Reactome Database ID Release 78 10350431 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=10350431 Reactome R-XTR-180500 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-XTR-180500.1 ACTIVATION activeUnit: #Protein25 Reactome Database ID Release 78 10350433 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=10350433 Reactome R-XTR-177926 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-XTR-177926.1 Dephosphorylation of CBP/PAG negatively regulates the recruitment of the Src inhibiting kinase, Csk. Src is not negatively regulated by phosphorylation by Csk. 14967142 Pubmed 2004 Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment Zhang, Si Qing Yang, Wentian Kontaridis, Maria I Bivona, Trever G Wen, Gengyun Araki, Toshiyuki Luo, Jincai Thompson, Julie A Schraven, Burkhart L Philips, Mark R Neel, Benjamin G Mol. Cell 13:341-55 LEFT-TO-RIGHT Sustained activation of SRC kinase by SHP2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> p-Y-PXN:CSK:MyrG,p-Y530-SRC Reactome DB_ID: 10350387 csk CSK A0A6I8SBQ3 Reactome DB_ID: 10350374 UniProt:A0A6I8SBQ3 csk UniProt A0A6I8SBQ3 1 EQUAL 450 EQUAL Reactome Database ID Release 78 10350374 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=10350374 Reactome R-XTR-180499 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-XTR-180499.1 1 F7B727 phospho-pxn p-Y-PXN Reactome DB_ID: 10350379 UniProt:F7B727 pxn UniProt F7B727 1 EQUAL 591 EQUAL Reactome Database ID Release 78 10350379 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=10350379 Reactome R-XTR-9031680 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-XTR-9031680.1 1 A0A6I8QGM2 phospho-src MyrG,p-Y530-SRC Reactome DB_ID: 10350385 530 EQUAL 2 EQUAL N-myristoylglycine MOD MOD:00068 2 EQUAL 536 EQUAL Reactome Database ID Release 78 10350385 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=10350385 Reactome R-XTR-377598 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-XTR-377598.1 1 Reactome Database ID Release 78 10350387 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=10350387 Reactome R-XTR-180522 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-XTR-180522.1 PXN:MyrG-SRC Reactome DB_ID: 10350393 src MyrG-SRC A0A6I8QGM2 Reactome DB_ID: 10350391 2 EQUAL 536 EQUAL Reactome Database ID Release 78 10350391 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=10350391 Reactome R-XTR-8876922 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-XTR-8876922.1 1 pxn PXN F7B727 Reactome DB_ID: 10350389 1 EQUAL 591 EQUAL Reactome Database ID Release 78 10350389 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=10350389 Reactome R-XTR-180493 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-XTR-180493.1 1 Reactome Database ID Release 78 10350393 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=10350393 Reactome R-XTR-180523 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-XTR-180523.1 ACTIVATION activeUnit: #Protein25 Reactome Database ID Release 78 10350414 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=10350414 Reactome R-XTR-177923 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-XTR-177923.1 SHP2 can dephosphorylate paxillin, which leads to Csk dissociation from the paxillin-Src complex and Src activation. Src is an SHP2 effector in EGF-stimulated Erk activation and cell migration. 15574420 Pubmed 2005 A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation Montagner, A Yart, A Dance, M Perret, B Salles, JP Raynal, P J Biol Chem 280:5350-60 14665621 Pubmed 2004 Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor Ren, Y Meng, S Mei, L Zhao, ZJ Jove, R Wu, J J Biol Chem 279:8497-505 Reactome Database ID Release 78 10424928 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=10424928 Reactome R-XTR-180292 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-XTR-180292.1 GAB1 is recruited to the activated EGFR indirectly, through GRB2. GAB1 acts as an adaptor protein that enables formation of an active PIK3, through recruitment of PIK3 regulatory subunit PIK3R1 (also known as PI3Kp85), which subsequently recruits PIK3 catalytic subunit PIK3CA (also known as PI3Kp110). PIK3, in complex with EGFR, GRB2 and GAB1, catalyzes phosphorylation of PIP2 and its conversion to PIP3, which leads to the activation of the AKT signaling. 15550174 Pubmed 2004 The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway Mattoon, DR Lamothe, B Lax, I Schlessinger, J BMC Biol 2:24 EGFR downregulation This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Binding of CBL to EGFR This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> cbl CBL F6YBB1 Reactome DB_ID: 10350545 UniProt:F6YBB1 cbl UniProt F6YBB1 1 EQUAL 906 EQUAL Reactome Database ID Release 78 10350545 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=10350545 Reactome R-XTR-112199 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-XTR-112199.1 2 EGF-like ligands:p-6Y-EGFR:CBL Reactome DB_ID: 10350547 2 1 Reactome Database ID Release 78 10350547 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=10350547 Reactome R-XTR-182960 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-XTR-182960.1 Reactome Database ID Release 78 10350699 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=10350699 Reactome R-XTR-183055 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-XTR-183055.1 Phosphorylation at tyrosine Y1045 of EGFR creates a major docking site for E3 ubiquitin-protein ligase, CBL (Casitas B-lineage lymphoma proto- oncogene) and is required to sort the EGFR to lysosomes for degradation. The E3 ligase CBL plays a crucial role in these events as it dually participates in early events of internalization via a CIN85-endophilin dependent mechanism and endocytic sorting by mediating multiple monoubiquitylation of the receptor. 15475003 Pubmed 2004 Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation Grovdal, LM Stang, E Sorkin, A Madshus, IH Exp Cell Res 300:388-95 LEFT-TO-RIGHT 2.7.10 Phosphorylation of CBL (EGFR:CBL) This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 2 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL Reactome DB_ID: 10350552 2 F6YBB1 phospho-cbl p-Y371-CBL Reactome DB_ID: 10350550 371 EQUAL 1 EQUAL 906 EQUAL Reactome Database ID Release 78 10350550 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=10350550 Reactome R-XTR-182940 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-XTR-182940.1 2 2 Reactome Database ID Release 78 10350552 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=10350552 Reactome R-XTR-182953 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-XTR-182953.1 ACTIVATION activeUnit: #Protein1 Reactome Database ID Release 78 10350553 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=10350553 Reactome Database ID Release 78 10350555 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=10350555 Reactome R-XTR-182969 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-XTR-182969.1 EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity. 7657591 Pubmed 1995 Tyrosine phosphorylation of the c-cbl proto-oncogene protein product and association with epidermal growth factor (EGF) receptor upon EGF stimulation Galisteo, ML Dikic, I Batzer, AG Langdon, WY Schlessinger, J J Biol Chem 270:20242-5 15117950 Pubmed 2004 Regulation of ubiquitin protein ligase activity in c-Cbl by phosphorylation-induced conformational change and constitutive activation by tyrosine to glutamate point mutations Kassenbrock, CK Anderson, SM J Biol Chem 279:28017-27 LEFT-TO-RIGHT 6.3.2.19 CBL binds and ubiquitinates phosphorylated Sprouty This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Ub ubiquitin Reactome DB_ID: 10340646 rps27a RPS27A(1-76) Q28I48 Reactome DB_ID: 10340638 UniProt:Q28I48 rps27a UniProt Q28I48 1 EQUAL 76 EQUAL Reactome Database ID Release 78 10340638 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=10340638 Reactome R-XTR-939205 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-XTR-939205.1 A0A6I8RD22 UBA52(1-76) Reactome DB_ID: 10340640 UniProt:A0A6I8RD22 UniProt A0A6I8RD22 1 EQUAL 76 EQUAL Reactome Database ID Release 78 10340640 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=10340640 Reactome R-XTR-939203 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-XTR-939203.1 Reactome Database ID Release 78 10340646 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=10340646 Reactome R-XTR-113595 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-XTR-113595.1 Converted from EntitySet in Reactome SPRY1/2 Sprouty Reactome DB_ID: 10350628 SPRY1 A0A6I8SCT0 Reactome DB_ID: 10350624 UniProt:A0A6I8SCT0 UniProt A0A6I8SCT0 1 EQUAL 319 EQUAL Reactome Database ID Release 78 10350624 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=10350624 Reactome R-XTR-182908 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-XTR-182908.1 spry2 SPRY2 F7B7L3 Reactome DB_ID: 10350626 UniProt:F7B7L3 spry2 UniProt F7B7L3 1 EQUAL 315 EQUAL Reactome Database ID Release 78 10350626 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=10350626 Reactome R-XTR-182949 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-XTR-182949.1 Reactome Database ID Release 78 10350628 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=10350628 Reactome R-XTR-182909 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-XTR-182909.1 EGF-like ligands:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2 Reactome DB_ID: 10350690 Ub-p-Y53/55-SPRY1/2 Reactome DB_ID: 10350688 1 Converted from EntitySet in Reactome Phospho-Sprouty p-Y53/55-SPRY1/2 Reactome DB_ID: 10350684 A0A6I8SCT0 phospho-p-Y53-SPRY1 Reactome DB_ID: 10350682 53 EQUAL 1 EQUAL 319 EQUAL Reactome Database ID Release 78 10350682 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=10350682 Reactome R-XTR-182933 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-XTR-182933.1 F7B7L3 phospho-spry2 p-Y55-SPRY2 Reactome DB_ID: 10350620 55 EQUAL 1 EQUAL 315 EQUAL Reactome Database ID Release 78 10350620 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=10350620 Reactome R-XTR-182950 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-XTR-182950.1 Reactome Database ID Release 78 10350684 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=10350684 Reactome R-XTR-182963 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-XTR-182963.1 1 Reactome Database ID Release 78 10350688 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=10350688 Reactome R-XTR-182967 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-XTR-182967.1 1 1 Reactome Database ID Release 78 10350690 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=10350690 Reactome R-XTR-182939 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-XTR-182939.1 ACTIVATION activeUnit: #Protein45 GENE ONTOLOGY GO:0004842 Reactome Database ID Release 78 10350645 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=10350645 F6YBB1 phospho-cbl p-Y371-CBL Reactome DB_ID: 10350603 1 EQUAL 906 EQUAL Reactome Database ID Release 78 10350603 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=10350603 Reactome R-XTR-182923 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-XTR-182923.1 Reactome Database ID Release 78 10350715 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=10350715 Reactome R-XTR-183089 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-XTR-183089.1 Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL.The CBL-mediated ubiquitination of Sprouty targets the protein for degradation by the 26S proteosome. 