Signaling by FGFR2 (Homo sapiens)

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Description

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.

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.

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.
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Stauber DJ, DiGabriele AD, Hendrickson WA.; ''Structural interactions of fibroblast growth factor receptor with its ligands.''; PubMed Europe PMC Scholia
Beer HD, Bittner M, Niklaus G, Munding C, Max N, Goppelt A, Werner S.; ''The fibroblast growth factor binding protein is a novel interaction partner of FGF-7, FGF-10 and FGF-22 and regulates FGF activity: implications for epithelial repair.''; PubMed Europe PMC Scholia
Klint P, Kanda S, Claesson-Welsh L.; ''Shc and a novel 89-kDa component couple to the Grb2-Sos complex in fibroblast growth factor-2-stimulated cells.''; PubMed Europe PMC Scholia
Baraniak AP, Chen JR, Garcia-Blanco MA.; ''Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice.''; PubMed Europe PMC Scholia
Hall AB, Jura N, DaSilva J, Jang YJ, Gong D, Bar-Sagi D.; ''hSpry2 is targeted to the ubiquitin-dependent proteasome pathway by c-Cbl.''; PubMed Europe PMC Scholia
Chellaiah A, Yuan W, Chellaiah M, Ornitz DM.; ''Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity.''; PubMed Europe PMC Scholia
Ong SH, Goh KC, Lim YP, Low BC, Klint P, Claesson-Welsh L, Cao X, Tan YH, Guy GR.; ''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.''; PubMed Europe PMC Scholia
Zhou W, Feng X, Wu Y, Benge J, Zhang Z, Chen Z.; ''FGF-receptor substrate 2 functions as a molecular sensor integrating external regulatory signals into the FGF pathway.''; PubMed Europe PMC Scholia
Cha JY, Lambert QT, Reuther GW, Der CJ.; ''Involvement of fibroblast growth factor receptor 2 isoform switching in mammary oncogenesis.''; PubMed Europe PMC Scholia
Kyriakis JM, Avruch J.; ''Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update.''; PubMed Europe PMC Scholia
Lao DH, Yusoff P, Chandramouli S, Philp RJ, Fong CW, Jackson RA, Saw TY, Yu CY, Guy GR.; ''Direct binding of PP2A to Sprouty2 and phosphorylation changes are a prerequisite for ERK inhibition downstream of fibroblast growth factor receptor stimulation.''; PubMed Europe PMC Scholia
Eswarakumar VP, Lax I, Schlessinger J.; ''Cellular signaling by fibroblast growth factor receptors.''; PubMed Europe PMC Scholia
Mohammadi M, Honegger AM, Rotin D, Fischer R, Bellot F, Li W, Dionne CA, Jaye M, Rubinstein M, Schlessinger J.; ''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.''; PubMed Europe PMC Scholia
Ahmed Z, Schüller AC, Suhling K, Tregidgo C, Ladbury JE.; ''Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signalling.''; PubMed Europe PMC Scholia
Raffioni S, Zhu YZ, Bradshaw RA, Thompson LM.; ''Effect of transmembrane and kinase domain mutations on fibroblast growth factor receptor 3 chimera signaling in PC12 cells. A model for the control of receptor tyrosine kinase activation.''; PubMed Europe PMC Scholia
Lim J, Wong ES, Ong SH, Yusoff P, Low BC, Guy GR.; ''Sprouty proteins are targeted to membrane ruffles upon growth factor receptor tyrosine kinase activation. Identification of a novel translocation domain.''; PubMed Europe PMC Scholia
Roskoski R.; ''MEK1/2 dual-specificity protein kinases: structure and regulation.''; PubMed Europe PMC Scholia
Warzecha CC, Sato TK, Nabet B, Hogenesch JB, Carstens RP.; ''ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing.''; PubMed Europe PMC Scholia
Mauger DM, Lin C, Garcia-Blanco MA.; ''hnRNP H and hnRNP F complex with Fox2 to silence fibroblast growth factor receptor 2 exon IIIc.''; PubMed Europe PMC Scholia
Itoh H, Hattori Y, Sakamoto H, Ishii H, Kishi T, Sasaki H, Yoshida T, Koono M, Sugimura T, Terada M.; ''Preferential alternative splicing in cancer generates a K-sam messenger RNA with higher transforming activity.''; PubMed Europe PMC Scholia
Xu H, Lee KW, Goldfarb M.; ''Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteins.''; PubMed Europe PMC Scholia
Fukumoto T, Kubota Y, Kitanaka A, Yamaoka G, Ohara-Waki F, Imataki O, Ohnishi H, Ishida T, Tanaka T.; ''Gab1 transduces PI3K-mediated erythropoietin signals to the Erk pathway and regulates erythropoietin-dependent proliferation and survival of erythroid cells.''; PubMed Europe PMC Scholia
Hadari YR, Kouhara H, Lax I, Schlessinger J.; ''Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation.''; PubMed Europe PMC Scholia
Wesche J, Haglund K, Haugsten EM.; ''Fibroblast growth factors and their receptors in cancer.''; PubMed Europe PMC Scholia
Hadari YR, Gotoh N, Kouhara H, Lax I, Schlessinger J.; ''Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways.''; PubMed Europe PMC Scholia
Cargnello M, Roux PP.; ''Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases.''; PubMed Europe PMC Scholia
Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J, Lax I.; ''FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors.''; PubMed Europe PMC Scholia
Del Gatto-Konczak F, Olive M, Gesnel MC, Breathnach R.; ''hnRNP A1 recruited to an exon in vivo can function as an exon splicing silencer.''; PubMed Europe PMC Scholia
Newman EA, Muh SJ, Hovhannisyan RH, Warzecha CC, Jones RB, McKeehan WL, Carstens RP.; ''Identification of RNA-binding proteins that regulate FGFR2 splicing through the use of sensitive and specific dual color fluorescence minigene assays.''; PubMed Europe PMC Scholia
Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, Teague J, Butler A, Edkins S, Stevens C, Parker A, O'Meara S, Avis T, Barthorpe S, Brackenbury L, Buck G, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J, Webb A, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Green A, Knowles M, Leung SY, Looijenga LH, Malkowicz B, Pierotti MA, Teh BT, Yuen ST, Lakhani SR, Easton DF, Weber BL, Goldstraw P, Nicholson AG, Wooster R, Stratton MR, Futreal PA.; ''Somatic mutations of the protein kinase gene family in human lung cancer.''; PubMed Europe PMC Scholia

History

View all...

Revision	Action	Time	User	Comment
113035	view	12:06, 30 October 2020	DeSl	Changed layout for 2 complexes (included at least one small DataNode at top left corner, stretching the whole complex visually).
