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 let-23 P24348 Reactome DB_ID: 10599111 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:P24348 let-23 Caenorhabditis elegans NCBI Taxonomy 6239 UniProt P24348 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 10599111 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599111 Reactome R-CEL-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-CEL-179837.1 Reactome http://www.reactome.org AAMP E0R7L2 Reactome DB_ID: 10656557 cytosol GENE ONTOLOGY GO:0005829 UniProt:E0R7L2 UniProt E0R7L2 1 EQUAL 434 EQUAL Reactome Database ID Release 78 10656557 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10656557 Reactome R-CEL-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-CEL-9674636.1 EGFR:AAMP Reactome DB_ID: 10656559 1 1 Reactome Database ID Release 78 10656559 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10656559 Reactome R-CEL-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-CEL-9674862.1 Reactome Database ID Release 78 10656561 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10656561 Reactome R-CEL-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-CEL-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> EGF G5EFK8 Reactome DB_ID: 10599116 extracellular region GENE ONTOLOGY GO:0005576 UniProt:G5EFK8 UniProt G5EFK8 971 EQUAL 1023 EQUAL Reactome Database ID Release 78 10599116 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599116 Reactome R-CEL-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-CEL-179863.1 EGFR:EGF-like ligands Reactome DB_ID: 10599118 1 1 Reactome Database ID Release 78 10599118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599118 Reactome R-CEL-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-CEL-9624419.1 Reactome Database ID Release 78 10599246 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599246 Reactome R-CEL-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-CEL-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 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: 10599120 2 Reactome Database ID Release 78 10599120 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599120 Reactome R-CEL-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-CEL-9624420.1 Reactome Database ID Release 78 10599122 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599122 Reactome R-CEL-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-CEL-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: 10599173 P24348 phospho-let-23 p-6Y-EGFR Reactome DB_ID: 10599171 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 10599171 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599171 Reactome R-CEL-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-CEL-179803.1 2 2 Reactome Database ID Release 78 10599173 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599173 Reactome R-CEL-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-CEL-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 10599209 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599209 Reactome Database ID Release 78 10599211 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599211 Reactome R-CEL-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-CEL-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-1 SRC-1 G5EE56 Reactome DB_ID: 10599223 UniProt:G5EE56 src-1 UniProt G5EE56 2 EQUAL 536 EQUAL Reactome Database ID Release 78 10599223 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599223 Reactome R-CEL-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-CEL-65043.1 Reactome Database ID Release 78 10599224 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599224 Reactome Database ID Release 78 10599226 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599226 Reactome R-CEL-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-CEL-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> plc-3 PLCG1 Q22070 Reactome DB_ID: 10602801 UniProt:Q22070 plc-3 UniProt Q22070 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 10602801 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10602801 Reactome R-CEL-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-CEL-202320.1 EGF-like ligands:p-6Y-EGFR:PLCG1 Reactome DB_ID: 10605051 1 1 Reactome Database ID Release 78 10605051 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10605051 Reactome R-CEL-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-CEL-212717.1 Reactome Database ID Release 78 10605053 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10605053 Reactome R-CEL-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-CEL-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 EGF-like ligand:p-6Y-EGFR:p-Y472,771,783,1254-PLCG1 Reactome DB_ID: 10605055 Q22070 phospho-plc-3 p-4Y-PLCG1 Reactome DB_ID: 10602835 472 EQUAL 771 EQUAL 783 EQUAL 1253 EQUAL 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 10602835 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10602835 Reactome R-CEL-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-CEL-167679.1 1 1 Reactome Database ID Release 78 10605055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10605055 Reactome R-CEL-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-CEL-212703.1 4 ACTIVATION activeUnit: #Protein4 Reactome Database ID Release 78 10605056 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10605056 Reactome Database ID Release 78 10605058 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10605058 Reactome R-CEL-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-CEL-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 10605060 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10605060 Reactome R-CEL-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-CEL-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 10658141 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10658141 Reactome R-CEL-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-CEL-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> sem-5 GRB2-1 P29355 Reactome DB_ID: 10593370 UniProt:P29355 sem-5 UniProt P29355 1 EQUAL 217 EQUAL Reactome Database ID Release 78 10593370 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10593370 Reactome R-CEL-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-CEL-74686.1 SOS1 sos-1 Q9N5D3 Reactome DB_ID: 10593375 UniProt:Q9N5D3 sos-1 UniProt Q9N5D3 1 EQUAL 1333 EQUAL Reactome Database ID Release 78 10593375 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10593375 Reactome R-CEL-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-CEL-64847.1 GRB2-1:SOS1 Reactome DB_ID: 10593377 1 1 Reactome Database ID Release 78 10593377 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10593377 Reactome R-CEL-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-CEL-109797.1 Reactome Database ID Release 78 10595426 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10595426 Reactome R-CEL-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-CEL-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: 10599230 1 1 Reactome Database ID Release 78 10599230 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599230 Reactome R-CEL-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-CEL-179820.1 Reactome Database ID Release 78 10599248 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599248 Reactome R-CEL-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-CEL-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> p21 RAS:GDP Reactome DB_ID: 10599228 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 let-60 S-Farn-Me-PalmS KRAS4A P22981 Reactome DB_ID: 10598472 UniProt:P22981 let-60 UniProt P22981 186 EQUAL S-farnesyl-L-cysteine methyl ester MOD MOD:01116 179 EQUAL S-palmitoyl-L-cysteine MOD MOD:00115 1 EQUAL 186 EQUAL Reactome Database ID Release 78 10598472 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10598472 Reactome R-CEL-9647915 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-9647915.1 1 Reactome Database ID Release 78 10599228 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599228 Reactome R-CEL-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-CEL-109796.1 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:GTP Reactome DB_ID: 10598482 1 1 Reactome Database ID Release 78 10598482 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10598482 Reactome R-CEL-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-CEL-109783.1 ACTIVATION activeUnit: #Protein9 GENE ONTOLOGY GO:0005085 Reactome Database ID Release 78 10599231 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599231 Reactome Database ID Release 78 10599233 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599233 Reactome R-CEL-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-CEL-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 10657427 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657427 Reactome R-CEL-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-CEL-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 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: #Protein9 EGF-like ligands:p-6Y-EGFR:p-Y349,350-SHC1:GRB2:SOS1 Reactome DB_ID: 10599254 1 EGF-like ligands:p-6Y-EGFR:p-Y349,350-SHC1 Reactome DB_ID: 10599252 Ghost homologue of p-Y349,Y350-SHC1 Reactome DB_ID: 10599250 Reactome Database ID Release 78 10599250 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599250 Reactome R-CEL-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-CEL-180276.1 1 1 Reactome Database ID Release 78 10599252 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599252 Reactome R-CEL-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-CEL-180337.1 1 Reactome Database ID Release 78 10599254 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599254 Reactome R-CEL-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-CEL-180331.1 Reactome Database ID Release 78 10599255 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599255 Reactome Database ID Release 78 10599257 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599257 Reactome R-CEL-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-CEL-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 10657865 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657865 Reactome R-CEL-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-CEL-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 Binding of GRB2 to 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> GAB1 soc-1 G5EDJ4 Reactome DB_ID: 10595147 UniProt:G5EDJ4 soc-1 UniProt G5EDJ4 1 EQUAL 694 EQUAL Reactome Database ID Release 78 10595147 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10595147 Reactome R-CEL-179795 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-179795.1 GRB2:GAB1 Reactome DB_ID: 10599104 1 1 Reactome Database ID Release 78 10599104 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599104 Reactome R-CEL-179849 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-179849.1 Reactome Database ID Release 78 10599106 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599106 Reactome R-CEL-177920 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-177920.1 GRB2 (Growth factor receptor-bound protein 2) binds to GAB1 (GRB2-associated binding protein 1). 