12593796 Pubmed 2003 hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl Hall, AB Jura, N DaSilva, J Jang, YJ Gong, D Bar-Sagi, Dafna Curr Biol 13:308-14 LEFT-TO-RIGHT 6.3.2.19 Ubiquitination of stimulated EGFR (CBL) This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 EGF-like ligands:Ub-p-6Y-EGFR:p-Y371-CBL Reactome DB_ID: 10350644 2 2 2 2 Reactome Database ID Release 78 10350644 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=10350644 Reactome R-XTR-182930 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-XTR-182930.1 ACTIVATION activeUnit: #Protein45 Reactome Database ID Release 78 10350647 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=10350647 Reactome R-XTR-182993 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-XTR-182993.1 CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation. The ubiquitin protein ligase activity of CBL (abbreviated as E3 activity) is mediated by its RING finger domain. Receptor-type tyrosine-protein phosphatase kappa (PTPRK/RPTPk/DEP1) dephosphorylates EGFR, thereby inhibiting receptor ubiquitylation (Ub) by c-CBL, which decelerates the rate of receptor internalization and diminishes MAPK signals generated at the membrane and in endosomes. PTPRK disrupts physical association of ubiquitin ligase complex with EGFR and impairs its internalization (Tarcic et al. 2009, Xu et al. 2005). 15021893 Pubmed 2004 Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases Marmor, MD Yarden, Y Oncogene 23:2057-70 10514377 Pubmed 1999 The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase Joazeiro, Claudio A Wing, SS Huang, H Leverson, JD Hunter, T Liu, YC Science 286:309-12 LEFT-TO-RIGHT CBL binds to GRB2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> CBL:GRB2 Reactome DB_ID: 10350695 1 1 Reactome Database ID Release 78 10350695 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=10350695 Reactome R-XTR-182910 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-XTR-182910.1 Reactome Database ID Release 78 10350697 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=10350697 Reactome R-XTR-183052 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-XTR-183052.1 CBL binds multiple signalling proteins including GRB2. The CBL:GRB2 complex translocates to the plasma membrane where it can bind to GRB2-specific docking sites on the EGF receptor. 8621719 Pubmed 1996 p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts in vivo with Fyn and Syk tyrosine kinases, Grb2 and Shc adaptors, and the p85 subunit of phosphatidylinositol 3-kinase Panchamoorthy, G Fukazawa, T Miyake, S Soltoff, S Reedquist, K Druker, B Shoelson, S Cantley, Lewis C Band, H J Biol Chem 271:3187-94 LEFT-TO-RIGHT Localization of CBL:GRB2 to the membrane This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 EGF-like ligands:p-6Y-EGFR:CBL:GRB2 Reactome DB_ID: 10350701 2 1 Reactome Database ID Release 78 10350701 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=10350701 Reactome R-XTR-182928 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-XTR-182928.1 Reactome Database ID Release 78 10350706 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=10350706 Reactome R-XTR-183067 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-XTR-183067.1 Upon EGF stimulation and consequent EGFR phosphorylation, GRB2 binds phosphorylated tyrosines 11823423 Pubmed 2002 A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling Waterman, H Katz, M Rubin, C Shtiegman, K Lavi, S Elson, A Jovin, T Yarden, Y EMBO J 21:303-13 LEFT-TO-RIGHT 2.7.10 Phosphorylation of CBL (EGFR:GRB2:CBL) This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 2 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:GRB2 Reactome DB_ID: 10350649 2 2 2 2 Reactome Database ID Release 78 10350649 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=10350649 Reactome R-XTR-182948 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-XTR-182948.1 ACTIVATION activeUnit: #Protein1 Reactome Database ID Release 78 10350702 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=10350702 Reactome Database ID Release 78 10350704 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=10350704 Reactome R-XTR-183058 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-XTR-183058.1 EGF (and indeed FGF, PDGF and NGF) stimulation results in CBL phosphorylation on Tyr-371. Phosphorylation is necessary for CBL to exhibit ubiquitin ligase activity. LEFT-TO-RIGHT 6.3.2.19 Ubiquitination of stimulated EGFR (CBL:GRB2) This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 EGF-like ligands:Ub-p-6Y-EGFR:p-Y371-CBL:GRB2 Reactome DB_ID: 10350671 p-Y371-CBL:GRB2 Reactome DB_ID: 10350669 1 1 Reactome Database ID Release 78 10350669 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=10350669 Reactome R-XTR-182964 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-XTR-182964.1 2 2 2 2 Reactome Database ID Release 78 10350671 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=10350671 Reactome R-XTR-182945 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-XTR-182945.1 ACTIVATION activeUnit: #Protein45 Reactome Database ID Release 78 10350672 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=10350672 Reactome Database ID Release 78 10350678 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=10350678 Reactome R-XTR-183036 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-XTR-183036.1 CBL down-regulates receptor tyrosine kinases by conjugating ubiquitin to them. This leads to receptor internalization and degradation. The ubiquitin protein ligase activity of CBL (abbreviated as E3 activity) is mediated by its RING finger domain. Receptor-type tyrosine-protein phosphatase kappa (PTPRK/RPTPk/DEP1) dephosphorylates EGFR, thereby inhibiting receptor ubiquitylation (Ub) by c-CBL, which decelerates the rate of receptor internalization and diminishes MAPK signals generated at the membrane and in endosomes. PTPRK disrupts physical association of ubiquitin ligase complex with EGFR and impairs its internalization (Tarcic et al. 2009, Xu et al. 2005). INHIBITION Reactome Database ID Release 78 10350679 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=10350679 ptprk PTPRK A0A6I8SNL7 Reactome DB_ID: 10350676 UniProt:A0A6I8SNL7 ptprk UniProt A0A6I8SNL7 27 EQUAL 1439 EQUAL Reactome Database ID Release 78 10350676 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=10350676 Reactome R-XTR-6785699 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-XTR-6785699.1 LEFT-TO-RIGHT Sprouty lures CBL away from EGFR This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> CBL:SPRY1/2 Reactome DB_ID: 10350630 1 1 Reactome Database ID Release 78 10350630 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=10350630 Reactome R-XTR-182914 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-XTR-182914.1 Reactome Database ID Release 78 10350632 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=10350632 Reactome R-XTR-182988 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-XTR-182988.1 The NEYTEG motif is very similar to the CBL binding motif around Tyr-1045 in EGFR. Tyrosine-phosphorylated Sprouty (hSpry) binds to CBL, which then cannot ubiquitinate EGFR. Sprouty acts as a decoy to lure CBL away from EGFR and targets it for degradation. 12234920 Pubmed 2002 Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling Wong, ES Fong, CW Lim, J Yusoff, P Low, BC Langdon, WY Guy, GR EMBO J 21:4796-808 12593795 Pubmed 2003 Sprouty fine-tunes EGF signaling through interlinked positive and negative feedback loops Rubin, C Litvak, V Medvedovsky, H Zwang, Y Lev, S Yarden, Y Curr Biol 13:297-307 LEFT-TO-RIGHT CDC42:GTP binds CBL:Beta-Pix CDC42 lures CBL away from the receptor This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Beta-Pix:CDC42:GTP Reactome DB_ID: 10350661 ARHGEF7 A0A6I8RQF4 Reactome DB_ID: 10350659 UniProt:A0A6I8RQF4 UniProt A0A6I8RQF4 1 EQUAL 803 EQUAL Reactome Database ID Release 78 10350659 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=10350659 Reactome R-XTR-430346 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-XTR-430346.1 1 CDC42:GTP Reactome DB_ID: 10350655 1 cdc42 CDC42 F6WZM1 Reactome DB_ID: 10350653 UniProt:F6WZM1 cdc42 UniProt F6WZM1 1 EQUAL 188 EQUAL Reactome Database ID Release 78 10350653 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=10350653 Reactome R-XTR-449545 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-XTR-449545.1 1 Reactome Database ID Release 78 10350655 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=10350655 Reactome R-XTR-182921 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-XTR-182921.1 1 Reactome Database ID Release 78 10350661 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=10350661 Reactome R-XTR-182917 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-XTR-182917.1 CBL:Beta-Pix:CDC42:GTP Reactome DB_ID: 10350717 1 1 Reactome Database ID Release 78 10350717 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=10350717 Reactome R-XTR-182956 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-XTR-182956.1 Reactome Database ID Release 78 10350719 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=10350719 Reactome R-XTR-183094 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-XTR-183094.1 Activated CDC42 binds to Beta-Pix (p85Cool-1), a protein that directly associates with CBL. This inhibits the binding of CBL to the EGF receptor and thus prevents CBL from catalyzing receptor ubiquitination. 14505571 Pubmed 2003 Activated Cdc42 sequesters c-Cbl and prevents EGF receptor degradation Wu, WJ Tu, S Cerione, RA Cell 114:715-25 LEFT-TO-RIGHT Beta-Pix pushes CIN85 away from CBL Beta-Pix:CDC42:GTP binds CBL in EGF:p-6Y-EGFR:CBL:CIN85 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin Reactome DB_ID: 10350663 2 2 2 2 CIN85:endophilin Reactome DB_ID: 10350599 Converted from EntitySet in Reactome SH3GLs endophilins Reactome DB_ID: 10350597 SH3GL1 dimer Reactome DB_ID: 10350589 sh3gl1 SH3GL1 Q6P836 Reactome DB_ID: 10350587 UniProt:Q6P836 sh3gl1 UniProt Q6P836 1 EQUAL 368 EQUAL Reactome Database ID Release 78 10350587 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=10350587 Reactome R-XTR-8867732 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-XTR-8867732.1 2 Reactome Database ID Release 78 10350589 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=10350589 Reactome R-XTR-8867743 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-XTR-8867743.1 SH3GL3 dimer Reactome DB_ID: 10350595 SH3GL3 A0A6I8RQU3 Reactome DB_ID: 10350593 UniProt:A0A6I8RQU3 UniProt A0A6I8RQU3 1 EQUAL 347 EQUAL Reactome Database ID Release 78 10350593 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=10350593 Reactome R-XTR-8867734 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-XTR-8867734.1 2 Reactome Database ID Release 78 10350595 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=10350595 Reactome R-XTR-8867739 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-XTR-8867739.1 Reactome Database ID Release 78 10350597 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=10350597 Reactome R-XTR-8867746 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-XTR-8867746.1 1 SH3KBP1 tetramer Reactome DB_ID: 10350583 F6YKG4 SH3KBP1 Reactome DB_ID: 10350581 UniProt:F6YKG4 UniProt F6YKG4 1 EQUAL 665 EQUAL Reactome Database ID Release 78 10350581 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=10350581 Reactome R-XTR-182957 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-XTR-182957.1 4 Reactome Database ID Release 78 10350583 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=10350583 Reactome R-XTR-8875475 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-XTR-8875475.1 1 Reactome Database ID Release 78 10350599 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=10350599 Reactome R-XTR-8875480 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-XTR-8875480.1 1 Reactome Database ID Release 78 10350663 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=10350663 Reactome R-XTR-182946 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-XTR-182946.1 EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP:CIN85 Reactome DB_ID: 10350665 2 1 Reactome Database ID Release 78 10350665 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=10350665 Reactome R-XTR-8951489 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-XTR-8951489.1 Reactome Database ID Release 78 10350667 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=10350667 Reactome R-XTR-183002 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-XTR-183002.1 High concentrations of active CDC42 (bound to GTP) and Beta-Pix may promote the binding of Beta-Pix to CBL, pushing out the usually preferred binding partner CIN85 (SH3KBP1) from the CBL complex. This competitive mechanism could block the CIN85-imposed clustering phenomenon on CBL that is required for tighter binding (Schmidt et al. 2006). 