112410	view	15:35, 9 October 2020	ReactomeTeam	Reactome version 73
101314	view	11:20, 1 November 2018	ReactomeTeam	reactome version 66
100851	view	20:52, 31 October 2018	ReactomeTeam	reactome version 65
100392	view	19:26, 31 October 2018	ReactomeTeam	reactome version 64
99940	view	16:10, 31 October 2018	ReactomeTeam	reactome version 63
99496	view	14:43, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
99145	view	12:41, 31 October 2018	ReactomeTeam	reactome version 62
94045	view	13:53, 16 August 2017	ReactomeTeam	reactome version 61
93670	view	11:30, 9 August 2017	ReactomeTeam	reactome version 61
87128	view	18:46, 18 July 2016	Egonw	Ontology Term : 'signaling pathway' added !
86794	view	09:26, 11 July 2016	ReactomeTeam	reactome version 56
83308	view	10:45, 18 November 2015	ReactomeTeam	Version54
81446	view	12:58, 21 August 2015	ReactomeTeam	New pathway

External references

DataNodes

View all...

Name	Type	Database reference	Comment
ADP	Metabolite	CHEBI:16761 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
AZ 2171	Metabolite	CHEBI:556867 (ChEBI)	A broad specificity ATP-competitive inhibitor of FGF-, VEGF-, PDGF- and KIT receptors that is in Phase I and II clinical trials for treatment of gastric, breast and endometrial cancers.
AZD4547	Metabolite	CHEBI:63453 (ChEBI)	AZD4547 (Astra Zeneca) is a pan-FGFR inhibitor in Phase I clinical trials for patients with advanced gastric cancer (NCT01457846) and for patient with advanced solid tumors with or without amplified FGFR1 or 2 (NCT00979134) and in Phase I/II trials for breast cancer patients with FGFR1 amplifications (NCT01202591).
Activated FGFR2 mutants:p-FRS2:GRB2:GAB1:PI3K	Complex	R-HSA-5655337 (Reactome)
Activated FGFR2 mutants:p-FRS2:GRB2:GAB1:PIK3R1	Complex	R-HSA-5655330 (Reactome)
Activated FGFR2:p-8T-FRS2	Complex	R-HSA-5654281 (Reactome)
Activated FGFR2:p-FRS2:GRB2:GAB1:PI3K	Complex	R-HSA-5654190 (Reactome)
Activated FGFR2:p-FRS2:GRB2:GAB1:PIK3R1	Complex	R-HSA-5654189 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11:GRB2:GAB1:PI3K	Complex	R-HSA-5654192 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11:GRB2:GAB1:PIK3R1	Complex	R-HSA-5654194 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11:p-CBL:GRB2	Complex	R-HSA-5654286 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11	Complex	R-HSA-5654184 (Reactome)
Activated FGFR2:p-FRS2	Complex	R-HSA-5654201 (Reactome)
Activated FGFR2:p-FRS3	Complex	R-HSA-5654284 (Reactome)
Activated FGFR2:p-FRS:GRB2:SOS1	Complex	R-HSA-5654287 (Reactome)
Activated FGFR2:p-FRS:PTPN11	Complex	R-HSA-5654290 (Reactome)
Activated FGFR2:p-FRS:p-PTPN11	Complex	R-HSA-5654291 (Reactome)
Activated FGFR2:p-FRS		R-HSA-5654283 (Reactome)
Activated FGFR2:pY-SHC1:GRB2:SOS1	Complex	R-HSA-5654296 (Reactome)
Activated FGFR2:pY-SHC1	Complex	R-HSA-5654294 (Reactome)
Activated overexpressed FGFR2 dimers		R-HSA-2029940 (Reactome)
Activated FGFR2 ligand-independent mutants		R-HSA-2029948 (Reactome)
Activated FGFR2 mutants with enhanced kinase activity		R-HSA-2033348 (Reactome)
Activated FGFR2 mutants:FRS2	Complex	R-HSA-5655257 (Reactome)
Activated FGFR2 mutants:PLCG1	Complex	R-HSA-5655346 (Reactome)
Activated FGFR2 mutants:p-4Y-PLCG1	Complex	R-HSA-5654745 (Reactome)
Activated FGFR2 mutants:p-FRS2	Complex	R-HSA-5655236 (Reactome)
Activated FGFR2 mutants		R-HSA-5654747 (Reactome)
Activated FGFR2:FRS2	Complex	R-HSA-5654178 (Reactome)
Activated FGFR2:FRS3	Complex	R-HSA-5654277 (Reactome)
Activated FGFR2:SHC1	Complex	R-HSA-5654279 (Reactome)
Activated FGFR2		R-HSA-5654152 (Reactome)
Activated FGFR2b homodimer bound to FGF		R-HSA-192606 (Reactome)
Activated FGFR2b mutants with enhanced ligand binding	Complex	R-HSA-2065931 (Reactome)
Activated FGFR2c homodimer bound to FGF		R-HSA-192616 (Reactome)
Activated FGFR2c mutants with enhanced ligand-binding	Complex	R-HSA-2065989 (Reactome)
BGJ398	Metabolite	CHEBI:63451 (ChEBI)	A pan-FGFR ATP-competitive inhibitor that is in phase I clinical trials for advanced solid malignancies with amplification or activation of FGFR1 and 2 or activation of FGFR3 (NCT01004224).
BRAF	Protein	P15056 (Uniprot-TrEMBL)
BRAF	Protein	P15056 (Uniprot-TrEMBL)
CBL	Protein	P22681 (Uniprot-TrEMBL)
CBL	Protein	P22681 (Uniprot-TrEMBL)
DAG and IP3 signaling	Pathway	R-HSA-1489509 (Reactome)	This pathway describes the generation of DAG and IP3 by the PLCgamma-mediated hydrolysis of PIP2 and the subsequent downstream signaling events.
E3810	Metabolite	CHEBI:65138 (ChEBI)	E-3810 is a dual VEGFR and FGFR inhibitor that has anti-angiogenic and anti-tumorigenic effects in preclinical studies (Bello, 2011). It is in Phase I clinical trials for patients with solid tumors (NCT01283945).
E7080	Metabolite	CHEBI:816009 (ChEBI)	E7080 is a broad-specificity tyrosine kinase inhibitor that is in Phase I clinical trials for a variety of solid malignancies, including metastatic endometrial cancer (NCT01111461). No specific data regarding its preclinical efficacy against activated FGF receptors is available.