12766170 Pubmed 2003 Grb2-independent recruitment of Gab1 requires the C-terminal lobe and structural integrity of the Met receptor kinase domain Lock, LS Frigault, MM Saucier, C Park, M J Biol Chem 278:30083-90 10913131 Pubmed 2000 Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyrosine kinases Lock, LS Royal, I Naujokas, MA Park, M J Biol Chem 275:31536-45 LEFT-TO-RIGHT GRB2:GAB1 binds to 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> Converted from EntitySet in Reactome GRB2:GAB1,GRB2:GAB1:PIP3 Reactome DB_ID: 10599196 GRB2:GAB1:PIP3 Reactome DB_ID: 10599194 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 1 1 Reactome Database ID Release 78 10599194 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599194 Reactome R-CEL-180282 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-180282.1 Reactome Database ID Release 78 10599196 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599196 Reactome R-CEL-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-CEL-9038397.1 EGF-like ligands:p-6Y-EGFR:GRB2:GAB1 Reactome DB_ID: 10599198 1 1 Reactome Database ID Release 78 10599198 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599198 Reactome R-CEL-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-CEL-180348.1 Reactome Database ID Release 78 10599244 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599244 Reactome R-CEL-177941 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-177941.1 The regulatory subunit of PIK3 mediates the association of GAB1 and receptor protein-tyrosine kinases such as the EGF receptor, which can phosphorylate GAB1. It appears that the PIK3 regulatory subunit acts as an adaptor protein allowing GAB1 to serve as a substrate for several tyrosine kinases. 9356464 Pubmed 1997 Grb2-associated binder-1 mediates phosphatidylinositol 3-kinase activation and the promotion of cell survival by nerve growth factor Holgado-Madruga, M Moscatello, DK Emlet, DR Dieterich, R Wong, AJ Proc Natl Acad Sci U S A 94:12419-24 LEFT-TO-RIGHT GAB1 binds phosphatidylinositol-3,4,5-trisphosphate 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 10599264 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599264 Reactome R-CEL-179467 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-179467.1 The pleckstrin homology (PH) domain of GAB1 binds to PIP3 and can target GAB1 to the plasma membrane in response to EGF stimulation. This mechanism provides a positive feedback loop with respect to PI3K activation, to enhance EGFR signalling. 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 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 5 EGF-like ligands:p-6Y-EGFR:GRB2:p-5Y-GAB1 Reactome DB_ID: 10599175 Converted from EntitySet in Reactome GRB2:p-5Y-GAB1,GRB2:p-5Y-GAB1:PIP3 Reactome DB_ID: 10599163 GRB2:Phospho-GAB1 Reactome DB_ID: 10599159 1 G5EDJ4 phospho-soc-1 p-5Y-GAB1 Reactome DB_ID: 10599157 627 EQUAL 659 EQUAL 447 EQUAL 472 EQUAL 589 EQUAL 1 EQUAL 694 EQUAL Reactome Database ID Release 78 10599157 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599157 Reactome R-CEL-180344 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-180344.1 1 Reactome Database ID Release 78 10599159 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599159 Reactome R-CEL-180304 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-180304.1 GRB2:p-5Y-GAB1:PIP3 Reactome DB_ID: 10599161 1 1 Reactome Database ID Release 78 10599161 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599161 Reactome R-CEL-9038396 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-9038396.1 Reactome Database ID Release 78 10599163 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599163 Reactome R-CEL-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-CEL-9038398.1 1 1 Reactome Database ID Release 78 10599175 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599175 Reactome R-CEL-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-CEL-180286.1 ACTIVATION activeUnit: #Protein4 Reactome Database ID Release 78 10599202 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599202 Reactome Database ID Release 78 10599204 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599204 Reactome R-CEL-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-CEL-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 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 ACTIVATION EGF-like ligands:p-6Y-EGFR:GRB2:p-5Y-GAB1:PI3K Reactome DB_ID: 10599239 PIK3CA:PIK3R1 Reactome DB_ID: 10599237 Ghost homologue of PIK3CA Reactome DB_ID: 10599235 Reactome Database ID Release 78 10599235 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599235 Reactome R-CEL-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-CEL-74787.1 1 aap-1 PIK3R1 G5EDP9 Reactome DB_ID: 10593382 UniProt:G5EDP9 aap-1 UniProt G5EDP9 1 EQUAL 724 EQUAL Reactome Database ID Release 78 10593382 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10593382 Reactome R-CEL-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-CEL-74789.1 1 Reactome Database ID Release 78 10599237 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599237 Reactome R-CEL-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-CEL-1806218.1 1 1 Reactome Database ID Release 78 10599239 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599239 Reactome R-CEL-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-CEL-179791.1 GENE ONTOLOGY GO:0046934 Reactome Database ID Release 78 10599240 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599240 Reactome Database ID Release 78 10599242 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599242 Reactome R-CEL-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-CEL-177939.1 The kinase activity of PIK3 mediates the phosphorylation of PIP2 to form PIP3 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> EGF-like ligands:p-6Y-EGFR:GRB2:p-5Y-GAB1:SHP2 Reactome DB_ID: 10599177 Ghost homologue of PTPN11 Reactome DB_ID: 10599150 Reactome Database ID Release 78 10599150 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599150 Reactome R-CEL-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-CEL-162563.1 1 1 Reactome Database ID Release 78 10599177 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599177 Reactome R-CEL-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-CEL-180269.1 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: 10599190 1 Converted from EntitySet in Reactome GRB2:p-Y627,Y659-GAB1,GRB2:p-Y627,Y659-GAB1:PIP3 Reactome DB_ID: 10599188 GRB2:Phospho-GAB1(partially dephosphorylated) Reactome DB_ID: 10599184 1 G5EDJ4 phospho-soc-1 p-Y627,Y659-GAB1 Reactome DB_ID: 10599182 1 EQUAL 694 EQUAL Reactome Database ID Release 78 10599182 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599182 Reactome R-CEL-180496 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-180496.1 1 Reactome Database ID Release 78 10599184 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599184 Reactome R-CEL-180511 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-180511.1 GRB2:p-GAB1(partially dephosphorylated):PIP3 Reactome DB_ID: 10599186 1 1 Reactome Database ID Release 78 10599186 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599186 Reactome R-CEL-9038477 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-9038477.1 Reactome Database ID Release 78 10599188 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599188 Reactome R-CEL-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-CEL-9038479.1 1 1 Reactome Database ID Release 78 10599190 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599190 Reactome R-CEL-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-CEL-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 GENE ONTOLOGY GO:0004726 Reactome Database ID Release 78 10599178 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599178 Reactome Database ID Release 78 10599192 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599192 Reactome R-CEL-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-CEL-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: 10599219 1 EGF-like ligands:Phospho-EGFR (-Y992) dimer Reactome DB_ID: 10599217 EGF-like ligands:Phospho-EGFR (- Y992) Reactome DB_ID: 10599215 P24348 phospho-let-23 p-4Y-EGFR Reactome DB_ID: 10599213 25 EQUAL 1210 EQUAL Reactome Database ID Release 78 10599213 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599213 Reactome R-CEL-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-CEL-180287.1 1 1 Reactome Database ID Release 78 10599215 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599215 Reactome R-CEL-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-CEL-180277.1 2 Reactome Database ID Release 78 10599217 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599217 Reactome R-CEL-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-CEL-180343.1 1 1 Reactome Database ID Release 78 10599219 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599219 Reactome R-CEL-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-CEL-180326.1 ACTIVATION Reactome Database ID Release 78 10599221 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599221 Reactome R-CEL-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-CEL-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 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: 10599142 CSK csk-1 G5ECJ6 Reactome DB_ID: 10599127 UniProt:G5ECJ6 csk-1 UniProt G5ECJ6 1 EQUAL 450 EQUAL Reactome Database ID Release 78 10599127 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599127 Reactome R-CEL-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-CEL-180499.1 1 G5EE56 phospho-src-1 MyrG,p-Y530-SRC Reactome DB_ID: 10599140 530 EQUAL 2 EQUAL N-myristoylglycine MOD MOD:00068 2 EQUAL 536 EQUAL Reactome Database ID Release 78 10599140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599140 Reactome R-CEL-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-CEL-377598.1 1 Q09476 phospho-pxl-1 p-Y-PXN Reactome DB_ID: 10599133 UniProt:Q09476 pxl-1 UniProt Q09476 1 EQUAL 591 EQUAL Reactome Database ID Release 78 10599133 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599133 Reactome R-CEL-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-CEL-9031680.1 1 Reactome Database ID Release 78 10599142 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599142 Reactome R-CEL-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-CEL-180522.1 PXN:MyrG-SRC Reactome DB_ID: 10599148 src-1 MyrG-SRC G5EE56 Reactome DB_ID: 10599146 2 EQUAL 536 EQUAL Reactome Database ID Release 78 10599146 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599146 Reactome R-CEL-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-CEL-8876922.1 1 PXN pxl-1 Q09476 Reactome DB_ID: 10599144 1 EQUAL 591 EQUAL Reactome Database ID Release 78 10599144 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599144 Reactome R-CEL-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-CEL-180493.1 1 Reactome Database ID Release 78 10599148 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599148 Reactome R-CEL-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-CEL-180523.1 ACTIVATION Reactome Database ID Release 78 10599180 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599180 Reactome R-CEL-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-CEL-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 10657837 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657837 Reactome R-CEL-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-CEL-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 sli-1 Q19019 Reactome DB_ID: 10599269 UniProt:Q19019 sli-1 UniProt Q19019 1 EQUAL 906 EQUAL Reactome Database ID Release 78 10599269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599269 Reactome R-CEL-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-CEL-112199.1 2 EGF-like ligands:p-6Y-EGFR:CBL Reactome DB_ID: 10599271 2 1 Reactome Database ID Release 78 10599271 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599271 Reactome R-CEL-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-CEL-182960.1 Reactome Database ID Release 78 10599404 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599404 Reactome R-CEL-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-CEL-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 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL Reactome DB_ID: 10599276 2 2 Q19019 phospho-sli-1 p-Y371-CBL Reactome DB_ID: 10599274 