16407834 Pubmed 2006 Cbl escapes Cdc42-mediated inhibition by downregulation of the adaptor molecule betaPix Schmidt, MH Husnjak, K Szymkiewicz, I Haglund, K Dikic, I Oncogene 25:3071-8 LEFT-TO-RIGHT 6.3.2.19 CBL escapes CDC42-mediated inhibition by down-regulating the adaptor molecule Beta-Pix This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP Reactome DB_ID: 10350708 2 1 Reactome Database ID Release 78 10350708 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=10350708 Reactome R-XTR-182932 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-XTR-182932.1 Ub-Beta-Pix:CDC42:GTP Reactome DB_ID: 10350710 1 1 1 Reactome Database ID Release 78 10350710 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=10350710 Reactome R-XTR-182915 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-XTR-182915.1 2 ACTIVATION activeUnit: #Protein34 Reactome Database ID Release 78 10350711 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=10350711 Reactome Database ID Release 78 10350713 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=10350713 Reactome R-XTR-183084 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-XTR-183084.1 Beta-Pix (Cool-1) associates with CBL, which appears to be a critical step in CDC42-mediated inhibition of EGFR ubiquitylation and downregulation. The SH3 domain of Beta-Pix specifically interacts with a proline-arginine motif (PxxxPR) present within CBL, which mediates ubiquitylation and subsequent degradation of Beta-Pix. LEFT-TO-RIGHT 6.3.2.19 CBL ubiquitinates Sprouty This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EGF-like ligands:p-6Y-EGFR:CBL:p-Y53/55-SPRY1/2 Reactome DB_ID: 10350686 1 1 Reactome Database ID Release 78 10350686 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=10350686 Reactome R-XTR-182935 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-XTR-182935.1 ACTIVATION Reactome Database ID Release 78 10350691 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=10350691 Reactome Database ID Release 78 10350693 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=10350693 Reactome R-XTR-183051 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-XTR-183051.1 Sprouty is ubiquitinated by CBL in an EGF-dependent manner. EGF stimulation induces the tyrosine phosphorylation of Sprouty, which in turn enhances the interaction of Sprouty with CBL. The CBL-mediated ubiquitination of Sprouty targets the protein for degradation by the 26S proteasome. LEFT-TO-RIGHT 6.3.2.19 CBL-mediated ubiquitination of CIN85 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15L1:Eps15 Reactome DB_ID: 10350601 EPS15:HGS:STAM Reactome DB_ID: 10350573 stam STAM F7CC92 Reactome DB_ID: 10350571 UniProt:F7CC92 stam UniProt F7CC92 2 EQUAL 540 EQUAL Reactome Database ID Release 78 10350571 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=10350571 Reactome R-XTR-182925 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-XTR-182925.1 1 HGS A0A6I8SV65 Reactome DB_ID: 10350567 UniProt:A0A6I8SV65 UniProt A0A6I8SV65 1 EQUAL 777 EQUAL Reactome Database ID Release 78 10350567 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=10350567 Reactome R-XTR-182954 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-XTR-182954.1 1 eps15 EPS15 F7E426 Reactome DB_ID: 10350563 UniProt:F7E426 eps15 UniProt F7E426 1 EQUAL 896 EQUAL Reactome Database ID Release 78 10350563 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=10350563 Reactome R-XTR-182920 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-XTR-182920.1 1 Reactome Database ID Release 78 10350573 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=10350573 Reactome R-XTR-182947 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-XTR-182947.1 1 EPN1 A0A6I8PX56 Reactome DB_ID: 10350559 UniProt:A0A6I8PX56 UniProt A0A6I8PX56 1 EQUAL 576 EQUAL Reactome Database ID Release 78 10350559 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=10350559 Reactome R-XTR-182952 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-XTR-182952.1 1 eps15l1 EPS15L1 A0A6I8PPY6 Reactome DB_ID: 10350577 UniProt:A0A6I8PPY6 eps15l1 UniProt A0A6I8PPY6 2 EQUAL 864 EQUAL Reactome Database ID Release 78 10350577 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=10350577 Reactome R-XTR-182937 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-XTR-182937.1 1 1 1 Reactome Database ID Release 78 10350601 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=10350601 Reactome R-XTR-182961 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-XTR-182961.1 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:Ub-CIN85:Endophilin:Epsin:Eps15L1:Eps15 Reactome DB_ID: 10350612 1 Ub-CIN85:endophilin Reactome DB_ID: 10350610 1 Ub-CIN85 Reactome DB_ID: 10350608 F6YKG4 Ub-SH3KBP1 Reactome DB_ID: 10350606 ubiquitinylated lysine MOD MOD:01148 1 EQUAL 665 EQUAL Reactome Database ID Release 78 10350606 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=10350606 Reactome R-XTR-182926 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-XTR-182926.1 4 Reactome Database ID Release 78 10350608 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=10350608 Reactome R-XTR-8934535 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-XTR-8934535.1 1 Reactome Database ID Release 78 10350610 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=10350610 Reactome R-XTR-8934537 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-XTR-8934537.1 1 2 2 1 1 2 Reactome Database ID Release 78 10350612 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=10350612 Reactome R-XTR-182936 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-XTR-182936.1 ACTIVATION activeUnit: #Protein34 Reactome Database ID Release 78 10350613 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=10350613 Reactome Database ID Release 78 10350615 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=10350615 Reactome R-XTR-182986 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-XTR-182986.1 The adaptor protein CIN85 is monoubiquitinated by CBL after EGF stimulation. Monoubiquitination is thought to regulate receptor internalization and endosomal sorting. 12218189 Pubmed 2002 Cbl-directed monoubiquitination of CIN85 is involved in regulation of ligand-induced degradation of EGF receptors Haglund, K Shimokawa, N Szymkiewicz, I Dikic, I Proc Natl Acad Sci U S A 99:12191-6 LEFT-TO-RIGHT Sprouty sequesters CBL away from active EGFR This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome SPRY1/2 Sprouty Reactome DB_ID: 10350638 SPRY1 A0A6I8SCT0 Reactome DB_ID: 10350634 1 EQUAL 319 EQUAL Reactome Database ID Release 78 10350634 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=10350634 Reactome R-XTR-182944 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-XTR-182944.1 spry2 SPRY2 F7B7L3 Reactome DB_ID: 10350636 1 EQUAL 315 EQUAL Reactome Database ID Release 78 10350636 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=10350636 Reactome R-XTR-182924 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-XTR-182924.1 Reactome Database ID Release 78 10350638 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=10350638 Reactome R-XTR-182912 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-XTR-182912.1 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:CIN85:SPRY1/2:Endophilin:Epsin:Eps15L1:EPS15 Reactome DB_ID: 10350640 1 1 Reactome Database ID Release 78 10350640 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=10350640 Reactome R-XTR-182931 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-XTR-182931.1 Reactome Database ID Release 78 10350642 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=10350642 Reactome R-XTR-182990 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-XTR-182990.1 Sprouty can constitutively interact with two SH3 domains of CIN85 whereas the third SH3 domain of CIN85 can still associate with CBL on cell activation with EGF. This allows Sprouty to block CIN85-mediated clustering of CBL molecules, stablization of CBL-EGFR interactions and efficient ubiquitination and down-regulation of EGFR. 15962011 Pubmed 2005 Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation Haglund, K Schmidt, MH Wong, ES Guy, GR Dikic, I EMBO Rep 6:635-41 LEFT-TO-RIGHT 3.1.3.48 PTPN12 dephosphorylates EGFR at Y1148 (Y1172) This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EGF:p-6Y-EGFR dimer Reactome DB_ID: 10414327 EGF:p-6Y-EGFR Reactome DB_ID: 10378303 1 1 Reactome Database ID Release 78 10378303 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=10378303 Reactome R-XTR-1248702 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-XTR-1248702.1 2 Reactome Database ID Release 78 10414327 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=10414327 Reactome R-XTR-179882 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-XTR-179882.1 2 EGF:p-EGFR dimer dephosphorylated at Y1148 (Y1172) Reactome DB_ID: 10414329 EGF:p-Y992,Y1045,Y1068,Y1086,Y1173-EGFR Reactome DB_ID: 10413945 1 A0A6I8RLP7 phospho-p-Y992,Y1045,Y1068,Y1086,Y1173-EGFR Reactome DB_ID: 10413943 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 10413943 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=10413943 Reactome R-XTR-8864019 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-XTR-8864019.1 1 Reactome Database ID Release 78 10413945 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=10413945 Reactome R-XTR-8864018 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-XTR-8864018.1 2 Reactome Database ID Release 78 10414329 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=10414329 Reactome R-XTR-8864028 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-XTR-8864028.1 2 ACTIVATION activeUnit: #Protein62 PTPN12 A0A6I8QFD3 Reactome DB_ID: 10413973 UniProt:A0A6I8QFD3 UniProt A0A6I8QFD3 1 EQUAL 780 EQUAL Reactome Database ID Release 78 10413973 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=10413973 Reactome R-XTR-432933 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-XTR-432933.1 GENE ONTOLOGY GO:0004725 Reactome Database ID Release 78 10413974 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=10413974 Reactome Database ID Release 78 10414331 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=10414331 Reactome R-XTR-8864029 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-XTR-8864029.1 GENE ONTOLOGY GO:1901185 PTPN12 protein tyrosine phosphatase dephosphorylates activated EGFR at tyrosine residue Y1148 (Y1148 corresponds to Y1172 in the nascent EGFR sequence which includes the 24 amino acid long signal peptide at the N-terminus). PTPN12-mediated dephosphorylation of activated EGFR inhibits SHC1 recruitment to the p-Y1148 docking site, thus attenuating downstream RAS activation (Sun et al. 2011). The recruitment of SHC1 to p-Y1148 of EGFR is mediated by the N-terminal phosphotyrosine interaction domain (PID) of SHC1 (Batzer et al. 1995, Songyang et al. 1995). 