FGF1	Protein	P05230 (Uniprot-TrEMBL)
FGF10	Protein	O15520 (Uniprot-TrEMBL)
FGF16	Protein	O43320 (Uniprot-TrEMBL)
FGF17-1	Protein	O60258-1 (Uniprot-TrEMBL)
FGF18	Protein	O76093 (Uniprot-TrEMBL)
FGF2(10-155)	Protein	P09038 (Uniprot-TrEMBL)
FGF2,7,10,22		R-HSA-5656048 (Reactome)
FGF20	Protein	Q9NP95 (Uniprot-TrEMBL)
FGF22	Protein	Q9HCT0 (Uniprot-TrEMBL)
FGF23(25-251)	Protein	Q9GZV9 (Uniprot-TrEMBL)
FGF3	Protein	P11487 (Uniprot-TrEMBL)
FGF4	Protein	P08620 (Uniprot-TrEMBL)
FGF5-1	Protein	P12034-1 (Uniprot-TrEMBL)
FGF6	Protein	P10767 (Uniprot-TrEMBL)
FGF7	Protein	P21781 (Uniprot-TrEMBL)
FGF8-1	Protein	P55075-1 (Uniprot-TrEMBL)
FGF9	Protein	P31371 (Uniprot-TrEMBL)
FGFBP:FGF	Complex	R-HSA-5656071 (Reactome)
FGFBP		R-HSA-5656046 (Reactome)
FGFR2 ligand-independent mutant dimers		R-HSA-2029952 (Reactome)
FGFR2 ligand-independent mutants		R-HSA-2029955 (Reactome)
FGFR2 mutants:p-FRS2:GRB2:SOS1	Complex	R-HSA-5655345 (Reactome)
FGFR2	Protein	P21802 (Uniprot-TrEMBL)
FGFR2 mutant dimers with enhanced kinase activity		R-HSA-2033349 (Reactome)
FGFR2 mutants with enhanced kinase activity		R-HSA-2033351 (Reactome)
FGFR2 point mutant dimers:TKIs	Complex	R-HSA-2077404 (Reactome)
FGFR2 point mutant dimers		R-HSA-2077401 (Reactome)
FGFR2b mutant-binding FGFs:FP-1039	Complex	R-HSA-2077406 (Reactome)
FGFR2b mutant-binding FGFs		R-HSA-2065925 (Reactome)
FGFR2b C3 variant	Protein	P21802-17 (Uniprot-TrEMBL)
FGFR2b P253R	Protein	P21802-3 (Uniprot-TrEMBL)	also Apert
FGFR2b S252W	Protein	P21802-3 (Uniprot-TrEMBL)	also Apert
FGFR2b homodimer bound to FGF		R-HSA-192615 (Reactome)
FGFR2b mutant dimers with enhanced ligand-binding bound to FGFs	Complex	R-HSA-2065929 (Reactome)
FGFR2b mutants with enhanced ligand binding		R-HSA-2033371 (Reactome)
FGFR2b-binding FGFs		R-HSA-189967 (Reactome)
FGFR2b		R-HSA-192604 (Reactome)
FGFR2c homodimer bound to FGF		R-HSA-192594 (Reactome)
FGFR2c mutant binding FGFs		R-HSA-2065982 (Reactome)
FGFR2c mutant dimers with enhanced ligand-binding bound to FGFs	Complex	R-HSA-2065986 (Reactome)
FGFR2c mutants with enhanced ligand binding		R-HSA-2033375 (Reactome)
FGFR2c-binding FGFs		R-HSA-189957 (Reactome)
FGFR2c		R-HSA-192596 (Reactome)
FP-1039		R-NUL-2077408 (Reactome)	FP-1039 is an FGFR1c:Fc fragment that acts as a broad FGF- ligand trap. Developed by FivePrime therapeutics (http://www.fiveprime.com/index.php?option=com_content&view=article&id=222&Itemid=153), FP-1039 is in Phase I clinical trials in solid malignancies and in Phase II trials in endometrial cancer patients carrying the FGFR2 S252W or P253R alleles.
FRS2	Protein	Q8WU20 (Uniprot-TrEMBL)
FRS2	Protein	Q8WU20 (Uniprot-TrEMBL)
FRS3	Protein	O43559 (Uniprot-TrEMBL)
FRS3	Protein	O43559 (Uniprot-TrEMBL)
GAB1	Protein	Q13480 (Uniprot-TrEMBL)
GDP	Metabolite	CHEBI:17552 (ChEBI)
GDP	Metabolite	CHEBI:17552 (ChEBI)
GP369		R-NUL-2067712 (Reactome)
GRB2-1	Protein	P62993-1 (Uniprot-TrEMBL)
GRB2-1:SOS1	Complex	R-HSA-109797 (Reactome)
GRB2-1	Protein	P62993-1 (Uniprot-TrEMBL)
GRB2:GAB1:PIK3R1	Complex	R-HSA-179864 (Reactome)
GRB2:GAB1	Complex	R-HSA-179849 (Reactome)
GTP	Metabolite	CHEBI:15996 (ChEBI)
GTP	Metabolite	CHEBI:15996 (ChEBI)
HRAS	Protein	P01112 (Uniprot-TrEMBL)
HS	Metabolite	CHEBI:28815 (ChEBI)
HS	Metabolite	CHEBI:28815 (ChEBI)
IL17RD-1	Protein	Q8NFM7-1 (Uniprot-TrEMBL)
IL17RD		R-HSA-1268209 (Reactome)
KRAS	Protein	P01116 (Uniprot-TrEMBL)
NRAS	Protein	P01111 (Uniprot-TrEMBL)
Overexpressed FGFR2:TKIs	Complex	R-HSA-2029966 (Reactome)
Overexpressed FGFR2 homodimers:GP369	Complex	R-HSA-2067714 (Reactome)
Overexpressed FGFR2 homodimers		R-HSA-2029963 (Reactome)
Overexpressed FGFR2		R-HSA-2029960 (Reactome)
PD173074	Metabolite	CHEBI:63448 (ChEBI)	PD173074 is potent pan-FGFR reversible inhibitor that interacts with residues in the ATP-binding pocket and inhibits tyrosine kinase activity and autophosphorylation (Mohammadi, 1998; Ezzat, 2005). PD173074 is not suitable for therapeutic use due to issues with toxicity.