371 EQUAL 1 EQUAL 906 EQUAL Reactome Database ID Release 78 10599274 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599274 Reactome R-CEL-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-CEL-182940.1 2 Reactome Database ID Release 78 10599276 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599276 Reactome R-CEL-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-CEL-182953.1 2 ACTIVATION activeUnit: #Protein1 Reactome Database ID Release 78 10599277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599277 Reactome Database ID Release 78 10599279 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599279 Reactome R-CEL-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-CEL-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 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> ubq-1 UBA52(1-76) P0CG71 Reactome DB_ID: 10588876 UniProt:P0CG71 ubq-1 UniProt P0CG71 1 EQUAL 76 EQUAL Reactome Database ID Release 78 10588876 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10588876 Reactome R-CEL-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-CEL-939203.1 2 EGF-like ligands:Ub-p-6Y-EGFR:p-Y371-CBL Reactome DB_ID: 10599346 2 2 2 2 Reactome Database ID Release 78 10599346 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599346 Reactome R-CEL-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-CEL-182930.1 ACTIVATION activeUnit: #Protein24 GENE ONTOLOGY GO:0004842 Reactome Database ID Release 78 10599347 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599347 Q19019 phospho-sli-1 p-Y371-CBL Reactome DB_ID: 10599332 1 EQUAL 906 EQUAL Reactome Database ID Release 78 10599332 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599332 Reactome R-CEL-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-CEL-182923.1 Reactome Database ID Release 78 10599349 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599349 Reactome R-CEL-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-CEL-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: 10599400 1 1 Reactome Database ID Release 78 10599400 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599400 Reactome R-CEL-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-CEL-182910.1 Reactome Database ID Release 78 10599402 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599402 Reactome R-CEL-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-CEL-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: 10599406 2 1 Reactome Database ID Release 78 10599406 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599406 Reactome R-CEL-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-CEL-182928.1 Reactome Database ID Release 78 10599411 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599411 Reactome R-CEL-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-CEL-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: 10599351 2 2 2 2 Reactome Database ID Release 78 10599351 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599351 Reactome R-CEL-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-CEL-182948.1 ACTIVATION activeUnit: #Protein1 Reactome Database ID Release 78 10599407 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599407 Reactome Database ID Release 78 10599409 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599409 Reactome R-CEL-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-CEL-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: 10599384 p-Y371-CBL:GRB2 Reactome DB_ID: 10599382 1 1 Reactome Database ID Release 78 10599382 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599382 Reactome R-CEL-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-CEL-182964.1 2 2 2 2 Reactome Database ID Release 78 10599384 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599384 Reactome R-CEL-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-CEL-182945.1 ACTIVATION activeUnit: #Protein24 Reactome Database ID Release 78 10599385 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599385 Reactome Database ID Release 78 10599387 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599387 Reactome R-CEL-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-CEL-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). 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: 10599376 CDC42:GTP Reactome DB_ID: 10599369 Converted from EntitySet in Reactome Homologues of CDC42 Reactome DB_ID: 10599367 crp-1 CDC42 O62422 Reactome DB_ID: 10599360 UniProt:O62422 crp-1 UniProt O62422 1 EQUAL 188 EQUAL Reactome Database ID Release 78 10599360 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599360 Reactome R-CEL-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-CEL-449545.1 CDC42 cdc-42 Q05062 Reactome DB_ID: 10599365 UniProt:Q05062 cdc-42 UniProt Q05062 1 EQUAL 188 EQUAL Reactome Database ID Release 78 10599365 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599365 Reactome R-CEL-449545-2 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-449545-2.1 Reactome Database ID Release 78 10599367 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599367 Reactome R-CEL-449545-3 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-449545-3.1 1 1 Reactome Database ID Release 78 10599369 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599369 Reactome R-CEL-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-CEL-182921.1 1 pix-1 ARHGEF7 Q21430 Reactome DB_ID: 10599374 UniProt:Q21430 pix-1 UniProt Q21430 1 EQUAL 803 EQUAL Reactome Database ID Release 78 10599374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599374 Reactome R-CEL-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-CEL-430346.1 1 Reactome Database ID Release 78 10599376 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599376 Reactome R-CEL-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-CEL-182917.1 CBL:Beta-Pix:CDC42:GTP Reactome DB_ID: 10599422 1 1 Reactome Database ID Release 78 10599422 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599422 Reactome R-CEL-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-CEL-182956.1 Reactome Database ID Release 78 10599424 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599424 Reactome R-CEL-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-CEL-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: 10599353 2 2 CIN85:endophilin Reactome DB_ID: 10599328 SH3KBP1 tetramer Reactome DB_ID: 10599312 cdap-2 SH3KBP1 Q6A573 Reactome DB_ID: 10599310 UniProt:Q6A573 cdap-2 UniProt Q6A573 1 EQUAL 665 EQUAL Reactome Database ID Release 78 10599310 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599310 Reactome R-CEL-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-CEL-182957.1 4 Reactome Database ID Release 78 10599312 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599312 Reactome R-CEL-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-CEL-8875475.1 1 Converted from EntitySet in Reactome SH3GLs endophilins Reactome DB_ID: 10599326 SH3GL2 dimer Reactome DB_ID: 10599316 unc-57 SH3GL2 B1V8A0 Reactome DB_ID: 10599314 UniProt:B1V8A0 unc-57 UniProt B1V8A0 1 EQUAL 352 EQUAL Reactome Database ID Release 78 10599314 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599314 Reactome R-CEL-182958 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-182958.1 2 Reactome Database ID Release 78 10599316 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599316 Reactome R-CEL-8867741 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8867741.1 SH3GL1 dimer Reactome DB_ID: 10599320 unc-57 SH3GL1 B1V8A0 Reactome DB_ID: 10599318 1 EQUAL 368 EQUAL Reactome Database ID Release 78 10599318 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599318 Reactome R-CEL-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-CEL-8867732.1 2 Reactome Database ID Release 78 10599320 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599320 Reactome R-CEL-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-CEL-8867743.1 SH3GL3 dimer Reactome DB_ID: 10599324 unc-57 SH3GL3 B1V8A0 Reactome DB_ID: 10599322 1 EQUAL 347 EQUAL Reactome Database ID Release 78 10599322 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599322 Reactome R-CEL-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-CEL-8867734.1 2 Reactome Database ID Release 78 10599324 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599324 Reactome R-CEL-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-CEL-8867739.1 Reactome Database ID Release 78 10599326 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599326 Reactome R-CEL-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-CEL-8867746.1 1 Reactome Database ID Release 78 10599328 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599328 Reactome R-CEL-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-CEL-8875480.1 1 2 2 Reactome Database ID Release 78 10599353 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599353 Reactome R-CEL-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-CEL-182946.1 EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP:CIN85 Reactome DB_ID: 10599378 2 1 Reactome Database ID Release 78 10599378 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599378 Reactome R-CEL-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-CEL-8951489.1 Reactome Database ID Release 78 10599380 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599380 Reactome R-CEL-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-CEL-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 CIN85 dissociates from EGF:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP: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:p-6Y-EGFR:CBL:Beta-Pix:CDC42:GTP Reactome DB_ID: 10599415 2 1 Reactome Database ID Release 78 10599415 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599415 Reactome R-CEL-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-CEL-182932.1 Reactome Database ID Release 78 10652480 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10652480 Reactome R-CEL-8951490 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8951490.1 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). 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 Ub-Beta-Pix:CDC42:GTP Reactome DB_ID: 10599417 1 1 1 Reactome Database ID Release 78 10599417 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599417 Reactome R-CEL-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-CEL-182915.1 2 ACTIVATION activeUnit: #Protein21 Reactome Database ID Release 78 10599418 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599418 Reactome Database ID Release 78 10599420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599420 Reactome R-CEL-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-CEL-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 Assembly of EGFR complex in clathrin-coated vesicles 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 10599355 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599355 Reactome R-CEL-182994 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-182994.1 CBL-CIN85-Endophilin complex mediates ligand-induced down-regulation of the EGF receptor. The BAR domain of endophilin induces membrane curvature. The three SH3 domains of CIN85 bind to atypical proline-arginine motifs (PxxxPR) present in the carboxyl termini of CBL and CBL-b. In this way, CIN85 clusters CBL molecules, which is crucial for efficient EGFR endocytosis and degradation (Soubeyran et al. 2002). 