21376233 Pubmed 2011 Activation of multiple proto-oncogenic tyrosine kinases in breast cancer via loss of the PTPN12 phosphatase Sun, Tingting Aceto, Nicola Meerbrey, Kristen L Kessler, Jessica D Zhou, Chunshui Migliaccio, Ilenia Nguyen, Don X Pavlova, Natalya N Botero, Maria Huang, Jian Bernardi, Ronald J Schmitt, Earlene Hu, Guang Li, Mamie Z Dephoure, Noah Gygi, SP Rao, Mitchell Creighton, Chad J Hilsenbeck, Susan G Shaw, Chad A Muzny, Donna Gibbs, Richard A Wheeler, David A Osborne, C Kent Schiff, Rachel Bentires-Alj, Mohamed Elledge, Stephen J Westbrook, Thomas F Cell 144:703-18 LEFT-TO-RIGHT EGFR binds EPS15, EPN1, EPS15L1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:EPN1:EPS15L1:EPS15:HGS:STAM Reactome DB_ID: 10414719 1 1 1 1 1 Reactome Database ID Release 78 10414719 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=10414719 Reactome R-XTR-8867034 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-XTR-8867034.1 Reactome Database ID Release 78 10414726 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=10414726 Reactome R-XTR-8867044 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-XTR-8867044.1 EH-containing proteins such as EPS15, EPN1 and EPS15L1 are required for the endocytosis of ligand-activated EGFR (Confalonieri et al, 2000; Huang et al, 2004; reviewed in van Bergen en Henegouwen, 2009). EPS15 and EPN1 bind components of the clathrin coated pit through DPF motifs and likely bind to EGFR through the ubiquitin interacting motifs (UIMs). In this way EH proteins may help cluster activated EGFR into nascent clathrin-coated pits (Kazazic et al, 2009; Benmerah et al, 2000; reviewed in van Bergen en Henegouwen, 2009). Note, however, that EH-containing proteins are also involved in the clathrin-independent endocytosis of EGFR (Sigismund et al, 2005) 10953014 Pubmed 2000 Tyrosine phosphorylation of Eps15 is required for ligand-regulated, but not constitutive, endocytosis Confalonieri, Stefano Salcini, Anna Elisabetta Puri, Claudia Tacchetti, Carlo Di Fiore, Pier Paolo J. Cell Biol. 150:905-12 19814798 Pubmed 2009 Eps15: a multifunctional adaptor protein regulating intracellular trafficking van Bergen En Henegouwen, Paul Mp Cell Commun. Signal 7:24 15701692 Pubmed 2005 Clathrin-independent endocytosis of ubiquitinated cargos Sigismund, S Woelk, T Puri, C Maspero, E Tacchetti, C Transidico, P Di Fiore, PP Polo, S Proc Natl Acad Sci U S A 102:2760-5 14985334 Pubmed 2004 Analysis of clathrin-mediated endocytosis of epidermal growth factor receptor by RNA interference Huang, Fangtian Khvorova, A Marshall, William Sorkin, Alexander J. Biol. Chem. 279:16657-61 19054389 Pubmed 2009 Epsin 1 is involved in recruitment of ubiquitinated EGF receptors into clathrin-coated pits Kazazic, Maja Bertelsen, Vibeke Pedersen, Ketil Winther Vuong, Tram Thu Grandal, Michael Vibo Rødland, Marianne Skeie Traub, Linton M Stang, Espen Madshus, Inger Helene Traffic 10:235-45 10652316 Pubmed 2000 Mapping of Eps15 domains involved in its targeting to clathrin-coated pits Benmerah, Alexandre Poupon, Viviane Cerf-Bensussan, Nadine Dautry-Varsat, Alice J. Biol. Chem. 275:3288-95 LEFT-TO-RIGHT 2.7.10 EGFR phosphorylates EPS15 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:GRB2:CIN85:Endophilin:EPN1:EPS15L1:p-EPS15:HGS:STAM Reactome DB_ID: 10414721 1 1 1 1 p-Eps15:HGS:STAM Reactome DB_ID: 10414633 1 1 F7E426 phospho-eps15 p-Y850 EPS15 Reactome DB_ID: 10414631 850 EQUAL 1 EQUAL 896 EQUAL Reactome Database ID Release 78 10414631 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=10414631 Reactome R-XTR-8867028 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-XTR-8867028.1 1 Reactome Database ID Release 78 10414633 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=10414633 Reactome R-XTR-8867032 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-XTR-8867032.1 1 Reactome Database ID Release 78 10414721 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=10414721 Reactome R-XTR-8867035 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-XTR-8867035.1 ACTIVATION activeUnit: #Protein1 Reactome Database ID Release 78 10414722 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=10414722 Reactome Database ID Release 78 10414724 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=10414724 Reactome R-XTR-8867041 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-XTR-8867041.1 EPS15 is phosphorylated at Y849 by activated EGFR (Confalonieri et al, 2000). While the roles of phosphorylation and ubiquitination in EGFR endocytosis are unclear, emerging evidence suggests that EPS15 phosphorylation may target the activated EGFR complex for endocytosis through a clathrin-mediated route, while dephosphorylation at Y849 may direct the receptor complex into a clathrin-independent route (Confalonieri et al, 2002; de Melker et al, 2004; Li et al, 2015; reviewed in van Bergen en Henegouwen, 2009). 15465819 Pubmed 2004 Ubiquitin ligase activity of c-Cbl guides the epidermal growth factor receptor into clathrin-coated pits by two distinct modes of Eps15 recruitment de Melker, Annemieke A van der Horst, Gerda Borst, Jannie J. Biol. Chem. 279:55465-73 25263444 Pubmed 2015 Protein tyrosine phosphatase PTPN3 inhibits lung cancer cell proliferation and migration by promoting EGFR endocytic degradation Li, M-Y Lai, P-L Chou, Y-T Chi, A-P Mi, Y-Z Khoo, K-H Chang, G-D Wu, C-W Meng, T-C Chen, Guang-Chao Oncogene 34:3791-803 Reactome Database ID Release 78 10424938 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=10424938 Reactome R-XTR-182971 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-XTR-182971.1 GENE ONTOLOGY GO:0042059 Regulation of receptor tyrosine kinase (RTK) activity is implicated in the control of almost all cellular functions. One of the best understood RTKs is epidermal growth factor receptor (EGFR). Growth factors can bind to EGFR and activate it to initiate signalling cascades within the cell. EGFRs can also be recruited to clathrin-coated pits which can be internalised into endocytic vesicles. From here, EGFRs can either be recycled back to the plasma membrane or directed to lysosomes for destruction.This provides a mechanism by which EGFR signalling is negatively regulated and controls the strength and duration of EGFR-induced signals. It also prevents EGFR hyperactivation as commonly seen in tumorigenesis.<br><br>The proto-oncogene Cbl can negatively regulate EGFR signalling. The Cbl family of RING-type ubiquitin ligases are able to poly-ubiquitinate EGFR, an essential step in EGFR degradation. All Cbl proteins have a unique domain that recognises phosphorylated tyrosine residues on activated EGFRs. They also direct the ubiquitination and degradation of activated EGFRs by recruiting ubiquitin-conjugation enzymes. Cbl proteins function by specifically targeting activated EGFRs and mediating their down-regulation, thus providing a means by which signaling processes can be negatively regulated.<br><br>Cbl also promotes receptor internalization via it's interaction with an adaptor protein, CIN85 (Cbl-interacting protein of 85kDa). CIN85 binds to Cbl via it's SH3 domain and is enhanced by the EGFR-induced tyrosine phosphorylation of Cbl. The proline-rich region of CIN85 interacts with endophilins which are regulatory components of clathrin-coated vesicles (CCVs). Endophilins bind to membranes and induce membrane curvature, in conjunction with other proteins involved in CCV formation. The rapid recruitment of endophilin to the activated receptor complex by CIN85 is the mechanism which controls receptor internalization. 11283727 Pubmed 2001 Cbl: many adaptations to regulate protein tyrosine kinases Thien, CB Langdon, WY Nat Rev Mol Cell Biol 2:294-307 14641021 Pubmed 2003 Mechanisms controlling EGF receptor endocytosis and degradation Dikic, I Biochem Soc Trans 31:1178-81 Reactome Database ID Release 78 10424400 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=10424400 Reactome R-XTR-177929 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-XTR-177929.1 GENE ONTOLOGY GO:0007173 The epidermal growth factor receptor (EGFR) is one member of the ERBB family of transmembrane glycoprotein tyrosine receptor kinases (RTK). Binding of EGFR to its ligands induces conformational change that unmasks the dimerization interface in the extracellular domain of EGFR, leading to receptor homo- or heterodimerization at the cell surface. Dimerization of the extracellular regions of EGFR triggers additional conformational change of the cytoplasmic EGFR regions, enabling the kinase domains of two EGFR molecules to achieve the catalytically active conformation. Ligand activated EGFR dimers trans-autophosphorylate on tyrosine residues in the cytoplasmic tail of the receptor. Phosphorylated tyrosines serve as binding sites for the recruitment of signal transducers and activators of intracellular substrates, which then stimulate intracellular signal transduction cascades that are involved in regulating cellular proliferation, differentiation, and survival. Recruitment of complexes containing GRB2 and SOS1 to phosphorylated EGFR dimers either directly, through phosphotyrosine residues that serve as GRB2 docking sites, or indirectly, through SHC1 recruitment, promotes GDP to GTP exchange on RAS, resulting in the activation of RAF/MAP kinase cascade. Binding of complexes of GRB2 and GAB1 to phosphorylated EGFR dimers leads to formation of the active PI3K complex, conversion of PIP2 into PIP3, and activation of AKT signaling. Phospholipase C-gamma1 (PLCG1) can also be recruited directly, through EGFR phosphotyrosine residues that serve as PLCG1 docking sites, which leads to PLCG1 phosphorylation by EGFR and activation of DAG and IP3 signaling. EGFR signaling is downregulated by the action of ubiquitin ligase CBL. CBL binds directly to the phosphorylated EGFR dimer through the phosphotyrosine Y1045 in the C-tail of EGFR, and after CBL is phosphorylated by EGFR, it becomes active and ubiquitinates phosphorylated EGFR dimers, targeting them for degradation. For a recent review of EGFR signaling, please refer to Avraham and Yarden, 2011. 10404636 Pubmed 1999 EGF receptor Wells, A Int J Biochem Cell Biol 31:637-43 12297041 Pubmed 2002 Ligand-induced, receptor-mediated dimerization and activation of EGF receptor Schlessinger, J Cell 110:669-72 21252999 Pubmed 2011 Feedback regulation of EGFR signalling: decision making by early and delayed loops Avraham, R Yarden, Y Nat Rev Mol Cell Biol 12:104-17 10459005 Pubmed 1999 Employment of the epidermal growth factor receptor in growth factor-independent signaling pathways Carpenter, G J Cell Biol 146:697-702 15142631 Pubmed 2004 Review of epidermal growth factor receptor biology Herbst, RS Int J Radiat Oncol Biol Phys 59:21-6 Signaling by FGFR Fibroblast Growth Factor Receptor (FGFR) signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Signaling by FGFR1 Fibroblast Growth Factor Receptor (FGFR) signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> FGFR1 ligand binding and activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> FGFR1b ligand binding and activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT FGFR1b binds to FGF This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome FGFR1b-binding FGFs Reactome DB_ID: 10345261 FGF1 F6XSB5 Reactome DB_ID: 10345251 UniProt:F6XSB5 UniProt F6XSB5 16 EQUAL 155 EQUAL Reactome Database ID Release 78 10345251 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=10345251 Reactome R-XTR-189856 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-XTR-189856.1 fgf3 FGF3 Q66IF7 Reactome DB_ID: 10345255 UniProt:Q66IF7 fgf3 UniProt Q66IF7 18 EQUAL 239 EQUAL Reactome Database ID Release 78 10345255 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=10345255 Reactome R-XTR-189886 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-XTR-189886.1 fgf10 FGF10 Q07G49 Reactome DB_ID: 10345259 UniProt:Q07G49 