PI(3,4,5)P3	Metabolite	CHEBI:16618 (ChEBI)
PI(3,4,5)P3	Metabolite	CHEBI:16618 (ChEBI)
PI(4,5)P2	Metabolite	CHEBI:18348 (ChEBI)
PIK3CA	Protein	P42336 (Uniprot-TrEMBL)
PIK3CA	Protein	P42336 (Uniprot-TrEMBL)
PIK3R1	Protein	P27986 (Uniprot-TrEMBL)
PIK3R1	Protein	P27986 (Uniprot-TrEMBL)
PIP3 activates AKT signaling	Pathway	R-HSA-1257604 (Reactome)	Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PLCG1	Protein	P19174 (Uniprot-TrEMBL)
PLCG1	Protein	P19174 (Uniprot-TrEMBL)
PP2A (A:C)	Complex	R-HSA-934544 (Reactome)
PP2A(A:C):S112/S121-pSPRY2	Complex	R-HSA-934578 (Reactome)
PP2A(A:C):SPRY2	Complex	R-HSA-934550 (Reactome)
PP2A(A:C):Y55/Y227-pSPRY2	Complex	R-HSA-934598 (Reactome)
PPA2A (A:C):S112/S115 p-SPRY2	Complex	R-HSA-1295605 (Reactome)
PPA2A (A:C):Y55/Y227 p-SPRY2:GRB2	Complex	R-HSA-1295625 (Reactome)
PPA2A(A:C):SPRY2	Complex	R-HSA-1295593 (Reactome)
PPP2CA	Protein	P67775 (Uniprot-TrEMBL)
PPP2CB	Protein	P62714 (Uniprot-TrEMBL)
PPP2R1A	Protein	P30153 (Uniprot-TrEMBL)
PTPN11	Protein	Q06124 (Uniprot-TrEMBL)
PTPN11	Protein	Q06124 (Uniprot-TrEMBL)
Phospho-MEK		R-HSA-169287 (Reactome)
Phosphorylated Fibroblast growth factor receptor 2b short	Protein	P21802-18 (Uniprot-TrEMBL)
Pi	Metabolite	CHEBI:18367 (ChEBI)
RAF/MAP kinase cascade	Pathway	R-HSA-5673001 (Reactome)	The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009). The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).
RPS27A(1-76)	Protein	P62979 (Uniprot-TrEMBL)
S111/S120 p-SPRY2:B-RAF	Complex	R-HSA-1295587 (Reactome)
SHC1 p46,p52		R-HSA-1169480 (Reactome)	SHC1 isoforms p46 and p52 are found in B cells (Smit et al. 1994).
SHC1-2	Protein	P29353-2 (Uniprot-TrEMBL)
SHC1-3	Protein	P29353-3 (Uniprot-TrEMBL)
SOS1	Protein	Q07889 (Uniprot-TrEMBL)
SPRY2	Protein	O43597 (Uniprot-TrEMBL)
SPRY2:B-RAF	Complex	R-HSA-1295598 (Reactome)
SRC-1	Protein	P12931-1 (Uniprot-TrEMBL)
SU5402	Metabolite	CHEBI:63449 (ChEBI)	SU5402 is an ATP-competitive FGFR and VEGFR inhibitor that is used as an in vitro reagent. Su5402 is not suitable for therapeutic use due to toxicity issues.
Tyrosine kinase inhibitors of overexpressed FGFR2		R-ALL-2029965 (Reactome)
Tyrosine kinase inhibitors of FGFR2 mutants		R-ALL-2077403 (Reactome)
UBA52(1-76)	Protein	P62987 (Uniprot-TrEMBL)
UBB(1-76)	Protein	P0CG47 (Uniprot-TrEMBL)
UBB(153-228)	Protein	P0CG47 (Uniprot-TrEMBL)
UBB(77-152)	Protein	P0CG47 (Uniprot-TrEMBL)
UBC(1-76)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(153-228)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(229-304)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(305-380)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(381-456)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(457-532)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(533-608)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(609-684)	Protein	P0CG48 (Uniprot-TrEMBL)
UBC(77-152)	Protein	P0CG48 (Uniprot-TrEMBL)
Ub-(Y55/Y227)p-SPRY2	Complex	R-HSA-1370875 (Reactome)
Ub-Activated FGFR2 complex:Ub-p-FRS2	Complex	R-HSA-5654360 (Reactome)
Ub:Y55/Y227-pSPRY2:CBL	Complex	R-HSA-934572 (Reactome)
Ub		R-HSA-113595 (Reactome)
Y55/Y227-pSPRY2:CBL	Complex	R-HSA-934576 (Reactome)
activated FGFR2:PLCG1	Complex	R-HSA-5654162 (Reactome)
activated FGFR2:p-4Y-PLCG1	Complex	R-HSA-5654150 (Reactome)
p-4Y-PLCG1	Protein	P19174 (Uniprot-TrEMBL)
p-4Y-PLCG1	Protein	P19174 (Uniprot-TrEMBL)
p-5Y-FRS3	Protein	O43559 (Uniprot-TrEMBL)	The phospho-tyrosine positions for FRS2-beta were inferred by similarity to the analogous positions in FRS2-alpha. Five out of six tyrosine positions in alpha are present in beta.
p-6Y-FGFR2b C3 variant	Protein	P21802-17 (Uniprot-TrEMBL)
p-6Y-FRS2	Protein	Q8WU20 (Uniprot-TrEMBL)
p-8T-FRS2	Protein	Q8WU20 (Uniprot-TrEMBL)
p-8Y-FGFR2	Protein	P21802 (Uniprot-TrEMBL)	This represents WT FGFR2 of either the IIIb or IIIc isoform that is found overexpressed in some cancers. Sites of tyrosine phosphorylation are marked as unknown to circumvent the numbering differences between the isoform variants.
p-8Y-FGFR2-3	Protein	P21802-3 (Uniprot-TrEMBL)
p-8Y-FGFR2-5	Protein	P21802-5 (Uniprot-TrEMBL)
p-8Y-FGFR2b P253R	Protein	P21802-3 (Uniprot-TrEMBL)	also Apert
p-8Y-FGFR2b S252W	Protein	P21802-3 (Uniprot-TrEMBL)	also Apert
p-8Y-FGFR2c long	Protein	P21802-1 (Uniprot-TrEMBL)
p-MEK:ERK		R-HSA-1268217 (Reactome)
p-MEK:p-ERK		R-HSA-1268207 (Reactome)
p-S111,S120-SPRY2	Protein	O43597 (Uniprot-TrEMBL)
p-S111,S120-SPRY2	Protein	O43597 (Uniprot-TrEMBL)
p-S112,S115-SPRY2	Protein	O43597 (Uniprot-TrEMBL)
p-S112,S121-SPRY2	Protein	O43597 (Uniprot-TrEMBL)
p-T,Y MAPK dimers		R-HSA-1268261 (Reactome)
p-T,Y MAPKs		R-HSA-169289 (Reactome)
p-T250,T255,T385,S437-MKNK1	Protein	Q9BUB5 (Uniprot-TrEMBL)
p-Y194,Y195,Y272-SHC1-1(156-583)	Protein	P29353-3 (Uniprot-TrEMBL)
p-Y239,Y240,Y317-SHC1-2	Protein	P29353-2 (Uniprot-TrEMBL)
p-Y371-CBL	Protein	P22681 (Uniprot-TrEMBL)
p-Y371-CBL:GRB2	Complex	R-HSA-182964 (Reactome)
p-Y546,Y584-PTPN11	Protein	Q06124 (Uniprot-TrEMBL)
p-Y55,Y227-SPRY2	Protein	O43597 (Uniprot-TrEMBL)
p21 RAS:GDP	Complex	R-HSA-109796 (Reactome)
p21 RAS:GTP	Complex	R-HSA-109783 (Reactome)

Annotated Interactions

View all...