11894095 Pubmed 2002 Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors Soubeyran, P Kowanetz, K Szymkiewicz, I Langdon, WY Dikic, I Nature 416:183-7 LEFT-TO-RIGHT EGFR non-clathrin mediated endocytosis 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> ehs-1 EPS15L1 Q9BIF4 Reactome DB_ID: 10599305 UniProt:Q9BIF4 ehs-1 UniProt Q9BIF4 2 EQUAL 864 EQUAL Reactome Database ID Release 78 10599305 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599305 Reactome R-CEL-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-CEL-182937.1 EPN1 epn-1 Q9BI71 Reactome DB_ID: 10599284 UniProt:Q9BI71 epn-1 UniProt Q9BI71 1 EQUAL 576 EQUAL Reactome Database ID Release 78 10599284 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599284 Reactome R-CEL-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-CEL-182952.1 EPS15:HGS:STAM Reactome DB_ID: 10599303 STAM stam-1 O01498 Reactome DB_ID: 10599299 UniProt:O01498 stam-1 UniProt O01498 2 EQUAL 540 EQUAL Reactome Database ID Release 78 10599299 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599299 Reactome R-CEL-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-CEL-182925.1 1 ehs-1 EPS15 Q9BIF4 Reactome DB_ID: 10599289 1 EQUAL 896 EQUAL Reactome Database ID Release 78 10599289 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599289 Reactome R-CEL-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-CEL-182920.1 1 HGS hgrs-1 Q17796 Reactome DB_ID: 10599294 UniProt:Q17796 hgrs-1 UniProt Q17796 1 EQUAL 777 EQUAL Reactome Database ID Release 78 10599294 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599294 Reactome R-CEL-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-CEL-182954.1 1 Reactome Database ID Release 78 10599303 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599303 Reactome R-CEL-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-CEL-182947.1 EGF-like ligands:p-6Y-EGFR:p-Y371-CBL:CIN85:Endophilin:Epsin:Eps15L1:Eps15 Reactome DB_ID: 10599330 1 1 1 1 1 Reactome Database ID Release 78 10599330 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599330 Reactome R-CEL-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-CEL-182961.1 Reactome Database ID Release 78 10599413 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599413 Reactome R-CEL-183072 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-183072.1 At higher concentrations of ligand, a substantial fraction of the receptor (>50%) is endocytosed through a clathrin independent, lipid-raft-dependent route as the receptor becomes Y1045 phosphorylated and ubiquitnated. Eps15 and Epsin are found in caveolae. Eps15 and Epsin are immunoprecipated with the EGF receptor. Non-clathrin internalization of ubiquitinated EGFR depends on its interaction with proteins harbouring the UIM Ub-interacting motif, as shown through the ablation of three Ub-interacting motif-containing proteins, Eps15, Eps15R and Epsin. 12072436 Pubmed 2002 A ubiquitin-interacting motif (UIM) is essential for Eps15 and Eps15R ubiquitination Klapisz, E Sorokina, I Lemeer, S Pijnenburg, M Verkleij, AJ van Bergen en Henegouwen, PM J Biol Chem 277:30746-53 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 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: 10599391 1 Ghost homologue of p-Y53/55-SPRY1/2 Reactome DB_ID: 10599389 Reactome Database ID Release 78 10599389 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599389 Reactome R-CEL-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-CEL-182963.1 1 Reactome Database ID Release 78 10599391 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599391 Reactome R-CEL-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-CEL-182935.1 EGF-like ligands:p-6Y-EGFR:CBL:Ub-p-Y53/55-SPRY1/2 Reactome DB_ID: 10599395 Ub-p-Y53/55-SPRY1/2 Reactome DB_ID: 10599393 1 1 Reactome Database ID Release 78 10599393 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599393 Reactome R-CEL-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-CEL-182967.1 1 1 Reactome Database ID Release 78 10599395 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599395 Reactome R-CEL-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-CEL-182939.1 ACTIVATION Reactome Database ID Release 78 10599396 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599396 Reactome Database ID Release 78 10599398 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599398 Reactome R-CEL-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-CEL-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. 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 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:Ub-CIN85:Endophilin:Epsin:Eps15L1:Eps15 Reactome DB_ID: 10599341 2 Ub-CIN85:endophilin Reactome DB_ID: 10599339 1 Ub-CIN85 Reactome DB_ID: 10599337 cdap-2 Ub-SH3KBP1 Q6A573 Reactome DB_ID: 10599335 ubiquitinylated lysine MOD MOD:01148 1 EQUAL 665 EQUAL Reactome Database ID Release 78 10599335 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599335 Reactome R-CEL-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-CEL-182926.1 4 Reactome Database ID Release 78 10599337 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599337 Reactome R-CEL-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-CEL-8934535.1 1 Reactome Database ID Release 78 10599339 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599339 Reactome R-CEL-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-CEL-8934537.1 1 2 2 1 1 1 Reactome Database ID Release 78 10599341 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599341 Reactome R-CEL-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-CEL-182936.1 ACTIVATION activeUnit: #Protein21 Reactome Database ID Release 78 10599342 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599342 Reactome Database ID Release 78 10599344 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599344 Reactome R-CEL-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-CEL-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 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: 10649743 1 1 1 1 1 Reactome Database ID Release 78 10649743 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649743 Reactome R-CEL-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-CEL-8867034.1 Reactome Database ID Release 78 10649750 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649750 Reactome R-CEL-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-CEL-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 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: 10649745 1 1 1 p-Eps15:HGS:STAM Reactome DB_ID: 10649666 Q9BIF4 phospho-ehs-1 p-Y850 EPS15 Reactome DB_ID: 10649664 850 EQUAL 1 EQUAL 896 EQUAL Reactome Database ID Release 78 10649664 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649664 Reactome R-CEL-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-CEL-8867028.1 1 1 1 Reactome Database ID Release 78 10649666 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649666 Reactome R-CEL-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-CEL-8867032.1 1 1 Reactome Database ID Release 78 10649745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649745 Reactome R-CEL-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-CEL-8867035.1 ACTIVATION activeUnit: #Protein1 Reactome Database ID Release 78 10649746 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649746 Reactome Database ID Release 78 10649748 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649748 Reactome R-CEL-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-CEL-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 LEFT-TO-RIGHT 3.1.3.48 PTPN3 dephosphorylates 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> ACTIVATION ptp-1 PTPN3 P28191 Reactome DB_ID: 10649755 UniProt:P28191 ptp-1 UniProt P28191 1 EQUAL 913 EQUAL Reactome Database ID Release 78 10649755 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649755 Reactome R-CEL-5490317 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5490317.1 GENE ONTOLOGY GO:0004725 Reactome Database ID Release 78 10649756 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649756 Reactome Database ID Release 78 10649758 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10649758 Reactome R-CEL-8867047 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8867047.1 While the roles of EGFR and EPS15 phosphorylation and ubiquitination are not completely clear, recent evidence supports the idea that EGFR-mediated phosphorylation of EPS15 promotes the clustering of the activated receptor into clathrin-coated pits, while the dephosphorylated EPS15 targets EGFR for endocytosis through a caveolin-and lipid raft-dependent route (reviewed in van Bergen en Henegouwen, 2009). Consistent with this, overexpression of the phosphatase PTPN3, which dephosphorylates EPS15 in vitro and in vivo, promotes the internalization of EGFR into caveolin-enriched structures and targets it for lysosomal degradation (Li et al, 2015). Reactome Database ID Release 78 10657867 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657867 Reactome R-CEL-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-CEL-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 10657429 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657429 Reactome R-CEL-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-CEL-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> 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 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> KAL1 kal-1 G5EDX1 Reactome DB_ID: 10636857 UniProt:G5EDX1 kal-1 UniProt G5EDX1 25 EQUAL 680 EQUAL Reactome Database ID Release 78 10636857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636857 Reactome R-CEL-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-CEL-5654345.1 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 KAL1:HS Reactome DB_ID: 10636859 1 1 Reactome Database ID Release 78 10636859 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636859 Reactome R-CEL-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-CEL-5654355.1 Reactome Database ID Release 78 10636861 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636861 Reactome R-CEL-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-CEL-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 10659149 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659149 Reactome R-CEL-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-CEL-190373.1 GENE ONTOLOGY GO:0008543 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. 