fgf10 UniProt Q07G49 38 EQUAL 208 EQUAL Reactome Database ID Release 78 10345259 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=10345259 Reactome R-XTR-189869 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-XTR-189869.1 Reactome Database ID Release 78 10345261 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=10345261 Reactome R-XTR-189963 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-XTR-189963.1 2 HS Heparan Sulphate heparan sulfate Reactome DB_ID: 190915 heparan sulfate [ChEBI:28815] heparan sulfate N-Acetylheparan sulfate Heparin monosulfate Heparatan sulfate Heparitin monosulfate Heparan sulphate Heparan N-sulfate Heparitin sulfate Heparin sulfate ChEBI CHEBI:28815 Reactome Database ID Release 78 190915 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=190915 Reactome R-ALL-190915 3 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-190915.3 FGFR1b A0A6I8S3W3 Reactome DB_ID: 10351080 UniProt:A0A6I8S3W3 UniProt A0A6I8S3W3 2 EQUAL 822 EQUAL Reactome Database ID Release 78 10351080 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=10351080 Reactome R-XTR-189878 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-XTR-189878.1 2 FGFR1b homodimer bound to FGF Reactome DB_ID: 10351084 2 1 FGFR1b homodimer Reactome DB_ID: 10351082 2 Reactome Database ID Release 78 10351082 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=10351082 Reactome R-XTR-190228 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-XTR-190228.1 1 Reactome Database ID Release 78 10351084 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=10351084 Reactome R-XTR-190226 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-XTR-190226.1 Reactome Database ID Release 78 10351086 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=10351086 Reactome R-XTR-190245 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-XTR-190245.1 In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. NCAM and other members of the CAM protein family directly or indirectly modulate this interaction in a variety of neural tissues. The details of this interaction in vivo have not been definitively established at the molecular level, but are thought to play a central role in the regulation of the development of these tissues. 16597617 Pubmed 2006 Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. Zhang, X Ibrahimi, OA Olsen, SK Umemori, H Mohammadi, M Ornitz, DM J Biol Chem 281:15694-700 15863029 Pubmed 2005 Structural basis for fibroblast growth factor receptor activation Mohammadi, M Olsen, SK Ibrahimi, OA Cytokine Growth Factor Rev 16:107-37 16709412 Pubmed 2006 The neural cell adhesion molecule binds to fibroblast growth factor receptor 2 Christensen, C Lauridsen, JB Berezin, V Bock, E Kiselyov, VV FEBS Lett 580:3386-90 12791257 Pubmed 2003 Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP Kiselyov, VV Skladchikova, G Hinsby, AM Jensen, PH Kulahin, N Soroka, V Pedersen, N Tsetlin, V Poulsen, FM Berezin, V Bock, E Structure 11:691-701 16045455 Pubmed 2005 Structural biology of NCAM homophilic binding and activation of FGFR Kiselyov, VV Soroka, V Berezin, V Bock, E J Neurochem 94:1169-79 7917292 Pubmed 1994 Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin Williams, EJ Furness, J Walsh, FS Doherty, P Neuron 13:583-94 ACTIVATION Reactome Database ID Release 78 190316 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=190316 Reactome R-HSA-190316 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-190316.1 LEFT-TO-RIGHT 2.7.10 Autocatalytic phosphorylation of FGFR1b This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 16 Activated FGFR1b homodimer Reactome DB_ID: 10345277 2 1 p-8Y-FGFR1b dimer Reactome DB_ID: 10345275 A0A6I8S3W3 phospho-p-8Y-FGFR1b Reactome DB_ID: 10345273 463 EQUAL 583 EQUAL 585 EQUAL 653 EQUAL 654 EQUAL 730 EQUAL 766 EQUAL 776 EQUAL 2 EQUAL 822 EQUAL Reactome Database ID Release 78 10345273 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=10345273 Reactome R-XTR-5656338 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-XTR-5656338.1 2 Reactome Database ID Release 78 10345275 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=10345275 Reactome R-XTR-5656340 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-XTR-5656340.1 1 Reactome Database ID Release 78 10345277 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=10345277 Reactome R-XTR-190430 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-XTR-190430.1 16 ACTIVATION Reactome Database ID Release 78 10351197 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=10351197 Reactome Database ID Release 78 10351199 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=10351199 Reactome R-XTR-190427 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-XTR-190427.1 Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. 1656221 Pubmed 1991 A tyrosine-phosphorylated carboxy-terminal peptide of the fibroblast growth factor receptor (Flg) is a binding site for the SH2 domain of phospholipase C-gamma 1 Mohammadi, M Honegger, AM Rotin, D Fischer, R Bellot, F Li, W Dionne, CA Jaye, M Rubinstein, M Schlessinger, J Mol Cell Biol 11:5068-78 1379698 Pubmed 1992 Point mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogenesis Mohammadi, M Dionne, CA Li, W Li, N Spivak, T Honegger, AM Jaye, M Schlessinger, J Nature 358:681-4 8622701 Pubmed 1996 Identification of six novel autophosphorylation sites on fibroblast growth factor receptor 1 and elucidation of their importance in receptor activation and signal transduction Mohammadi, M Dikic, I Sorokin, A Burgess, WH Jaye, M Schlessinger, J Mol Cell Biol 16:977-89 16507368 Pubmed 2006 Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction Furdui, CM Lew, ED Schlessinger, J Anderson, KS Mol Cell 21:711-7 Reactome Database ID Release 78 10424970 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=10424970 Reactome R-XTR-190370 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-XTR-190370.1 GENE ONTOLOGY GO:0008543 This pathway depicts the binding of an experimentally-verified range of ligands to FGFR1b. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. FGFR1c ligand binding and activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT FGFR1c binds to FGF This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome FGFR1c-binding FGFs Reactome DB_ID: 10345300 FGF5-1 A0A6I8PJL4 Reactome DB_ID: 10345281 UniProt:A0A6I8PJL4 UniProt A0A6I8PJL4 18 EQUAL 268 EQUAL Reactome Database ID Release 78 10345281 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=10345281 Reactome R-XTR-189903 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-XTR-189903.1 fgf6 FGF6 B7U3X8 Reactome DB_ID: 10345285 UniProt:B7U3X8 fgf6 UniProt B7U3X8 38 EQUAL 208 EQUAL Reactome Database ID Release 78 10345285 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=10345285 Reactome R-XTR-189881 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-XTR-189881.1 fgf9 FGF9 F6ZB49 Reactome DB_ID: 10345289 UniProt:F6ZB49 fgf9 UniProt F6ZB49 4 EQUAL 208 EQUAL Reactome Database ID Release 78 10345289 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=10345289 Reactome R-XTR-189870 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-XTR-189870.1 FGF20 F7BZ47 Reactome DB_ID: 10345293 UniProt:F7BZ47 UniProt F7BZ47 1 EQUAL 211 EQUAL Reactome Database ID Release 78 10345293 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=10345293 Reactome R-XTR-189862 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-XTR-189862.1 A0A6I8PM12 GalNAc-T178-FGF23(25-251) Reactome DB_ID: 10345298 UniProt:A0A6I8PM12 UniProt A0A6I8PM12 178 EQUAL O-(N-acetylamino)galactosyl-L-threonine MOD MOD:00164 25 EQUAL 251 EQUAL Reactome Database ID Release 78 10345298 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=10345298 Reactome R-XTR-8851633 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-XTR-8851633.1 Reactome Database ID Release 78 10345300 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=10345300 Reactome R-XTR-189953 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-XTR-189953.1 2 FGFR1c A0A6I8S3W3 Reactome DB_ID: 10351088 22 EQUAL 822 EQUAL Reactome Database ID Release 78 10351088 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=10351088 Reactome R-XTR-189897 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-XTR-189897.1 2 FGFR1c homodimer bound to FGF Reactome DB_ID: 10351092 FGFR1c homodimer Reactome DB_ID: 10351090 2 Reactome Database ID Release 78 10351090 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=10351090 Reactome R-XTR-190222 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-XTR-190222.1 1 1 2 Reactome Database ID Release 78 10351092 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=10351092 Reactome R-XTR-190233 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-XTR-190233.1 Reactome Database ID Release 78 10351102 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=10351102 Reactome R-XTR-190256 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-XTR-190256.1 In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. INHIBITION Reactome Database ID Release 78 10351103 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=10351103 FGFR1c:KAL1 Reactome DB_ID: 10351098 KAL1 A9JRI8 Reactome DB_ID: 10351096 UniProt:A9JRI8 UniProt A9JRI8 25 EQUAL 680 EQUAL Reactome Database ID Release 78 10351096 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=10351096 Reactome R-XTR-5654345 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-XTR-5654345.1 1 1 Reactome Database ID Release 78 10351098 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=10351098 Reactome R-XTR-5654346 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-XTR-5654346.1 ACTIVATION ACTIVATION Reactome Database ID Release 78 10351104 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=10351104 KAL1:HS Reactome DB_ID: 10351100 1 1 Reactome Database ID Release 78 10351100 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=10351100 Reactome R-XTR-5654355 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-XTR-5654355.1 LEFT-TO-RIGHT 2.7.10 Autocatalytic phosphorylation of FGFR1c This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 16 16 Activated FGFR1c homodimer Reactome DB_ID: 10345304 1 2 A0A6I8S3W3 phospho-p-8Y-FGFR1c Reactome DB_ID: 10345302 22 EQUAL 822 EQUAL Reactome Database ID Release 78 10345302 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=10345302 Reactome R-XTR-190434 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-XTR-190434.1 2 Reactome Database ID Release 78 10345304 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=10345304 Reactome R-XTR-190425 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-XTR-190425.1 ACTIVATION Reactome Database ID Release 78 10351200 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=10351200 Reactome Database ID Release 78 10351202 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=10351202 Reactome R-XTR-190429 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-XTR-190429.1 Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. 9139660 Pubmed 1997 Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors Mohammadi, M McMahon, G Sun, L Tang, C Hirth, P Yeh, BK Hubbard, SR Schlessinger, J Science 276:955-60 11294897 Pubmed 2001 Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation Hart, KC Robertson, SC Donoghue, DJ Mol Biol Cell 12:931-42 LEFT-TO-RIGHT KAL1 binds HS This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome Database ID Release 78 10399669 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=10399669 Reactome R-XTR-5654515 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-XTR-5654515.1 KAL1 is an extracellular matrix-associated protein that modulates signaling by FGFR1c. Mutations in the KAL1 gene are associated with Kallmann syndrome, a genetic disorder characterized by olfactory bulb dysgenesis and hypogonadotrophic hypogonadism (Dode et al, 2003; Pitteloud et al, 2006; reviewed in Yu and Bouloux, 2010). KAL1 has been shown to interact with both FGFR1c and with heparan sulfate, with opposing effects on downstream signaling. Preformation of an FGFR1c:KAL1 complex inhibits the association of FGF ligand with the complex and subsequent receptor dimerization and in this way negatively regulates FGFR1c ligand-dependent signaling. In contrast, preformation of a KAL1:heparan sulfate complex promotes stable FGF ligand:receptor interaction thereby enhancing FGFR1c signal transduction (Hu et al, 2009; Hu et al, 2004; Soussi-Yanicostas et al, 1998). 