Source	Target	Type	Database reference	Comment
	ADP	Arrow	R-HSA-1268210 (Reactome)
	ADP	Arrow	R-HSA-1295609 (Reactome)
	ADP	Arrow	R-HSA-190408 (Reactome)
	ADP	Arrow	R-HSA-190413 (Reactome)
	ADP	Arrow	R-HSA-2029984 (Reactome)
	ADP	Arrow	R-HSA-2029989 (Reactome)
	ADP	Arrow	R-HSA-2033486 (Reactome)
	ADP	Arrow	R-HSA-2033488 (Reactome)
	ADP	Arrow	R-HSA-2033490 (Reactome)
	ADP	Arrow	R-HSA-5654147 (Reactome)
	ADP	Arrow	R-HSA-5654397 (Reactome)
	ADP	Arrow	R-HSA-5654407 (Reactome)
	ADP	Arrow	R-HSA-5654562 (Reactome)
	ADP	Arrow	R-HSA-5654605 (Reactome)
	ADP	Arrow	R-HSA-5654607 (Reactome)
	ADP	Arrow	R-HSA-5654697 (Reactome)
	ADP	Arrow	R-HSA-5654701 (Reactome)
	ADP	Arrow	R-HSA-5655268 (Reactome)
	ADP	Arrow	R-HSA-5655301 (Reactome)
	ADP	Arrow	R-HSA-5655323 (Reactome)
	ADP	Arrow	R-HSA-934559 (Reactome)
ATP			R-HSA-1268210 (Reactome)
ATP			R-HSA-1295609 (Reactome)
ATP			R-HSA-190408 (Reactome)
ATP			R-HSA-190413 (Reactome)
ATP			R-HSA-2029984 (Reactome)
ATP			R-HSA-2029989 (Reactome)
ATP			R-HSA-2033486 (Reactome)
ATP			R-HSA-2033488 (Reactome)
ATP			R-HSA-2033490 (Reactome)
ATP			R-HSA-5654147 (Reactome)
ATP			R-HSA-5654397 (Reactome)
ATP			R-HSA-5654407 (Reactome)
ATP			R-HSA-5654562 (Reactome)
ATP			R-HSA-5654605 (Reactome)
ATP			R-HSA-5654607 (Reactome)
ATP			R-HSA-5654697 (Reactome)
ATP			R-HSA-5654701 (Reactome)
ATP			R-HSA-5655268 (Reactome)
ATP			R-HSA-5655301 (Reactome)
ATP			R-HSA-5655323 (Reactome)
ATP			R-HSA-934559 (Reactome)
	Activated FGFR2 mutants:p-FRS2:GRB2:GAB1:PI3K	Arrow	R-HSA-5655245 (Reactome)
Activated FGFR2 mutants:p-FRS2:GRB2:GAB1:PI3K		mim-catalysis	R-HSA-5655323 (Reactome)
	Activated FGFR2 mutants:p-FRS2:GRB2:GAB1:PIK3R1	Arrow	R-HSA-5655320 (Reactome)
Activated FGFR2 mutants:p-FRS2:GRB2:GAB1:PIK3R1			R-HSA-5655245 (Reactome)
	Activated FGFR2:p-8T-FRS2	Arrow	R-HSA-5654562 (Reactome)
Activated FGFR2:p-8T-FRS2		TBar	R-HSA-5654397 (Reactome)
	Activated FGFR2:p-FRS2:GRB2:GAB1:PI3K	Arrow	R-HSA-5654614 (Reactome)
Activated FGFR2:p-FRS2:GRB2:GAB1:PI3K		mim-catalysis	R-HSA-5654701 (Reactome)
	Activated FGFR2:p-FRS2:GRB2:GAB1:PIK3R1	Arrow	R-HSA-5654612 (Reactome)
Activated FGFR2:p-FRS2:GRB2:GAB1:PIK3R1			R-HSA-5654614 (Reactome)
	Activated FGFR2:p-FRS2:p-PTPN11:GRB2:GAB1:PI3K	Arrow	R-HSA-5654622 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11:GRB2:GAB1:PI3K		mim-catalysis	R-HSA-5654697 (Reactome)
	Activated FGFR2:p-FRS2:p-PTPN11:GRB2:GAB1:PIK3R1	Arrow	R-HSA-5654620 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11:GRB2:GAB1:PIK3R1			R-HSA-5654622 (Reactome)
	Activated FGFR2:p-FRS2:p-PTPN11:p-CBL:GRB2	Arrow	R-HSA-5654729 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11:p-CBL:GRB2			R-HSA-5654677 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11:p-CBL:GRB2		mim-catalysis	R-HSA-5654677 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11			R-HSA-5654620 (Reactome)
Activated FGFR2:p-FRS2:p-PTPN11			R-HSA-5654729 (Reactome)
	Activated FGFR2:p-FRS2	Arrow	R-HSA-5654397 (Reactome)
Activated FGFR2:p-FRS2			R-HSA-5654612 (Reactome)
	Activated FGFR2:p-FRS3	Arrow	R-HSA-5654605 (Reactome)
	Activated FGFR2:p-FRS:GRB2:SOS1	Arrow	R-HSA-5654615 (Reactome)
Activated FGFR2:p-FRS:GRB2:SOS1		mim-catalysis	R-HSA-5654618 (Reactome)
	Activated FGFR2:p-FRS:PTPN11	Arrow	R-HSA-5654608 (Reactome)
Activated FGFR2:p-FRS:PTPN11			R-HSA-5654607 (Reactome)
Activated FGFR2:p-FRS:PTPN11		mim-catalysis	R-HSA-5654607 (Reactome)
Activated FGFR2:p-FRS:p-PTPN11		Arrow	R-HSA-5654402 (Reactome)
	Activated FGFR2:p-FRS:p-PTPN11	Arrow	R-HSA-5654607 (Reactome)
Activated FGFR2:p-FRS			R-HSA-5654608 (Reactome)
Activated FGFR2:p-FRS			R-HSA-5654615 (Reactome)
	Activated FGFR2:pY-SHC1:GRB2:SOS1	Arrow	R-HSA-5654406 (Reactome)
Activated FGFR2:pY-SHC1:GRB2:SOS1		mim-catalysis	R-HSA-5654402 (Reactome)
	Activated FGFR2:pY-SHC1	Arrow	R-HSA-5654407 (Reactome)
Activated FGFR2:pY-SHC1			R-HSA-5654406 (Reactome)
	Activated overexpressed FGFR2 dimers	Arrow	R-HSA-2029989 (Reactome)
	Activated FGFR2 ligand-independent mutants	Arrow	R-HSA-2029984 (Reactome)