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 Reactome Database ID Release 78 10659151 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659151 Reactome R-CEL-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-CEL-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 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 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> FGFRL1 dimer Reactome DB_ID: 10636846 igcm-4 FGFRL1 Q95XJ7 Reactome DB_ID: 10636844 UniProt:Q95XJ7 igcm-4 UniProt Q95XJ7 25 EQUAL 504 EQUAL Reactome Database ID Release 78 10636844 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636844 Reactome R-CEL-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-CEL-197650.1 2 Reactome Database ID Release 78 10636846 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636846 Reactome R-CEL-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-CEL-5654348.1 Converted from EntitySet in Reactome FGFRL1-binding FGFs Reactome DB_ID: 10636848 FGF3 let-756 Q11184 Reactome DB_ID: 10600483 UniProt:Q11184 let-756 UniProt Q11184 18 EQUAL 239 EQUAL Reactome Database ID Release 78 10600483 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10600483 Reactome R-CEL-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-CEL-189886.1 egl-17 FGF8-1 G5EEF1 Reactome DB_ID: 10600496 UniProt:G5EEF1 egl-17 UniProt G5EEF1 23 EQUAL 233 EQUAL Reactome Database ID Release 78 10600496 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10600496 Reactome R-CEL-189892 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-189892.1 Reactome Database ID Release 78 10636848 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636848 Reactome R-CEL-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-CEL-5654351.1 2 FGFRL1-binding FGFs:FGFRL1 dimer Reactome DB_ID: 10636850 1 1 2 Reactome Database ID Release 78 10636850 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636850 Reactome R-CEL-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-CEL-5654354.1 Reactome Database ID Release 78 10636852 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636852 Reactome R-CEL-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-CEL-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 Reactome Database ID Release 78 10659147 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659147 Reactome R-CEL-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-CEL-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 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> Activated FGFR1:FRS2 Reactome DB_ID: 10636863 FRS2 rog-1 E6N0V1 Reactome DB_ID: 10636821 UniProt:E6N0V1 rog-1 UniProt E6N0V1 1 EQUAL 508 EQUAL Reactome Database ID Release 78 10636821 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636821 Reactome R-CEL-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-CEL-170963.1 1 Ghost homologue of Activated FGFR1 Reactome DB_ID: 10627114 Reactome Database ID Release 78 10627114 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10627114 Reactome R-CEL-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-CEL-5654170.1 1 Reactome Database ID Release 78 10636863 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636863 Reactome R-CEL-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-CEL-5654176.1 6 6 Activated FGFR1:p-FRS2 Reactome DB_ID: 10627116 1 E6N0V1 phospho-rog-1 p-6Y-FRS2 Reactome DB_ID: 10595160 436 EQUAL 196 EQUAL 306 EQUAL 349 EQUAL 392 EQUAL 471 EQUAL 1 EQUAL 508 EQUAL Reactome Database ID Release 78 10595160 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10595160 Reactome R-CEL-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-CEL-170959.1 1 Reactome Database ID Release 78 10627116 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10627116 Reactome R-CEL-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-CEL-5654200.1 ACTIVATION Reactome Database ID Release 78 10636873 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636873 Reactome Database ID Release 78 10636875 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636875 Reactome R-CEL-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-CEL-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> Activated FGFR1:FRS3 Reactome DB_ID: 10636877 1 FRS3 rog-1 E6N0V1 Reactome DB_ID: 10636872 2 EQUAL 492 EQUAL Reactome Database ID Release 78 10636872 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636872 Reactome R-CEL-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-CEL-191482.1 1 Reactome Database ID Release 78 10636877 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636877 Reactome R-CEL-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-CEL-5654255.1 5 5 Activated FGFR1:p-FRS3 Reactome DB_ID: 10636805 E6N0V1 phospho-rog-1 p-5Y-FRS3 Reactome DB_ID: 10636803 191 EQUAL 286 EQUAL 321 EQUAL 416 EQUAL 454 EQUAL 2 EQUAL 492 EQUAL Reactome Database ID Release 78 10636803 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636803 Reactome R-CEL-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-CEL-191475.1 1 1 Reactome Database ID Release 78 10636805 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636805 Reactome R-CEL-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-CEL-5654261.1 ACTIVATION Reactome Database ID Release 78 10636878 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636878 Reactome Database ID Release 78 10636880 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636880 Reactome R-CEL-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-CEL-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: 10636807 Reactome Database ID Release 78 10636807 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636807 Reactome R-CEL-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-CEL-5654262.1 Activated FGFR1:p-FRS2:GRB2:SOS1 Reactome DB_ID: 10636809 1 1 Reactome Database ID Release 78 10636809 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636809 Reactome R-CEL-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-CEL-5654264.1 Reactome Database ID Release 78 10636882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636882 Reactome R-CEL-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-CEL-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 10636810 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636810 Reactome Database ID Release 78 10636812 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636812 Reactome R-CEL-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-CEL-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. Reactome Database ID Release 78 10659141 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659141 Reactome R-CEL-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-CEL-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 18452557 Pubmed 2008 Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins Gotoh, N Cancer Sci 99:1319-25 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 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 activated FGFR1:PLCG1 Reactome DB_ID: 10636784 1 plc-3 PLCG1 Q22070 Reactome DB_ID: 10599927 2 EQUAL 1290 EQUAL Reactome Database ID Release 78 10599927 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599927 Reactome R-CEL-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-CEL-167682.1 1 1 Reactome Database ID Release 78 10636784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636784 Reactome R-CEL-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-CEL-5654155.1 4 activated FGFR1:p-4Y-PLCG1 Reactome DB_ID: 10636786 1 1 Reactome Database ID Release 78 10636786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636786 Reactome R-CEL-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-CEL-5654154.1 ACTIVATION Reactome Database ID Release 78 10636787 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636787 Reactome Database ID Release 78 10636789 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636789 Reactome R-CEL-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-CEL-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. Reactome Database ID Release 78 10659137 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659137 Reactome R-CEL-5654219 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654219.1 Phospholipase C-gamma (PLC-gamma) is a substrate of the fibroblast growth factor receptor (FGFR) and other receptors with tyrosine kinase activity. It is known that the src homology region 2 (SH2 domain) of PLC-gamma and of other signaling molecules (such as GTPase-activating protein and phosphatidylinositol 3-kinase-associated p85) direct their binding toward autophosphorylated tyrosine residues of the FGFR. Recruitment of PLC-gamma results in its phosphorylation and activation by the receptor. Activated PLC-gamma hydrolyzes phosphatidyl inositol[4,5] P2 to form the second messengers diacylglycerol (DAG) and Ins [1,4,5]P3, which stimulate calcium release and activation of calcium/calmodulin dependent kinases.<br> 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 PI-3K 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 Binding of PIK3 regulatory alpha subunit to 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> GRB2:GAB1:PIK3R1 Reactome DB_ID: 10599206 1 1 Reactome Database ID Release 78 10599206 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599206 Reactome R-CEL-179864 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-179864.1 Reactome Database ID Release 78 10599208 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10599208 Reactome R-CEL-177931 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-177931.1 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. 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 Activated FGFR1:p-FRS2 binds GRB2:GAB1:PIK3R1 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-FRS2:GRB2:GAB1:PIK3R1 Reactome DB_ID: 10627118 1 1 Reactome Database ID Release 78 10627118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10627118 Reactome R-CEL-5654186 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654186.1 Reactome Database ID Release 78 10636884 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636884 Reactome R-CEL-5654592 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654592.1 The direct GRB2-binding sites of FRS2 have a major role in activation of the PI3K pathway. 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 2.7.1.153 FGFR1-associated PI3K phosphorylates PIP2 to 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> ACTIVATION Activated FGFR1:p-FRS2:GRB2:GAB1:PI3K Reactome DB_ID: 10627120 1 1 Reactome Database ID Release 78 10627120 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10627120 Reactome R-CEL-5654205 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654205.1 Reactome Database ID Release 78 10636914 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636914 Reactome Database ID Release 78 10636916 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636916 Reactome R-CEL-5654690 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654690.1 Once recruited to the membrane, PI3K catalyzes the phosphorylation of PI(4,5)P2 to PI(3,4,5)P3. Reactome Database ID Release 78 10657859 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657859 Reactome R-CEL-5654689 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654689.1 The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals. 10918587 Pubmed 2000 Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4 Hart, KC Robertson, SC Kanemitsu, MY Meyer, AN Tynan, JA Donoghue, DJ Oncogene 19:3309-20 11057895 Pubmed 2000 Cell signaling by receptor tyrosine kinases Schlessinger, J Cell 103:211-25 12089343 Pubmed 2002 The phosphatidylinositol 3-kinase/Akt signaling pathway modulates the endocrine differentiation of trophoblast cells Kamei, T Jones, SR Chapman, BM MCGonigle, KL Dai, G Soares, MJ Mol Endocrinol 16:1469-81 12558974 Pubmed 2003 The role of phosphatidylinositol 3-kinase in neural cell adhesion molecule-mediated neuronal differentiation and survival Ditlevsen, DK Kohler, LB Pedersen, MV Risell, M Kolkova, K Meyer, M Berezin, V Bock, E J Neurochem 84:546-56 Reactome Database ID Release 78 10657861 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657861 Reactome R-CEL-5654687 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654687.1 Signaling via FGFRs is mediated via direct recruitment of signaling proteins that bind to tyrosine auto-phosphorylation sites on the activated receptor and via closely linked docking proteins that become tyrosine phosphorylated in response to FGF-stimulation and form a complex with additional complement of signaling proteins. <br><br>The activation loop in the catalytic domain of FGFR maintains the PTK domain in an inactive or low activity state. The activation-loop of FGFR1, for instance, contains two tyrosine residues that must be autophosphorylated for maintaining the catalytic domain in an active state. In the autoinhibited configuration, a kinase invariant proline residue at the C-terminal end of the activation loop interferes with substrate binding while allowing access to ATP in the nucleotide binding site.