12627230 Pubmed 2003 Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome Dodé, Catherine Levilliers, Jacqueline Dupont, Jean-Michel De Paepe, Anne Le Dû, Nathalie Soussi-Yanicostas, Nadia Coimbra, Roney S Delmaghani, Sedigheh Compain-Nouaille, Sylvie Baverel, Françoise Pêcheux, Christophe Le Tessier, Dominique Cruaud, C Delpech, Marc Speleman, Frank Vermeulen, Stefan Amalfitano, Andrea Bachelot, Yvan Bouchard, Philippe Cabrol, Sylvie Carel, Jean-Claude Delemarre-van de Waal, Henriette Goulet-Salmon, Barbara Kottler, Marie-Laure Richard, Odile Sanchez-Franco, Franco Saura, Robert Young, Jacques Petit, Christine Hardelin, Jean-Pierre Nat. Genet. 33:463-5 9730987 Pubmed 1998 Anosmin-1 underlying the X chromosome-linked Kallmann syndrome is an adhesion molecule that can modulate neurite growth in a cell-type specific manner Soussi-Yanicostas, Nadia Faivre-Sarrailh, Catherine Hardelin, Jean-Pierre Levilliers, Jacqueline Rougon, Geneviève Petit, Christine J. Cell. Sci. 111:2953-65 15324302 Pubmed 2004 Cross-talk of anosmin-1, the protein implicated in X-linked Kallmann's syndrome, with heparan sulphate and urokinase-type plasminogen activator Hu, Youli González-Martínez, David Kim, Soo-Hyun Bouloux, Pierre Marc Gilles Biochem. J. 384:495-505 20117945 Pubmed 2010 Novel insights in FGFR1 regulation: lessons from Kallmann syndrome Hu, Youli Bouloux, Pierre-Marc Trends Endocrinol. Metab. 21:385-93 19696444 Pubmed 2009 Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1 Hu, Youli Guimond, Scott E Travers, Paul Cadman, Steven Hohenester, Erhard Turnbull, Jeremy E Kim, Soo-Hyun Bouloux, Pierre-Marc J. Biol. Chem. 284:29905-20 16764984 Pubmed 2006 Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes Pitteloud, Nelly Meysing, Astrid Quinton, Richard Acierno, James S Dwyer, Andrew A Plummer, Lacey Fliers, Eric Boepple, Paul Hayes, Frances Seminara, Stephanie Hughes, Viriginia A Ma, J Bouloux, Pierre Mohammadi, M Crowley, William F Mol. Cell. Endocrinol. 254:60-9 Reactome Database ID Release 78 10424978 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=10424978 Reactome R-XTR-190373 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-XTR-190373.1 This pathway depicts the binding of an experimentally-verified range of ligands to FGFR1c. While binding affinities may vary considerably within this set, the ligands listed have been established to bring about receptor activation at their reported physiological concentrations. FGFR1c and Klotho ligand binding and activation This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT FGFR1c binds to Klotho-bound FGF23 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Klotho bound to FGF23 Reactome DB_ID: 10345322 Klotho homodimer Reactome DB_ID: 10345320 Converted from EntitySet in Reactome Klotho Reactome DB_ID: 10345318 Membrane-bound Klotho homodimer Reactome DB_ID: 10345312 KL-1 A0A6I8SJT2 Reactome DB_ID: 10345310 UniProt:A0A6I8SJT2 UniProt A0A6I8SJT2 34 EQUAL 1012 EQUAL Reactome Database ID Release 78 10345310 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=10345310 Reactome R-XTR-190198 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-XTR-190198.1 2 Reactome Database ID Release 78 10345312 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=10345312 Reactome R-XTR-190204 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-XTR-190204.1 Secreted Klotho homodimer Reactome DB_ID: 10345316 KL-2 A0A6I8SJT2 Reactome DB_ID: 10345314 34 EQUAL 549 EQUAL Reactome Database ID Release 78 10345314 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=10345314 Reactome R-XTR-190201 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-XTR-190201.1 2 Reactome Database ID Release 78 10345316 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=10345316 Reactome R-XTR-190203 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-XTR-190203.1 Reactome Database ID Release 78 10345318 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=10345318 Reactome R-XTR-190207 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-XTR-190207.1 2 Reactome Database ID Release 78 10345320 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=10345320 Reactome R-XTR-190309 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-XTR-190309.1 1 A0A6I8PM12 FGF23(25-251) Reactome DB_ID: 10345306 25 EQUAL 251 EQUAL Reactome Database ID Release 78 10345306 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=10345306 Reactome R-XTR-189891 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-XTR-189891.1 1 Reactome Database ID Release 78 10345322 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=10345322 Reactome R-XTR-190208 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-XTR-190208.1 2 2 FGF23 bound to Klotho and FGFR1c Reactome DB_ID: 10351179 1 2 1 Reactome Database ID Release 78 10351179 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=10351179 Reactome R-XTR-190218 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-XTR-190218.1 Reactome Database ID Release 78 10351181 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=10351181 Reactome R-XTR-190268 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-XTR-190268.1 In this reaction, FGF receptor in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. 17086194 Pubmed 2006 Klotho converts canonical FGF receptor into a specific receptor for FGF23 Fujita, Toshiro Fukumoto, S Hasegawa, H Iijima, K Okawa, K Shimada, T Urakawa, I Yamazaki, Y Yameshita, T Nature ACTIVATION LEFT-TO-RIGHT 2.7.10 Autocatalytic phosphorylation of Klotho-bound FGFR1c This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 16 16 Activated FGFR1c bound to FGF23:Klotho Reactome DB_ID: 10345324 2 1 2 Reactome Database ID Release 78 10345324 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=10345324 Reactome R-XTR-500333 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-XTR-500333.1 ACTIVATION Reactome Database ID Release 78 10351392 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=10351392 Reactome Database ID Release 78 10351394 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=10351394 Reactome R-XTR-191062 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-XTR-191062.1 Studies have mapped 8 tyrosine residues in the cytoplasmic domain of FGFR1 that are important for signaling. Autophosphorylation of residues 653 and 654, located in the activation loop of the kinase, is necessary to maintain the receptor in the active state. Phosphorylation of other tyrosine residues by the intrinsic protein tyrosine kinase activity of the activated receptor creates binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Reactome Database ID Release 78 10425000 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=10425000 Reactome R-XTR-190374 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-XTR-190374.1 FGF23 is a member of the endocrine subfamily of FGFs. It is produced in bone tissue and regulates kidney functions. Klotho is essential for endogenous FGF23 function as it converts FGFR1c into a specific FGF23 receptor. 16436388 Pubmed 2006 Regulation of fibroblast growth factor-23 signaling by klotho Kurosu, H Ogawa, Y Miyoshi, M Yamamoto, M Nandi, A Rosenblatt, KP Baum, MG Schiavi, S Hu, MC Moe, OW Kuro-O, M J Biol Chem 281:6120-3 Reactome Database ID Release 78 10424972 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=10424972 Reactome R-XTR-190242 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-XTR-190242.1 The vertebrate fibroblast growth factor receptor 1 (FGFR1) is alternatively spliced generating multiple variants that are differentially expressed during embryo development and in the adult body. The restricted expression patterns of FGFR1 isoforms, together with differential expression and binding of specific ligands, leads to activation of common FGFR1 signal transduction pathways, but may result in distinctively different biological responses as a result of differences in cellular context. FGFR1 isoforms are also present in the nucleus in complex with various fibroblast growth factors where they function to regulate transcription of target genes. <br><br>FGFR is probably activated by NCAM very differently from the way by which it is activated by FGFs, reflecting the different conditions for NCAM-FGFR and FGF-FGFR interactions. The affinity of FGF for FGFR is approximately 10e6 times higher than that of NCAM for FGFR. Moreover, in the brain NCAM is constantly present on the cell surface at a much higher (micromolar) concentration than FGFs, which only appear transiently in the extracellular environment in the nanomolar range. 12141425 Pubmed 2002 The structure and function of vertebrate fibroblast growth factor receptor 1 Groth, C Lardelli, M Int J Dev Biol 46:393-400 FGFRL1 modulation of FGFR1 signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT FGFRL1 dimer binds FGFs This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome FGFRL1-binding FGFs Reactome DB_ID: 10399661 Reactome Database ID Release 78 10399661 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=10399661 Reactome R-XTR-5654351 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-XTR-5654351.1 2 FGFRL1 dimer Reactome DB_ID: 10399641 FGFRL1 B1H3C3 Reactome DB_ID: 10399639 UniProt:B1H3C3 UniProt B1H3C3 25 EQUAL 504 EQUAL Reactome Database ID Release 78 10399639 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=10399639 Reactome R-XTR-197650 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-XTR-197650.1 2 Reactome Database ID Release 78 10399641 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=10399641 Reactome R-XTR-5654348 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-XTR-5654348.1 FGFRL1-binding FGFs:FGFRL1 dimer Reactome DB_ID: 10399663 2 1 1 Reactome Database ID Release 78 10399663 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=10399663 Reactome R-XTR-5654354 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-XTR-5654354.1 Reactome Database ID Release 78 10399665 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=10399665 Reactome R-XTR-5654511 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-XTR-5654511.1 FGFRL1 is a fifth member of the FGFR family of receptors that shares 40% sequence similarity with the extracellular region of FGFR1-4, but FGFRL1 lacks the internal kinase domain required for typical downstream FGFR signaling. Instead, FGFRL1 has a short intracellular domain with a C-terminal histidine rich region that has been shown to interact with the MAP kinase regulator SPRED proteins (Sleeman et al, 2001; Zhuang et al, 2011; reviewed in Trueb et al, 2013). FGFRL1 forms constitutive dimers and has been shown to bind to a wide range of FGF ligands, including FGF3,4,8,10, 22 and with lower affinity to FGF2,5,17,18 and 23 (Reickman et al, 2008; Steinberg et al, 2010). FGFRL1 knockout mice die shortly after birth from lung and renal defects (Gerber et al, 2009; Gerber et al, 2012; Trueb et al, 2013). FGFRL1 has been postulated to act as a decoy receptor that sequesters ligand away from canonical FGF receptors; more recently, however, alternate roles for FGFRL1 in enhancing ERK1/2 activation or promoting FGFR1-mediated signaling have been suggested (Sleeman et al, 2001; Steinberg et al, 2010; Silva et al, 2013; Amann and Trueb, 2013). Further work will be required to elucidate the role(s) of FGFRL1. 