	Activated FGFR2 mutants with enhanced kinase activity	Arrow	R-HSA-2033490 (Reactome)
	Activated FGFR2 mutants:FRS2	Arrow	R-HSA-5655339 (Reactome)
Activated FGFR2 mutants:FRS2			R-HSA-5655268 (Reactome)
Activated FGFR2 mutants:FRS2		mim-catalysis	R-HSA-5655268 (Reactome)
	Activated FGFR2 mutants:PLCG1	Arrow	R-HSA-5655343 (Reactome)
Activated FGFR2 mutants:PLCG1			R-HSA-5655301 (Reactome)
Activated FGFR2 mutants:PLCG1		mim-catalysis	R-HSA-5655301 (Reactome)
	Activated FGFR2 mutants:p-4Y-PLCG1	Arrow	R-HSA-5655301 (Reactome)
Activated FGFR2 mutants:p-4Y-PLCG1			R-HSA-5654748 (Reactome)
	Activated FGFR2 mutants:p-FRS2	Arrow	R-HSA-5655268 (Reactome)
Activated FGFR2 mutants:p-FRS2			R-HSA-5655233 (Reactome)
Activated FGFR2 mutants:p-FRS2			R-HSA-5655320 (Reactome)
	Activated FGFR2 mutants	Arrow	R-HSA-5654748 (Reactome)
Activated FGFR2 mutants			R-HSA-5655339 (Reactome)
Activated FGFR2 mutants			R-HSA-5655343 (Reactome)
	Activated FGFR2:FRS2	Arrow	R-HSA-5654399 (Reactome)
Activated FGFR2:FRS2			R-HSA-5654397 (Reactome)
Activated FGFR2:FRS2			R-HSA-5654562 (Reactome)
Activated FGFR2:FRS2		mim-catalysis	R-HSA-5654397 (Reactome)
	Activated FGFR2:FRS3	Arrow	R-HSA-5654603 (Reactome)
Activated FGFR2:FRS3			R-HSA-5654605 (Reactome)
Activated FGFR2:FRS3		mim-catalysis	R-HSA-5654605 (Reactome)
	Activated FGFR2:SHC1	Arrow	R-HSA-5654404 (Reactome)
Activated FGFR2:SHC1			R-HSA-5654407 (Reactome)
Activated FGFR2:SHC1		mim-catalysis	R-HSA-5654407 (Reactome)
	Activated FGFR2	Arrow	R-HSA-5654157 (Reactome)
Activated FGFR2			R-HSA-5654159 (Reactome)
Activated FGFR2			R-HSA-5654399 (Reactome)
Activated FGFR2			R-HSA-5654404 (Reactome)
Activated FGFR2			R-HSA-5654603 (Reactome)
	Activated FGFR2b homodimer bound to FGF	Arrow	R-HSA-190408 (Reactome)
	Activated FGFR2b mutants with enhanced ligand binding	Arrow	R-HSA-2033488 (Reactome)
	Activated FGFR2c homodimer bound to FGF	Arrow	R-HSA-190413 (Reactome)
	Activated FGFR2c mutants with enhanced ligand-binding	Arrow	R-HSA-2033486 (Reactome)
	BRAF	Arrow	R-HSA-1295604 (Reactome)
	CBL	Arrow	R-HSA-1295621 (Reactome)
CBL			R-HSA-1295622 (Reactome)
FGF2,7,10,22			R-HSA-5656070 (Reactome)
FGFBP:FGF		Arrow	R-HSA-190260 (Reactome)
	FGFBP:FGF	Arrow	R-HSA-5656070 (Reactome)
FGFBP			R-HSA-5656070 (Reactome)
	FGFR2 ligand-independent mutant dimers	Arrow	R-HSA-2029983 (Reactome)
FGFR2 ligand-independent mutant dimers			R-HSA-2029984 (Reactome)
FGFR2 ligand-independent mutant dimers		mim-catalysis	R-HSA-2029984 (Reactome)
FGFR2 ligand-independent mutants			R-HSA-2029983 (Reactome)
	FGFR2 mutants:p-FRS2:GRB2:SOS1	Arrow	R-HSA-5655233 (Reactome)
FGFR2 mutants:p-FRS2:GRB2:SOS1		mim-catalysis	R-HSA-5655241 (Reactome)
	FGFR2 mutant dimers with enhanced kinase activity	Arrow	R-HSA-2033479 (Reactome)
FGFR2 mutant dimers with enhanced kinase activity			R-HSA-2033490 (Reactome)
FGFR2 mutant dimers with enhanced kinase activity		mim-catalysis	R-HSA-2033490 (Reactome)
FGFR2 mutants with enhanced kinase activity			R-HSA-2033479 (Reactome)
	FGFR2 point mutant dimers:TKIs	Arrow	R-HSA-2077424 (Reactome)
FGFR2 point mutant dimers			R-HSA-2077424 (Reactome)
	FGFR2b mutant-binding FGFs:FP-1039	Arrow	R-HSA-2077421 (Reactome)
FGFR2b mutant-binding FGFs			R-HSA-2033474 (Reactome)
FGFR2b mutant-binding FGFs			R-HSA-2077421 (Reactome)
	FGFR2b homodimer bound to FGF	Arrow	R-HSA-190260 (Reactome)
FGFR2b homodimer bound to FGF			R-HSA-190408 (Reactome)
FGFR2b homodimer bound to FGF		mim-catalysis	R-HSA-190408 (Reactome)
	FGFR2b mutant dimers with enhanced ligand-binding bound to FGFs	Arrow	R-HSA-2033474 (Reactome)
FGFR2b mutant dimers with enhanced ligand-binding bound to FGFs			R-HSA-2033488 (Reactome)
FGFR2b mutant dimers with enhanced ligand-binding bound to FGFs		mim-catalysis	R-HSA-2033488 (Reactome)
FGFR2b mutants with enhanced ligand binding			R-HSA-2033474 (Reactome)
FGFR2b-binding FGFs			R-HSA-190260 (Reactome)
FGFR2b			R-HSA-190260 (Reactome)
	FGFR2c homodimer bound to FGF	Arrow	R-HSA-190258 (Reactome)