<br>In addition to the catalytic PTK core, the cytoplasmic domain of FGFR contains several regulatory sequences. The juxtamembrane domain of FGFRs is considerably longer than that of other receptor tyrosine kinases. This region contains a highly conserved sequence that serves as a binding site for the phosphotyrosine binding (PTB) domain of FRS2. A variety of signaling proteins are phosphorylated in response to FGF stimulation, including Shc, phospholipase-C gamma and FRS2 leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape. 8752212 Pubmed 1996 Structure of the FGF receptor tyrosine kinase domain reveals a novel autoinhibitory mechanism Mohammadi, M Schlessinger, J Hubbard, SR Cell 86:577-87 15863038 Pubmed 2005 Mechanisms underlying differential responses to FGF signaling Dailey, L Ambrosetti, D Mansukhani, A Basilico, C Cytokine Growth Factor Rev 16:233-47 Negative regulation 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 2.7.11.24 Activated ERK1/2 threonine-phosphorylates FGFR1-associated 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> 8 8 Activated FGFR1:p-8T-FRS2 Reactome DB_ID: 10636865 E6N0V1 phospho-rog-1 p-8T-FRS2 Reactome DB_ID: 10636834 132 EQUAL O-phospho-L-threonine MOD MOD:00047 135 EQUAL 138 EQUAL 376 EQUAL 452 EQUAL 455 EQUAL 458 EQUAL 463 EQUAL 2 EQUAL 508 EQUAL Reactome Database ID Release 78 10636834 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636834 Reactome R-CEL-1270462 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-1270462.1 1 1 Reactome Database ID Release 78 10636865 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636865 Reactome R-CEL-5654260 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654260.1 ACTIVATION Converted from EntitySet in Reactome p-ERK dimer p-T,Y MAPK dimers Reactome DB_ID: 10598531 p-T202, Y204 MAPK3 dimer Reactome DB_ID: 10598527 Converted from EntitySet in Reactome Homologues of p-T202,Y204-MAPK3 Reactome DB_ID: 10595469 P39745 phospho-mpk-1 p-T202,Y204-MAPK3 Reactome DB_ID: 10595463 UniProt:P39745 mpk-1 UniProt P39745 202 EQUAL 204 EQUAL 2 EQUAL 379 EQUAL Reactome Database ID Release 78 10595463 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10595463 Reactome R-CEL-109842 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-109842.1 U4PDY6 phospho-p-T202,Y204-MAPK3 Reactome DB_ID: 10595467 UniProt:U4PDY6 UniProt U4PDY6 202 EQUAL 204 EQUAL 2 EQUAL 379 EQUAL Reactome Database ID Release 78 10595467 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10595467 Reactome R-CEL-109842-2 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-109842-2.1 Reactome Database ID Release 78 10595469 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10595469 Reactome R-CEL-109842-3 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-109842-3.1 2 Reactome Database ID Release 78 10598527 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10598527 Reactome R-CEL-109844 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-109844.1 p-T185,Y187 MAPK1 dimer Reactome DB_ID: 10598529 P39745 phospho-mpk-1 p-T185,Y187-MAPK1 Reactome DB_ID: 10595485 185 EQUAL 187 EQUAL 2 EQUAL 360 EQUAL Reactome Database ID Release 78 10595485 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10595485 Reactome R-CEL-109853 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-109853.1 2 Reactome Database ID Release 78 10598529 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10598529 Reactome R-CEL-109855 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-109855.1 Reactome Database ID Release 78 10598531 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10598531 Reactome R-CEL-1268261 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-1268261.1 GENE ONTOLOGY GO:0004707 Reactome Database ID Release 78 10636866 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636866 Reactome Database ID Release 78 10636868 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636868 Reactome R-CEL-5654560 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654560.1 FRS2 has 8 canonical MAPK phosphorylation sites which are phosphorylated by activated ERK1/2 after FGF stimulation. Phosphorylation of these 8 threonine residues counteracts the activating effect of tyrosine phosphorylation of FRS2, although the exact mechanism for this negative regulation is not known. Expression of a version of FRS2 in which the 8 threonine residues are mutated to valine results in enhanced tyrosine phosphorylation of FRS2, enhanced GRB2-SOS1 recruitment and a more sustained MAPK response. The 8 threonine residues are not conserved in FRS3; as a result, signaling through FRS3 complexes do not appear to be subject to this downregulation. 12974390 Pubmed 2003 EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2 Wu, Y Chen, Z Ullrich, A Biol Chem 384:1215-26 19652666 Pubmed 2009 FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway Zhou, W Feng, X Wu, Y Benge, J Zhang, Z Chen, Z Cell Res 19:1165-77 Reactome Database ID Release 78 10659153 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659153 Reactome R-CEL-5654726 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654726.1 Once activated, the FGFR signaling pathway is regulated by numerous negative feedback mechanisms. These include downregulation of receptors through CBL-mediated ubiquitination and endocytosis, ERK-mediated inhibition of FRS2-tyrosine phosphorylation and the attenuation of ERK signaling through the action of dual-specificity phosphatases, IL17RD/SEF, Sprouty and Spred proteins. A number of these inhibitors are themselves transcriptional targets of the activated FGFR pathway. 12815057 Pubmed 2003 Tyrosine phosphorylation of Sprouty2 enhances its interaction with c-Cbl and is crucial for its function Fong, CW Leong, HF Wong, ES Lim, J Yusoff, P Guy, GR J Biol Chem 278:33456-64 20940169 Pubmed 2011 Fibroblast growth factors: from molecular evolution to roles in development, metabolism and disease Itoh, N Ornitz, DM J Biochem 149:121-30 11997436 Pubmed 2002 FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl Wong, A Lamothe, B Lee, A Schlessinger, J Lax, I Proc Natl Acad Sci U S A 99:6684-9 Reactome Database ID Release 78 10657863 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657863 Reactome R-CEL-5654736 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654736.1 The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.<br><br>Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.<br><br>This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.<br> 19247306 Pubmed 2009 The FGF family: biology, pathophysiology and therapy Beenken, A Mohammadi, M Nat Rev Drug Discov 8:235-53 20602996 Pubmed 2010 Cell signaling by receptor tyrosine kinases Lemmon, MA Schlessinger, J Cell 141:1117-34 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 15567848 Pubmed 2004 Common and distinct elements in cellular signaling via EGF and FGF receptors Schlessinger, J Science 306:1506-7 12080084 Pubmed 2002 FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease Ornitz, DM Marie, PJ Genes Dev 16:1446-65 Signaling by FGFR2 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> FGFR2 alternative splicing 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 PTB and hnRNPA1 bind FGFR2 pre-mRNA to repress IIIb splicing and promote formation of FGFR2c mRNA 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> ptb-1 PTBP1 Q18999 Reactome DB_ID: 10590957 nucleoplasm GENE ONTOLOGY GO:0005654 UniProt:Q18999 ptb-1 UniProt Q18999 1 EQUAL 531 EQUAL Reactome Database ID Release 78 10590957 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590957 Reactome R-CEL-71923 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-71923.1 capped, methylated pre-FGFR2 mRNA:CBC complex Reactome DB_ID: 10646422 Cap Binding Complex (CBC) Reactome DB_ID: 10590856 NCBP1 ncbp-1 O01763 Reactome DB_ID: 10590854 UniProt:O01763 ncbp-1 UniProt O01763 1 EQUAL 790 EQUAL Reactome Database ID Release 78 10590854 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590854 Reactome R-CEL-51469 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-51469.1 1 NCBP2 ncbp-2 Q93594 Reactome DB_ID: 10590849 UniProt:Q93594 ncbp-2 UniProt Q93594 1 EQUAL 156 EQUAL Reactome Database ID Release 78 10590849 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590849 Reactome R-CEL-51463 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-51463.1 1 Reactome Database ID Release 78 10590856 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590856 Reactome R-CEL-77088 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-77088.1 1 Ghost homologue of capped, methylated FGFR2 nascent transcript Reactome DB_ID: 10646420 Reactome Database ID Release 78 10646420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10646420 Reactome R-CEL-6803521 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-6803521.1 1 RNA Polymerase II (unphosphorylated):TFIIF complex Reactome DB_ID: 10590943 RNA Polymerase II holoenzyme complex (unphosphorylated) Reactome DB_ID: 10590941 rpb-2 POLR2B Q10578 Reactome DB_ID: 10590877 UniProt:Q10578 rpb-2 UniProt Q10578 1 EQUAL 1174 EQUAL Reactome Database ID Release 78 10590877 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590877 Reactome R-CEL-63504 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-63504.1 1 rpb-4 POLR2D O02092 Reactome DB_ID: 10590882 UniProt:O02092 rpb-4 UniProt O02092 1 EQUAL 142 EQUAL Reactome Database ID Release 78 10590882 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590882 Reactome R-CEL-63508 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-63508.1 1 rpb-9 POLR2I Q965S0 Reactome DB_ID: 10590872 UniProt:Q965S0 rpb-9 UniProt Q965S0 1 EQUAL 125 EQUAL Reactome Database ID Release 78 10590872 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590872 Reactome R-CEL-63525 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-63525.1 1 ama-1 POLR2A P16356 Reactome DB_ID: 10590939 UniProt:P16356 ama-1 UniProt P16356 1 EQUAL 1970 EQUAL Reactome Database ID Release 78 10590939 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590939 Reactome R-CEL-63502 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-63502.1 1 rpb-7 POLR2G Q9N3C9 Reactome DB_ID: 10590887 UniProt:Q9N3C9 rpb-7 UniProt Q9N3C9 1 EQUAL 172 EQUAL Reactome Database ID Release 78 10590887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590887 Reactome R-CEL-63517 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-63517.1 1 rpb-6 POLR2F Q17684 Reactome DB_ID: 10590912 UniProt:Q17684 rpb-6 UniProt Q17684 2 EQUAL 127 EQUAL Reactome Database ID Release 78 10590912 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590912 Reactome R-CEL-83714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-83714.1 1 rpb-10 POLR2L Q9GR61 Reactome DB_ID: 10590917 UniProt:Q9GR61 rpb-10 UniProt Q9GR61 1 EQUAL 67 EQUAL Reactome Database ID Release 78 10590917 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590917 Reactome R-CEL-83715 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-83715.1 1 rpb-5 POLR2E Q9N5K2 Reactome DB_ID: 10590907 UniProt:Q9N5K2 rpb-5 UniProt Q9N5K2 1 EQUAL 210 EQUAL Reactome Database ID Release 78 10590907 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590907 Reactome R-CEL-83713 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-83713.1 1 rpb-11 POLR2J Q9XVH6 Reactome DB_ID: 10590867 UniProt:Q9XVH6 rpb-11 UniProt Q9XVH6 1 EQUAL 117 EQUAL Reactome Database ID Release 78 10590867 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590867 Reactome R-CEL-63531 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-63531.1 1 rpb-8 POLR2H Q19826 Reactome DB_ID: 10590897 UniProt:Q19826 rpb-8 UniProt Q19826 2 EQUAL 150 EQUAL Reactome Database ID Release 78 10590897 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590897 Reactome R-CEL-63523 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-63523.1 1 rpb-3 POLR2C Q93338 Reactome DB_ID: 10590892 UniProt:Q93338 rpb-3 UniProt Q93338 2 EQUAL 275 EQUAL Reactome Database ID Release 78 10590892 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590892 Reactome R-CEL-63506 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-63506.1 1 rpb-12 POLR2K Q9U3I0 Reactome DB_ID: 10590902 UniProt:Q9U3I0 rpb-12 UniProt Q9U3I0 1 EQUAL 58 