18061161 Pubmed 2008 The cell surface receptor FGFRL1 forms constitutive dimers that promote cell adhesion Rieckmann, Thorsten Kotevic, Ivana Trueb, Beat Exp. Cell Res. 314:1071-81 19920134 Pubmed 2010 The FGFRL1 receptor is shed from cell membranes, binds fibroblast growth factors (FGFs), and antagonizes FGF signaling in Xenopus embryos Steinberg, Florian Zhuang, Lei Beyeler, Michael Kälin, Roland E Mullis, Primus E Brändli, André W Trueb, Beat J. Biol. Chem. 285:2193-202 19715689 Pubmed 2009 The murine Fgfrl1 receptor is essential for the development of the metanephric kidney Gerber, Simon D Steinberg, Florian Beyeler, Michael Villiger, Peter M Trueb, Beat Dev. Biol. 335:106-19 22432025 Pubmed 2012 Comparison of the gene expression profiles from normal and Fgfrl1 deficient mouse kidneys reveals downstream targets of Fgfrl1 signaling Gerber, Simon D Amann, Ruth Wyder, Stefan Trueb, Beat PLoS ONE 7:e33457 23112089 Pubmed 2013 Role of FGFRL1 and other FGF signaling proteins in early kidney development Trueb, Beat Amann, Ruth Gerber, Simon D Cell. Mol. Life Sci. 70:2505-18 11418238 Pubmed 2001 Identification of a new fibroblast growth factor receptor, FGFR5 Sleeman, Matthew Fraser, Jonathan McDonald, Megan Yuan, Shining White, Damian Grandison, Prudence Kumble, Krishnanand Watson, James D Murison, J Greg Gene 271:171-82 23640895 Pubmed 2013 Fibroblast growth factor receptor like-1 (FGFRL1) interacts with SHP-1 phosphatase at insulin secretory granules and induces beta-cell ERK1/2 protein activation Silva, Pamuditha N Altamentova, Svetlana M Kilkenny, Dawn M Rocheleau, Jonathan V J. Biol. Chem. 288:17859-70 21616146 Pubmed 2011 Interaction of the receptor FGFRL1 with the negative regulator Spred1 Zhuang, Lei Villiger, Peter Trueb, Beat Cell. Signal. 23:1496-504 24026051 Pubmed 2013 Evidence that the novel receptor FGFRL1 signals indirectly via FGFR1 Amann, Ruth Trueb, Beat Int. J. Mol. Med. 32:983-8 LEFT-TO-RIGHT FGFRL1 binds SPRED1/2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome SPRED1/2 dimer Reactome DB_ID: 10399655 SPRED1 dimer Reactome DB_ID: 10399647 spred1 SPRED1 Q66JG9 Reactome DB_ID: 10399645 UniProt:Q66JG9 spred1 UniProt Q66JG9 2 EQUAL 444 EQUAL Reactome Database ID Release 78 10399645 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=10399645 Reactome R-XTR-5654207 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-XTR-5654207.1 2 Reactome Database ID Release 78 10399647 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=10399647 Reactome R-XTR-5654209 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-XTR-5654209.1 SPRED2 dimer Reactome DB_ID: 10399653 spred2 SPRED2 Q5Y171 Reactome DB_ID: 10399651 UniProt:Q5Y171 spred2 UniProt Q5Y171 1 EQUAL 418 EQUAL Reactome Database ID Release 78 10399651 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=10399651 Reactome R-XTR-5654211 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-XTR-5654211.1 2 Reactome Database ID Release 78 10399653 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=10399653 Reactome R-XTR-5654213 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-XTR-5654213.1 Reactome Database ID Release 78 10399655 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=10399655 Reactome R-XTR-5654215 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-XTR-5654215.1 FGFRL1 dimer:SPRED1/2 dimer Reactome DB_ID: 10399657 1 1 Reactome Database ID Release 78 10399657 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=10399657 Reactome R-XTR-5654350 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-XTR-5654350.1 Reactome Database ID Release 78 10399659 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=10399659 Reactome R-XTR-5654510 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-XTR-5654510.1 FGFRL1 binds to SPRED1 and 2 and Sprouty1 as assessed by co-immunoprecipitation, although the exact stoichiometry of the complex remains to be determined. The interaction requires the C-terminal residues of the short intracellular domain of FGFRL1 (Zhuang et al, 2011). The SPRED proteins are members of the Sprouty family, with established roles as negative regulators of the Ras/Raf/Erk signaling pathway (reviewed in McClatchey and Cichowski, 2012). 22802525 Pubmed 2012 SPRED proteins provide a NF-ty link to Ras suppression McClatchey, Andrea I Cichowski, Karen Genes Dev. 26:1515-9 Reactome Database ID Release 78 10426456 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=10426456 Reactome R-XTR-5658623 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-XTR-5658623.1 FGFRL1 is a fifth member of the FGFR family of receptors. The extracellular region has 40% sequence similarity with FGFR1-4, but FGFRL1 lacks the internal kinase domain of the other FGF receptors and how it acts in FGFR signaling is unclear. Some models suggest FGFRL1 restricts canonical FGFR signaling by sequestering ligand away from kinase-active receptors, while other models suggest that FGFRL1 may promote canonical signaling by nucleating signaling complexes or enhancing ERK1/2 activation (reviewed in Trueb, 2011; Trueb et al, 2013). 21080029 Pubmed 2011 Biology of FGFRL1, the fifth fibroblast growth factor receptor Trueb, Beat Cell. Mol. Life Sci. 68:951-64 Downstream signaling of activated FGFR1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> FRS-mediated FGFR1 signaling This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Activated FGFR1 binds FRS2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> FRS2 F6UAJ7 Reactome DB_ID: 10399542 UniProt:F6UAJ7 UniProt F6UAJ7 1 EQUAL 508 EQUAL Reactome Database ID Release 78 10399542 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=10399542 Reactome R-XTR-170963 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-XTR-170963.1 Converted from EntitySet in Reactome Activated FGFR1 Reactome DB_ID: 10387786 Reactome Database ID Release 78 10387786 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=10387786 Reactome R-XTR-5654170 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-XTR-5654170.1 Activated FGFR1:FRS2 Reactome DB_ID: 10399671 1 1 Reactome Database ID Release 78 10399671 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=10399671 Reactome R-XTR-5654176 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-XTR-5654176.1 Reactome Database ID Release 78 10399684 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=10399684 Reactome R-XTR-5654569 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-XTR-5654569.1 FRS2 (also known as FRS2alpha) is broadly expressed in adult and fetal tissues. Membrane-bound FRS2 interacts with FGFR as a first step in the phosphorylation of this docking protein. The juxtamembrane binding site for FRS2 does not contain tyrosine, so binding may be independent of receptor activation and/or constitutive. Activation of the FGFR receptor is required for FRS2 phosphorylation and subsequent recruitment of downstream effectors. 18373495 Pubmed 2008 Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling Ahmed, Z Schüller, AC Suhling, K Tregidgo, C Ladbury, JE Biochem J 413:37-49 10629055 Pubmed 2000 FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors Ong, SH Guy, GR Hadari, YR Laks, S Gotoh, N Schlessinger, J Lax, I Mol Cell Biol 20:979-89 9660748 Pubmed 1998 Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteins Xu, H Lee, KW Goldfarb, M J Biol Chem 273:17987-90 LEFT-TO-RIGHT Activated FGFR1 binds FRS3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> frs3 FRS3 A9UMH6 Reactome DB_ID: 10399686 UniProt:A9UMH6 frs3 UniProt A9UMH6 2 EQUAL 492 EQUAL Reactome Database ID Release 78 10399686 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=10399686 Reactome R-XTR-191482 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-XTR-191482.1 Activated FGFR1:FRS3 Reactome DB_ID: 10399688 1 1 Reactome Database ID Release 78 10399688 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=10399688 Reactome R-XTR-5654255 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-XTR-5654255.1 Reactome Database ID Release 78 10399690 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=10399690 Reactome R-XTR-5654571 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-XTR-5654571.1 FRS3 (also known as FRS2beta) is predominantly expressed in the developing and adult neuroepithelium. As is the case for FRS2 (also known as FRS2alpha), binding of FRS3 to FGFR may be constitutive and/or independent of receptor activation. Elements of the downstream signaling mediated by the two FRS family members appear to be at least partially conserved, as FRS3 is phosphorylated upon FGF stimulation, binds PPTN11/SHP2 and GRB2 and results in ERK activation. Moreover, expression of FRS3 in FRS2-/- MEFs restores ERK activation. 19187780 Pubmed 2009 Prominent expression of FRS2beta protein in neural cells and its association with intracellular vesicles Minegishi, Y Iwanari, H Mochizuki, Y Horii, T Hoshino, T Kodama, T Hamakubo, T Gotoh, N FEBS Lett 583:807-14 15094036 Pubmed 2004 FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial-temporal patterns of expression of their transcripts Gotoh, N Laks, S Nakashima, M Lax, I Schlessinger, J FEBS Lett 564:14-8 LEFT-TO-RIGHT 2.7.10 Activated FGFR1 phosphorylates FRS2 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 6 Activated FGFR1:p-FRS2 Reactome DB_ID: 10387788 F6UAJ7 phospho-p-6Y-FRS2 Reactome DB_ID: 10345439 436 EQUAL 196 EQUAL 306 EQUAL 349 EQUAL 392 EQUAL 471 EQUAL 1 EQUAL 508 EQUAL Reactome Database ID Release 78 10345439 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=10345439 Reactome R-XTR-170959 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-XTR-170959.1 1 1 Reactome Database ID Release 78 10387788 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=10387788 Reactome R-XTR-5654200 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-XTR-5654200.1 6 ACTIVATION Reactome Database ID Release 78 10399695 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=10399695 Reactome Database ID Release 78 10399697 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=10399697 Reactome R-XTR-5654575 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-XTR-5654575.1 FRS2 (also known as FRS alpha is activated through tyrosine phosphorylation catalyzed by the protein kinase domain of the activated FGFR. FRS2 contains four binding sites for the adaptor protein GRB2 at residues Y196, Y306, Y349 and Y392, and two binding sites for the protein tyrosine phosphatase PPTN11/SHP2 at residues Y436 and Y471. Different FGFR isoforms may generate different phosphorylation patterns on FRS2 leading to alternate downstream signaling. 