FGFR2c homodimer bound to FGF			R-HSA-190413 (Reactome)
FGFR2c homodimer bound to FGF		mim-catalysis	R-HSA-190413 (Reactome)
FGFR2c mutant binding FGFs			R-HSA-2033472 (Reactome)
	FGFR2c mutant dimers with enhanced ligand-binding bound to FGFs	Arrow	R-HSA-2033472 (Reactome)
FGFR2c mutant dimers with enhanced ligand-binding bound to FGFs			R-HSA-2033486 (Reactome)
FGFR2c mutant dimers with enhanced ligand-binding bound to FGFs		mim-catalysis	R-HSA-2033486 (Reactome)
FGFR2c mutants with enhanced ligand binding			R-HSA-2033472 (Reactome)
FGFR2c-binding FGFs			R-HSA-190258 (Reactome)
FGFR2c			R-HSA-190258 (Reactome)
FP-1039			R-HSA-2077421 (Reactome)
FRS2			R-HSA-5654399 (Reactome)
FRS2			R-HSA-5655339 (Reactome)
FRS3			R-HSA-5654603 (Reactome)
	GDP	Arrow	R-HSA-5654402 (Reactome)
	GDP	Arrow	R-HSA-5654618 (Reactome)
	GDP	Arrow	R-HSA-5655241 (Reactome)
GP369			R-HSA-2067713 (Reactome)
GRB2-1:SOS1			R-HSA-5654406 (Reactome)
GRB2-1:SOS1			R-HSA-5654615 (Reactome)
GRB2-1:SOS1			R-HSA-5655233 (Reactome)
	GRB2-1	Arrow	R-HSA-1549564 (Reactome)
GRB2-1			R-HSA-1295613 (Reactome)
	GRB2:GAB1:PIK3R1	Arrow	R-HSA-177931 (Reactome)
GRB2:GAB1:PIK3R1			R-HSA-5654612 (Reactome)
GRB2:GAB1:PIK3R1			R-HSA-5654620 (Reactome)
GRB2:GAB1:PIK3R1			R-HSA-5655320 (Reactome)
GRB2:GAB1			R-HSA-177931 (Reactome)
GTP			R-HSA-5654402 (Reactome)
GTP			R-HSA-5654618 (Reactome)
GTP			R-HSA-5655241 (Reactome)
HS		Arrow	R-HSA-190258 (Reactome)
HS		Arrow	R-HSA-190260 (Reactome)
HS			R-HSA-190258 (Reactome)
HS			R-HSA-190260 (Reactome)
HS			R-HSA-2033472 (Reactome)
HS			R-HSA-2033474 (Reactome)
IL17RD-1		TBar	R-HSA-1268206 (Reactome)
IL17RD		TBar	R-HSA-1268210 (Reactome)
	Overexpressed FGFR2:TKIs	Arrow	R-HSA-2029992 (Reactome)
	Overexpressed FGFR2 homodimers:GP369	Arrow	R-HSA-2067713 (Reactome)
	Overexpressed FGFR2 homodimers	Arrow	R-HSA-2029988 (Reactome)
Overexpressed FGFR2 homodimers			R-HSA-2029989 (Reactome)
Overexpressed FGFR2 homodimers			R-HSA-2029992 (Reactome)
Overexpressed FGFR2 homodimers			R-HSA-2067713 (Reactome)
Overexpressed FGFR2 homodimers		mim-catalysis	R-HSA-2029989 (Reactome)
Overexpressed FGFR2			R-HSA-2029988 (Reactome)
	PI(3,4,5)P3	Arrow	R-HSA-5654697 (Reactome)
	PI(3,4,5)P3	Arrow	R-HSA-5654701 (Reactome)
	PI(3,4,5)P3	Arrow	R-HSA-5655323 (Reactome)
PI(3,4,5)P3			R-HSA-5654159 (Reactome)
PI(3,4,5)P3			R-HSA-5655343 (Reactome)
PI(4,5)P2			R-HSA-5654697 (Reactome)
PI(4,5)P2			R-HSA-5654701 (Reactome)
PI(4,5)P2			R-HSA-5655323 (Reactome)
PIK3CA			R-HSA-5654614 (Reactome)
PIK3CA			R-HSA-5654622 (Reactome)
PIK3CA			R-HSA-5655245 (Reactome)
PIK3R1			R-HSA-177931 (Reactome)
PLCG1			R-HSA-5654159 (Reactome)
PLCG1			R-HSA-5655343 (Reactome)
	PP2A (A:C)	Arrow	R-HSA-1295622 (Reactome)
	PP2A(A:C):S112/S121-pSPRY2	Arrow	R-HSA-934559 (Reactome)
PP2A(A:C):S112/S121-pSPRY2		TBar	R-HSA-1295609 (Reactome)
	PP2A(A:C):SPRY2	Arrow	R-HSA-1295599 (Reactome)
PP2A(A:C):SPRY2			R-HSA-1295609 (Reactome)
PP2A(A:C):SPRY2			R-HSA-934559 (Reactome)
	PP2A(A:C):Y55/Y227-pSPRY2	Arrow	R-HSA-1295609 (Reactome)
	PP2A(A:C):Y55/Y227-pSPRY2	Arrow	R-HSA-1549564 (Reactome)
PP2A(A:C):Y55/Y227-pSPRY2			R-HSA-1295613 (Reactome)
PP2A(A:C):Y55/Y227-pSPRY2			R-HSA-1295622 (Reactome)
PPA2A (A:C):S112/S115 p-SPRY2			R-HSA-1295632 (Reactome)
PPA2A (A:C):S112/S115 p-SPRY2		mim-catalysis	R-HSA-1295632 (Reactome)
	PPA2A (A:C):Y55/Y227 p-SPRY2:GRB2	Arrow	R-HSA-1295613 (Reactome)
PPA2A (A:C):Y55/Y227 p-SPRY2:GRB2			R-HSA-1549564 (Reactome)
	PPA2A(A:C):SPRY2	Arrow	R-HSA-1295632 (Reactome)
PPA2A(A:C):SPRY2			R-HSA-1295599 (Reactome)
PTPN11			R-HSA-5654608 (Reactome)
PTPN11		mim-catalysis	R-HSA-1549564 (Reactome)
	Phospho-MEK	Arrow	R-HSA-1268206 (Reactome)
	Pi	Arrow	R-HSA-1295632 (Reactome)
			R-HSA-1268206 (Reactome)	p-ERK1/2 dissociates from p-MEK1/2, allowing dimerization of the activated MAPKs and translocation to the nucleus. In FGFR signaling, there is evidence that this dissociation event is negatively regulated by the golgi membrane form of IL17RD, preventing the nuclear localization of activated ERK1/2.