EQUAL Reactome Database ID Release 78 10590902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590902 Reactome R-CEL-63537 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-63537.1 1 Reactome Database ID Release 78 10590941 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590941 Reactome R-CEL-113401 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-113401.1 1 TFIIF Reactome DB_ID: 10590931 GTF2F1 gtf-2f1 Q17558 Reactome DB_ID: 10590924 UniProt:Q17558 gtf-2f1 UniProt Q17558 2 EQUAL 517 EQUAL Reactome Database ID Release 78 10590924 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590924 Reactome R-CEL-65565 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-65565.1 1 GTF2F2 gtf-2f2 Q8MYM8 Reactome DB_ID: 10590929 UniProt:Q8MYM8 gtf-2f2 UniProt Q8MYM8 2 EQUAL 249 EQUAL Reactome Database ID Release 78 10590929 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590929 Reactome R-CEL-65567 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-65567.1 1 Reactome Database ID Release 78 10590931 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590931 Reactome R-CEL-109631 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-109631.1 1 Reactome Database ID Release 78 10590943 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590943 Reactome R-CEL-71307 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-71307.1 1 Reactome Database ID Release 78 10646422 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10646422 Reactome R-CEL-6803524 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-6803524.1 Converted from EntitySet in Reactome Homologues of HNRNPA1 Reactome DB_ID: 10590971 P34541 HNRNPA1 Reactome DB_ID: 10590964 UniProt:P34541 UniProt P34541 2 EQUAL 372 EQUAL Reactome Database ID Release 78 10590964 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590964 Reactome R-CEL-71927 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-71927.1 sqd-1 HNRNPA1 Q4W5P0 Reactome DB_ID: 10590969 UniProt:Q4W5P0 sqd-1 UniProt Q4W5P0 2 EQUAL 372 EQUAL Reactome Database ID Release 78 10590969 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590969 Reactome R-CEL-71927-2 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-71927-2.1 Reactome Database ID Release 78 10590971 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10590971 Reactome R-CEL-71927-3 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-71927-3.1 FGFR2 IIIc-specific splicing complex Reactome DB_ID: 10646424 1 1 1 Reactome Database ID Release 78 10646424 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10646424 Reactome R-CEL-6803522 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-6803522.1 Reactome Database ID Release 78 10646426 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10646426 Reactome R-CEL-6803523 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-6803523.1 Repression of FGFR2 exon IIIb splicing in mesenchymal cells depends on intronic splicing silencer (ISS) sequences upstream of exon IIIb as well as an exonic splicing element (ESE) within exon IIIb. These elements are bound by PTB1 and hnRNPA1, respectively, as part of a larger splicing complex, promoting the formation and expression of mature FGFR2c mRNA in mesenchymal cells (Carstens et al, 2000; Gil et al, 1991; Del Gatto et al, 1997; Del Gatto et al, 1999). For more detailed information on splicing and pre-mRNA maturation, please see the mRNA splicing pathway. 9271388 Pubmed 1997 Multiple interdependent sequence elements control splicing of a fibroblast growth factor receptor 2 alternative exon Del Gatto, Fabienne Plet, Ariane Gesnel, Marie-Claude Fort, Cécile Breathnach, Richard Mol. Cell. Biol. 17:5106-16 1906035 Pubmed 1991 Characterization of cDNAs encoding the polypyrimidine tract-binding protein Gil, Anna Sharp, Phillip A Jamison, Sharon F Garcia-Blanco, Mariano A Genes Dev. 5:1224-36 9858549 Pubmed 1999 hnRNP A1 recruited to an exon in vivo can function as an exon splicing silencer Del Gatto-Konczak, Fabienne Olive, Michelle Gesnel, Marie-Claude Breathnach, Richard Mol. Cell. Biol. 19:251-60 10982855 Pubmed 2000 An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein Carstens, Russ P Wagner, Eric J Garcia-Blanco, Mariano A Mol. Cell. Biol. 20:7388-400 Reactome Database ID Release 78 10659285 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659285 Reactome R-CEL-6803529 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-6803529.1 Alternative splicing of the FGFR2 nascent mRNA generates an epithelial specific isoform (FGFR2 IIIb) and a mesenchymal specific isoform (FGFR2 IIIc). The inclusion of exon 8 in FGFR2 IIIb or exon 9 in FGFR2 IIIc alters the C-terminal half of the D3 loop of the receptor and is responsible for the different ligand-binding specificities of the two isoforms (reviewed in Eswarakumar et al, 2005). In recent years, a number of cis- and trans-acting elements have been identified that regulate the alternative splicing event. Exon IIIb repression is mediated by the presence of weak splice sites flanking the exon, an exonic silencing sequence (ESS) within the IIIb exon and both intronic silencing sequences (ISS) upstream and downstream (Carstens et al, 2000; Del Gatto and Breathnach, 1995; Del Gatto et al, 1996; Wagner et al 2005; Wagner and Garcia-Blanco, 2001). Binding of hnRNPA1, PTB1, SR family proteins and other factors to these elements represses the IIIb exon and promotes FGFR2 IIIc expression in mesenchymal cells (Del Gatto-Konczak et al, 1999; Carstens et al, 2000; Wagner et al, 2005; Wagner and Garcia-Blanco, 2001; Wagner and Garcia-Blanco, 2002). In epithelial cells, recruitment of epithelial specific factors shifts the splicing events to favour inclusion of exon 8. ESPN1 and ESPN2 are epithelial-specific factors that bind to an ISE/ISS-3 (intronic splicing enhancer/intronic splicing silencer-3) region within intron 8 to promote FGFR2 IIIb-specific splicing (Warzecha et al, 2009). A complex of RBFOX2, hnRNPH1 and hnRNPF also contribute to epithelial-specific splicing by competing for binding to a site that is occupied by the SR proteins ASF/SF2 in mesenchymal cells (Baraniak et al, 2006; Mauger et al, 2008). Other proteins and sequences have also been identified that appear to contribute to the regulated expression of FGFR2b and FGFR2c, but the full details of the alternative splicing event remain to be worked out (Muh et al, 2002; Newman et al, 2006; Del Gatto et al, 2000; Hovhannisyan and Carstens, 2007). 12419237 Pubmed 2002 RNAi-mediated PTB depletion leads to enhanced exon definition Wagner, Eric J Garcia-Blanco, Mariano A Mol. Cell 10:943-9 10938105 Pubmed 2000 The RNA-binding protein TIA-1 is a novel mammalian splicing regulator acting through intron sequences adjacent to a 5' splice site Del Gatto-Konczak, Fabienne Bourgeois, Cyril F Le Guiner, Caroline Kister, Liliane Gesnel, Marie-Claude Stévenin, James Breathnach, Richard Mol. Cell. Biol. 20:6287-99 11313454 Pubmed 2001 Polypyrimidine tract binding protein antagonizes exon definition Wagner, Eric J Garcia-Blanco, Mariano A Mol. Cell. Biol. 21:3281-8 16603716 Pubmed 2006 Identification of RNA-binding proteins that regulate FGFR2 splicing through the use of sensitive and specific dual color fluorescence minigene assays Newman, Emily A Muh, Stephanie J Hovhannisyan, Ruben H Warzecha, Claude C Jones, Richard B McKeehan, Wallace L Carstens, Russ P RNA 12:1129-41 16449636 Pubmed 2006 Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice Baraniak, Andrew P Chen, Jing R Garcia-Blanco, Mariano A Mol. Cell. Biol. 26:1209-22 12393912 Pubmed 2002 A Non-sequence-specific double-stranded RNA structural element regulates splicing of two mutually exclusive exons of fibroblast growth factor receptor 2 (FGFR2) Muh, Stephanie J Hovhannisyan, Ruben H Carstens, Russ P J. Biol. Chem. 277:50143-54 15684416 Pubmed 2005 Characterization of the intronic splicing silencers flanking FGFR2 exon IIIb Wagner, Eric J Baraniak, Andrew P Sessions, October M Mauger, David Moskowitz, Eric Garcia-Blanco, Mariano A J. Biol. Chem. 280:14017-27 17959601 Pubmed 2007 Heterogeneous ribonucleoprotein m is a splicing regulatory protein that can enhance or silence splicing of alternatively spliced exons Hovhannisyan, Ruben H Carstens, Russ P J. Biol. Chem. 282:36265-74 19285943 Pubmed 2009 ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing Warzecha, Claude C Sato, Trey K Nabet, Behnam Hogenesch, John B Carstens, Russ P Mol. Cell 33:591-601 18573884 Pubmed 2008 hnRNP H and hnRNP F complex with Fox2 to silence fibroblast growth factor receptor 2 exon IIIc Mauger, David M Lin, Carolina Garcia-Blanco, Mariano A Mol. Cell. Biol. 28:5403-19 7651400 Pubmed 1995 Exon and intron sequences, respectively, repress and activate splicing of a fibroblast growth factor receptor 2 alternative exon Del Gatto, Fabienne Breathnach, Richard Mol. Cell. Biol. 15:4825-34 8668531 Pubmed 1996 The exon sequence TAGG can inhibit splicing Del Gatto, Fabienne Gesnel, Marie-Claude Breathnach, Richard Nucleic Acids Res. 24:2017-21 Downstream signaling of activated FGFR2 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 FGFR2 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 FGFR2:p-FRS2: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 Activated FGFR2:p-FRS:GRB2:SOS1 Reactome DB_ID: 10636892 Ghost homologue of Activated FGFR2:p-FRS Reactome DB_ID: 10636890 Reactome Database ID Release 78 10636890 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636890 Reactome R-CEL-5654283 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654283.1 1 1 Reactome Database ID Release 78 10636892 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636892 Reactome R-CEL-5654287 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654287.1 Reactome Database ID Release 78 10636893 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636893 Reactome Database ID Release 78 10636895 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636895 Reactome R-CEL-5654618 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654618.1 SOS, recruited by GRB2:p-FRS2 to activated FGFR, activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state. Reactome Database ID Release 78 10659157 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659157 Reactome R-CEL-5654700 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654700.1 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> PI-3K cascade:FGFR2 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 10657853 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657853 Reactome R-CEL-5654695 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654695.1 The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals. Reactome Database ID Release 78 10657855 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657855 Reactome R-CEL-5654696 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654696.1 Signaling via FGFRs is mediated via direct recruitment of signaling proteins that bind to tyrosine auto-phosphorylation sites on the activated receptor and via closely linked docking proteins that become tyrosine phosphorylated in response to FGF-stimulation and form a complex with additional complement of signaling proteins. <br><br>The activation loop in the catalytic domain of FGFR maintains the PTK domain in an inactive or low activity state. The activation-loop of FGFR1, for instance, contains two tyrosine residues that must be autophosphorylated for maintaining the catalytic domain in an active state. In the autoinhibited configuration, a kinase invariant proline residue at the C-terminal end of the activation loop interferes with substrate binding while allowing access to ATP in the nucleotide binding site.