9182757 Pubmed 1997 A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway Kouhara, H Hadari, YR Spivak-Kroizman, T Schilling, J Bar-Sagi, Dafna Lax, I Schlessinger, J Cell 89:693-702 8780727 Pubmed 1996 Suc1-associated neurotrophic factor target (SNT) protein is a major FGF-stimulated tyrosine phosphorylated 90-kDa protein which binds to the SH2 domain of GRB2 Ong, SH Goh, KC Lim, YP Low, BC Klint, P Claesson-Welsh, Lena Cao, X Tan, YH Guy, GR Biochem Biophys Res Commun 225:1021-6 12026167 Pubmed 2002 Cell- and receptor isotype-specific phosphorylation of SNT1 by fibroblast growth factor receptor tyrosine kinases Wang, F In Vitro Cell Dev Biol Anim 38:178-83 9632781 Pubmed 1998 Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation Hadari, YR Kouhara, H Lax, I Schlessinger, J Mol Cell Biol 18:3966-73 LEFT-TO-RIGHT 2.7.10 Activated FGFR1 phosphorylates FRS3 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 5 5 Activated FGFR1:p-FRS3 Reactome DB_ID: 10399533 A9UMH6 phospho-frs3 p-5Y-FRS3 Reactome DB_ID: 10399531 191 EQUAL 286 EQUAL 321 EQUAL 416 EQUAL 454 EQUAL 2 EQUAL 492 EQUAL Reactome Database ID Release 78 10399531 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=10399531 Reactome R-XTR-191475 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-XTR-191475.1 1 1 Reactome Database ID Release 78 10399533 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=10399533 Reactome R-XTR-5654261 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-XTR-5654261.1 ACTIVATION Reactome Database ID Release 78 10399698 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=10399698 Reactome Database ID Release 78 10399700 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=10399700 Reactome R-XTR-5654578 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-XTR-5654578.1 FRS3 (also known as FRS2 beta) is activated through tyrosine phosphorylation catalyzed by the protein kinase domain of the activated FGFR. By sequence comparison, FRS3 has the 2 PPTN11/SHP2-binding sites and has three of the four GRB2-binding sites. 12419216 Pubmed 2002 The docking protein FRS2alpha controls a MAP kinase-mediated negative feedback mechanism for signaling by FGF receptors Lax, I Wong, A Lamothe, B Lee, A Frost, A Hawes, J Schlessinger, J Mol Cell 10:709-19 LEFT-TO-RIGHT Activated FGFR1:p-FRS binds GRB2:SOS1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Activated FGFR1:p-FRS Reactome DB_ID: 10399535 Reactome Database ID Release 78 10399535 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=10399535 Reactome R-XTR-5654262 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-XTR-5654262.1 Activated FGFR1:p-FRS2:GRB2:SOS1 Reactome DB_ID: 10399537 1 1 Reactome Database ID Release 78 10399537 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=10399537 Reactome R-XTR-5654264 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-XTR-5654264.1 Reactome Database ID Release 78 10399711 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=10399711 Reactome R-XTR-5654586 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-XTR-5654586.1 Tyrosine phosphorylated FRS2 recruits GRB2:SOS1 complex by means of the SH3 domain of GRB2, leading to RAS-MAP kinase activation. The FRS2:GRB2-mediated pathway plays a minor role in the activation of RAS-MAP kinase pathway compared to that mediated by FRS2:PPTN11. 11353842 Pubmed 2001 Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins Ong, SH Hadari, YR Gotoh, N Guy, GR Schlessinger, J Lax, I Proc Natl Acad Sci U S A 98:6074-9 11447289 Pubmed 2001 Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways Hadari, YR Gotoh, N Kouhara, H Lax, I Schlessinger, J Proc Natl Acad Sci U S A 98:8578-83 7559490 Pubmed 1995 Shc and a novel 89-kDa component couple to the Grb2-Sos complex in fibroblast growth factor-2-stimulated cells Klint, P Kanda, S Claesson-Welsh, Lena J Biol Chem 270:23337-44 LEFT-TO-RIGHT Activated FGFR1:p-FRS:GRB2:SOS1 activates RAS nucleotide exchange This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> ACTIVATION Reactome Database ID Release 78 10399538 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=10399538 Reactome Database ID Release 78 10399540 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=10399540 Reactome R-XTR-5654392 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-XTR-5654392.1 SOS, recruited by GRB2:p-FRS2 to activated FGFR, activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state. LEFT-TO-RIGHT Activated FGFR1:p-FRS bind to PPTN11 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Activated FGFR1:p-FRS:PTPN11 Reactome DB_ID: 10399707 1 1 Reactome Database ID Release 78 10399707 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=10399707 Reactome R-XTR-5654268 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-XTR-5654268.1 Reactome Database ID Release 78 10399709 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=10399709 Reactome R-XTR-5654584 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-XTR-5654584.1 p-FRS2 has two PPTN11/SHP2-binding sites at pY436 and pY471. 14534538 Pubmed 2003 The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3 Agazie, YM Movilla, N Ischenko, I Hayman, MJ Oncogene 22:6909-18 LEFT-TO-RIGHT 2.7.10 Activated FGFR1:p-FRS phosphorylates PPTN11 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 2 2 Activated FGFR1:p-FRS:p-PTPN11 Reactome DB_ID: 10399713 1 A0A6I8SAV8 phospho-p-Y546,Y584-PTPN11 Reactome DB_ID: 10345447 546 EQUAL 584 EQUAL 1 EQUAL 597 EQUAL Reactome Database ID Release 78 10345447 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=10345447 Reactome R-XTR-162573 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-XTR-162573.1 1 Reactome Database ID Release 78 10399713 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=10399713 Reactome R-XTR-5654271 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-XTR-5654271.1 ACTIVATION Reactome Database ID Release 78 10399714 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=10399714 Reactome Database ID Release 78 10399716 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=10399716 Reactome R-XTR-5654587 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-XTR-5654587.1 Tyrosine phosphorylation of PPTN11/SHP2 by FGFR kinase is required for activation of the phosphatase activity of PPTN11 and for downstream signaling. Tyrosine phosphorylated PPTN11 plays a major role in the activation of RAS-MAP kinase pathway, although the precise role is not yet clear. 9299490 Pubmed 1997 SHP2 associates directly with tyrosine phosphorylated p90 (SNT) protein in FGF-stimulated cells Ong, SH Lim, YP Low, BC Guy, GR Biochem Biophys Res Commun 238:261-6 LEFT-TO-RIGHT Activated FGFR1:p-FRS:p-PTPN11 activates RAS nucleotide exchange This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Reactome Database ID Release 78 10417541 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=10417541 Reactome R-XTR-8941623 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-XTR-8941623.1 RAS nucleotide is stimulated downstream of activated FGFR1 in a p-PTPN11-dependent manner. The phosphatase activity of PTPN11 is required for activation of the RAS-MAP kinase pathway, although the mechanism for RAS pathway activation is not yet clear (Hadari et al, 1998; reviewed in Mohi et al, 2007; Gotoh et al, 2008). 17227708 Pubmed 2007 The role of Shp2 (PTPN11) in cancer Mohi, M Golam Neel, Benjamin G Curr. Opin. Genet. Dev. 17:23-30 18452557 Pubmed 2008 Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins Gotoh, N Cancer Sci 99:1319-25 ACTIVATION Reactome Database ID Release 78 10417542 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=10417542 Reactome Database ID Release 78 10426444 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=10426444 Reactome R-XTR-5654693 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-XTR-5654693.1 The FRS family of scaffolding adaptor proteins has two members, FRS2 (also known as FRS2 alpha) and FRS3 (also known as FRS2beta or SNT-2). Activation of FGFR tyrosine kinase allows FRS proteins to become phosphorylated on tyrosine residues and then bind to the adaptor GRB2 and the tyrosine phosphatase PPTN11/SHP2. Subsequently, PPTN11 activates the RAS-MAP kinase pathway and GRB2 activates the RAS-MAP kinase , PI-3-kinase and ubiquitinations/degradation pathways by binding to SOS, GAB1 and CBL, respectively, via the SH3 domains of GRB2. FRS2 acts as a central mediator in FGF signaling mainly because it induces sustained levels of activation of ERK with ubiquitous expression.<br><br><br> 10377388 Pubmed 1999 Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cells Raffioni, S Thomas, D Foehr, ED Thompson, LM Bradshaw, RA Proc Natl Acad Sci U S A 96:7178-83 15863030 Pubmed 2005 Cellular signaling by fibroblast growth factor receptors Eswarakumar, VP Lax, I Schlessinger, J Cytokine Growth Factor Rev 16:139-49 16682955 Pubmed 2006 Expression of the SNT-1/FRS2 phosphotyrosine binding domain inhibits activation of MAP kinase and PI3-kinase pathways and antiestrogen resistant growth induced by FGF-1 in human breast carcinoma cells Manuvakhova, M Thottassery, JV Hays, S Qu, Z Rentz, SS Westbrook, L Kern, FG Oncogene 25:6003-14 Phospholipase C-mediated cascade: FGFR1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT Activated FGFR1 binds PLCG1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> PLCG1 A0A6I8S1M1 Reactome DB_ID: 10350781 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 10350781 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=10350781 Reactome R-XTR-167682 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-XTR-167682.1 activated FGFR1:PLCG1 Reactome DB_ID: 10399491 1 1 1 Reactome Database ID Release 78 10399491 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=10399491 Reactome R-XTR-5654155 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-XTR-5654155.1 Reactome Database ID Release 78 10399513 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=10399513 Reactome R-XTR-5654167 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-XTR-5654167.1 Recruitment of PLC-gamma by FGF receptors has been best studied in FGFR1c signaling, where it has been shown that autophosphorylation of Tyr766 in the C-terminal tail of FGFR1c creates a specific binding site for the SH2 domain of PLC-gamma. A mutant FGFR1c in which Y766 is replaced by phenylalanine is unable to activate PI hydrolysis and Ca2+ release in response to FGF stimulation. Membrane recruitment of PLC-gamma is also aided by binding of the Pleckstrin homology (PH) domain of this enzyme to PtIns(3,4,5) P3 molecules that are generated in response to PI-3 kinase stimulation. By sequence comparison, Y766 is conserved in all FGFR isoforms, and PLC-gamma signaling is observed, to a greater or lesser extent, downstream of all FGFR receptors upon stimulation with FGFs. 16844695 Pubmed 2006 Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F Hatch, NE Hudson, M Seto, ML Cunningham, ML Bothwell, M J Biol Chem 281:27292-305 10652257 Pubmed 2000 Tyrosine 766 in the fibroblast growth factor receptor-1 is required for FGF-stimulation of phospholipase C, phospholipase D, phospholipase A(2), phosphoinositide 3-kinase and cytoskeletal reorganisation in porcine aortic endothelial cells Cross, MJ Hodgkin, MN Roberts, S Landgren, E Wakelam, MJ Claesson-Welsh, Lena J Cell Sci 113:643-51 9430633 Pubmed 1998 Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting Falasca, M Logan, SK Lehto, VP Baccante, G Lemmon, MA Schlessinger, J EMBO J 17:414-22 LEFT-TO-RIGHT 2.7.10 Activated FGFR1 phosphorylates PLCG1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>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.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> 4 4 activated FGFR1:p-4Y-PLCG1 Reactome DB_ID: 10399493 1 1 Reactome Database ID Release 78 10399493 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=10399493 Reactome R-XTR-5654154 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-XTR-5654154.1 ACTIVATION Reactome Database ID Release 78 10399494 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=10399494 Reactome Database ID Release 78 10399496 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=10399496 Reactome R-XTR-5654149 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-XTR-5654149.1 PLC gamma is phosphorylated by activated FGFR, resulting in PLC gamma activation, stimulation of phosphatidyl inositol hydrolysis and generation of two second messengers, diacylglycerol and inositol (1,4,5) P3. Tyrosine phosphorylation of PLCgamma by FGFR4 is weaker than that seen by other isoforms of FGFR. LEFT-TO-RIGHT