<br>In addition to the catalytic PTK core, the cytoplasmic domain of FGFR contains several regulatory sequences. The juxtamembrane domain of FGFRs is considerably longer than that of other receptor tyrosine kinases. This region contains a highly conserved sequence that serves as a binding site for the phosphotyrosine binding (PTB) domain of FRS2. A variety of signaling proteins are phosphorylated in response to FGF stimulation, including Shc, phospholipase-C gamma and FRS2 leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape. Reactome Database ID Release 78 10657857 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657857 Reactome R-CEL-5654738 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654738.1 The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.<br><br>Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.<br><br>This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.<br> Signaling by FGFR3 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> FGFR3 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> FGFR3c 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 2.4.1.41 GALNT3 transfers GalNAc to 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> Q11184 let-756 FGF23(25-251) Reactome DB_ID: 10648491 Golgi lumen GENE ONTOLOGY GO:0005796 25 EQUAL 251 EQUAL Reactome Database ID Release 78 10648491 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10648491 Reactome R-CEL-8851630 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8851630.1 UDP-GalNAc UDP--N-acetylgalactosamine UDP-N-acetyl-D-galactosamine Reactome DB_ID: 735700 UDP-N-acetyl-D-galactosamine [ChEBI:16650] UDP-N-acetyl-D-galactosamine ChEBI CHEBI:16650 Reactome Database ID Release 78 735700 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=735700 Reactome R-ALL-735700 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-735700.3 Q11184 let-756 GalNAc-T178-FGF23(25-251) Reactome DB_ID: 10648493 178 EQUAL O-(N-acetylamino)galactosyl-L-threonine MOD MOD:00164 25 EQUAL 251 EQUAL Reactome Database ID Release 78 10648493 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10648493 Reactome R-CEL-8851624 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8851624.1 UDP uridine 5'-diphosphate Reactome DB_ID: 205687 UDP(3-) [ChEBI:58223] UDP(3-) 5'-O-[(phosphonatooxy)phosphinato]uridine UDP uridine 5'-diphosphate trianion uridine 5'-diphosphate(3-) UDP trianion uridine 5'-diphosphate ChEBI CHEBI:58223 Reactome Database ID Release 78 205687 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=205687 Reactome R-ALL-205687 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-205687.3 ACTIVATION Converted from EntitySet in Reactome Homologues of GALNT3 Reactome DB_ID: 10616063 gly-6 GALNT3 O61394 Reactome DB_ID: 10616059 Golgi membrane GENE ONTOLOGY GO:0000139 UniProt:O61394 gly-6 UniProt O61394 1 EQUAL 633 EQUAL Reactome Database ID Release 78 10616059 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10616059 Reactome R-CEL-913620 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-913620.1 gly-3 GALNT3 P34678 Reactome DB_ID: 10616061 UniProt:P34678 gly-3 UniProt P34678 1 EQUAL 633 EQUAL Reactome Database ID Release 78 10616061 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10616061 Reactome R-CEL-913620-2 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-913620-2.1 Reactome Database ID Release 78 10616063 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10616063 Reactome R-CEL-913620-3 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-913620-3.1 GENE ONTOLOGY GO:0004653 Reactome Database ID Release 78 10648494 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10648494 Reactome Database ID Release 78 10648496 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10648496 Reactome R-CEL-8851619 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8851619.1 Fibroblast growth factor 23 (FGF23, aka phosphatonin) is a regulator of phosphate homeostasis and vitamin D metabolism. Its effects are thought to be mediated via the FGFR3c receptor. Glycosylation is necessary for FGF23 secretion from the cell and that is mediated by polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3), which transfers an N-acetylgalactosaminyl (GalNAc) moiety from a high energy donor to threonine 178 on FGF23 (Kato et al. 2006). Competition between proprotein convertase cleavage and O-glycosylation determines the level of secreted active FGF23. 16638743 Pubmed 2006 Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation Kato, Kentaro Jeanneau, Charlotte Tarp, Mads Agervig Benet-Pages, Anna Lorenz-Depiereux, Bettina Bennett, Eric Paul Mandel, Ulla Strom, TM Clausen, H J. Biol. Chem. 281:18370-7 LEFT-TO-RIGHT GalNAc-T178-FGF23(25-251) translocates from Golgi lumen to extracellular region 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> Q11184 let-756 GalNAc-T178-FGF23(25-251) Reactome DB_ID: 10600505 25 EQUAL 251 EQUAL Reactome Database ID Release 78 10600505 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10600505 Reactome R-CEL-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-CEL-8851633.1 Reactome Database ID Release 78 10648498 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10648498 Reactome R-CEL-8851632 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-8851632.1 Once fibroblast growth factor 23 (FGF23, aka phosphatonin) is glycosylated by GALNT3, it is secreted from the cell (Kato et al. 2006). Reactome Database ID Release 78 10659337 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659337 Reactome R-CEL-190372 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-190372.1 This pathway depicts the binding of an experimentally-verified range of ligands to FGFR3c. 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. Reactome Database ID Release 78 10659339 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659339 Reactome R-CEL-190239 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-190239.1 FGFR3 is a receptor tyrosine kinase of the FGF receptor family, known to have a negative regulatory effect on long bone growth. Somatically, some of the same activating mutations are associated with hypochondroplasia, multiple myeloma, and cervical and vesical carcinoma. 15748888 Pubmed 2005 Cell responses to FGFR3 signalling: growth, differentiation and apoptosis L'Hote, CG Knowles, MA Exp Cell Res 304:417-31 9045692 Pubmed 1997 Signal transduction pathway of human fibroblast growth factor receptor 3. Identification of a novel 66-kDa phosphoprotein. Kanai, M Goke, M Tsunekawa, S Podolsky, DK J Biol Chem 272:6621-8 Downstream signaling of activated FGFR3 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 FGFR3 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 FGFR3:p-FRS2: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 Activated FGFR3:p-FRS:GRB2:SOS1 Reactome DB_ID: 10636816 1 Ghost homologue of Activated FGFR3:p-FRS Reactome DB_ID: 10636814 Reactome Database ID Release 78 10636814 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636814 Reactome R-CEL-5654305 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654305.1 1 Reactome Database ID Release 78 10636816 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636816 Reactome R-CEL-5654308 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654308.1 Reactome Database ID Release 78 10636817 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636817 Reactome Database ID Release 78 10636819 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10636819 Reactome R-CEL-5654413 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654413.1 SOS, recruited by GRB2:p-FRS2 to activated FGFR, activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state. Reactome Database ID Release 78 10659143 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10659143 Reactome R-CEL-5654706 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654706.1 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> PI-3K cascade:FGFR3 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 10657847 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657847 Reactome R-CEL-5654710 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654710.1 The ability of growth factors to protect from apoptosis is primarily due to the activation of the AKT survival pathway. P-I-3-kinase dependent activation of PDK leads to the activation of AKT which in turn affects the activity or expression of pro-apoptotic factors, which contribute to protection from apoptosis. AKT activation also blocks the activity of GSK-3b which could lead to additional antiapoptotic signals. Reactome Database ID Release 78 10657849 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657849 Reactome R-CEL-5654708 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654708.1 Signaling via FGFRs is mediated via direct recruitment of signaling proteins that bind to tyrosine auto-phosphorylation sites on the activated receptor and via closely linked docking proteins that become tyrosine phosphorylated in response to FGF-stimulation and form a complex with additional complement of signaling proteins. <br><br>The activation loop in the catalytic domain of FGFR maintains the PTK domain in an inactive or low activity state. The activation-loop of FGFR1, for instance, contains two tyrosine residues that must be autophosphorylated for maintaining the catalytic domain in an active state. In the autoinhibited configuration, a kinase invariant proline residue at the C-terminal end of the activation loop interferes with substrate binding while allowing access to ATP in the nucleotide binding site.<br>In addition to the catalytic PTK core, the cytoplasmic domain of FGFR contains several regulatory sequences. The juxtamembrane domain of FGFRs is considerably longer than that of other receptor tyrosine kinases. This region contains a highly conserved sequence that serves as a binding site for the phosphotyrosine binding (PTB) domain of FRS2. A variety of signaling proteins are phosphorylated in response to FGF stimulation, including Shc, phospholipase-C gamma and FRS2 leading to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape. Reactome Database ID Release 78 10657851 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10657851 Reactome R-CEL-5654741 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-CEL-5654741.1 The 22 members of the fibroblast growth factor (FGF) family of growth factors mediate their cellular responses by binding to and activating the different isoforms encoded by the four receptor tyrosine kinases (RTKs) designated FGFR1, FGFR2, FGFR3 and FGFR4. These receptors are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. Unlike other growth factors, FGFs act in concert with heparin or heparan sulfate proteoglycan (HSPG) to activate FGFRs and to induce the pleiotropic responses that lead to the variety of cellular responses induced by this large family of growth factors. An alternative, FGF-independent, source of FGFR activation originates from the interaction with cell adhesion molecules, typically in the context of interactions on neural cell membranes and is crucial for neuronal survival and development.<br><br>Upon ligand binding, receptor dimers are formed and their intrinsic tyrosine kinase is activated causing phosphorylation of multiple tyrosine residues on the receptors. These then serve as docking sites for the recruitment of SH2 (src homology-2) or PTB (phosphotyrosine binding) domains of adaptors, docking proteins or signaling enzymes. Signaling complexes are assembled and recruited to the active receptors resulting in a cascade of phosphorylation events.<br><br>This leads to stimulation of intracellular signaling pathways that control cell proliferation, cell differentiation, cell migration, cell survival and cell shape, depending on the cell type or stage of maturation.<br> Signaling by FGFR4 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>