			R-HSA-1268210 (Reactome)	MEK1/2 phosphorylate critical tyrosine and threonine residues on ERK1/2, activating the kinase activity of the MAPKs. In FGFR signaling, this reaction appears to be negatively regulated by IL17RD through an unknown mechanism, limiting the extent of MAPK signaling after FGF stimulation.
			R-HSA-1295599 (Reactome)	SPRY2 translocates to the plasma membrane upon activation of cells with FGF, and translocation is required for the inhibition of growth factor-stimulated cell migration, proliferation and differentiation. Translocation may be mediated by interactions with PIP2 in the membrane, palmitoylation of the C-terminal region of SPRY2 and/or interactions with caveolin-1.
			R-HSA-1295604 (Reactome)	MAPK-dependent serine phosphorylation of SPRY2 disrupts complex formation with B-RAF.
			R-HSA-1295609 (Reactome)	Sprouty 2 protein is phosphorylated on tyrosine residue 55. The ability of SRC kinase to catalyze this reaction has been demonstrated with purified proteins in vitro (Li et al. 2004) and in cultured cells with studies of the effects of SRC-family pharmacological inhibitors and of dominant-negative mutant SRC proteins (Mason et al. 2004). SRC kinase also phosphorylates numerous tyrosine residues in the C terminal region of SPRY2 including Y227, in response to FGF but not EGF stimulation.
			R-HSA-1295613 (Reactome)	Some evidence suggests that SPRY2 may exert its negative effect by binding to GRB2 and competing with the GRB2:SOS1 interaction that is required for MAPK activation. SPRY2 phosphorylation at Y55 is stimulated in response to both FGF and EGF, and is required for SPRY2 to act as a negative regulator of FGF signaling. Y55 is not thought to be a GRB2 binding site, however. Instead, phosphorylation at Y55 is thought to cause a conformational change in SPRY2 that reveals a cryptic PXXPXPR GRB2-docking site in the C-terminal of SPRY2. SPRY2 has also been shown to be phosphorylated at multiple tyrosine residues in its C-terminal in response to FGF, but not EGF, stimulation. This phosphorylation, in particular at residue 227, is thought to augment the ability of SPRY2 to inhibit FGF signaling through the MAPK cascade, although the mechanism remains to be elucidated.
			R-HSA-1295621 (Reactome)	After ubiquitination, CBL dissociates from SPRY2
			R-HSA-1295622 (Reactome)	The N terminal TKB domain of CBL binds to the phospho-tyrosine 55 of SPRY2, targeting SPRY2 for degradation by the 26S proteasome. Y55 is also a binding site for PP2A, which dephosphorylates numerous serine and threonine residues on SPRY2, allowing a conformational change that may promote a SPRY2:GRB2 interaction and limit the extent of MAPK activation following FGF stimulation.
			R-HSA-1295628 (Reactome)	After being phosphorylated, p-ERK1/2 dissociate from MEK1/2 and dimerize.
			R-HSA-1295632 (Reactome)	In unstimulated cells, SPRY2 has been shown to be phosphorylated on multiple serine and threonine residues. In these cells, SPRY2 exists in a complex with the regulatory and catalytic subunits (A and C, respectively) of the serine/threonine phosphatase PP2A. After stimulation with FGF, the catalytic activity of PP2A increases and the phosphatase dephophorylates SPRY at serine 112 and serine 115. This is thought to promote changes in tertiary structure that promote GRB2 binding and phosphorylation of Y55 and Y227.
			R-HSA-1295634 (Reactome)	Some evidence suggests that SPRY2 can exert its negative role on FGF signaling at the level of RAF activation. Hypophosphorylated SPRY2 binds to inactive B-RAF, preventing it from activating ERK signaling. MAPK activation results in phosphorylation of SPRY2 on six serine residues (S7, S42, S111, S120, S140 and S167), and inhibits B-RAF binding. Phosphorylation at S111 and S120 directly affects B-RAF binding while the remaining four sites appear to contribute indirectly. Oncogenic forms of B-RAF such as B-RAF V600E, which adopt active kinase conformations, do not associate with SPRY2, regardless of its phosphorylation status. This suggests that two mechanisms affect the SPRY2:B-RAF interaction: SPRY2 phosphorylation and B-RAF conformation.
			R-HSA-1549564 (Reactome)	PPTN11 (also known as SHP2) may exert its positive effects on MAPK activation in response to FGF stimulation by catalyzing the dephosphorylation of tyrosine resides on SPRY2. This dephosphorylation promotes dissociation of the GRB2/SPRY2 complex and as a consequence stimulates GRB2 association with the activated receptor, leading to sustained MAPK signaling.
			R-HSA-177931 (Reactome)	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.
			R-HSA-190258 (Reactome)	In this reaction, FGF receptor 2c in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Two isoforms of FGFR2c generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in ligand binding and dimerization but differ in their abilities to interact with downstream targets.
			R-HSA-190260 (Reactome)	In this reaction, FGF receptor 2b in the plasma membrane binds an associating extracellular ligand, a requisite step for subsequent activation. The resulting complex consists of dimerized receptor, two ligand molecules, and heparan sulfate. Two isoforms of FGFR2b generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in ligand binding and dimerization but differ in their abilities to interact with downstream targets.
			R-HSA-190408 (Reactome)	The intrinsic protein tyrosine kinase activity of the activated FGFR2b receptor leads to multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Two isoforms of FGFR2b generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in ligand binding and dimerization but differ in their abilities to interact with downstream targets. Based on sequence alignment, FGFR2 contains all 8 of the cytoplasmic tyrosine residues identified in FGFR1.
			R-HSA-190413 (Reactome)	The intrinsic protein tyrosine kinase activity of the activated FGFR2c receptor leads to multiple phosphorylation events, creating a number of binding sites on its cytoplasmic tail for membrane bound docking proteins to gather intracellular signaling mediators. Two isoforms of FGFR2c generated by alternative splicing and differing only by the presence ("long") or absence ("short") of two amino acid residues at positions 428-429 are equally active in autophosphorylation, but differ in their abilities to interact with downstream targets. Based on sequence alignment, FGFR2 contains all 8 of the cytoplasmic tyrosine residues identified in FGFR1.
			R-HSA-2029983 (Reactome)	Point mutations in FGFR2 that are thought to promote ligand-independent dimerization in the context of autosomal bone development disorders have also been identified in endometrial, ovarian, gastric and lung cancer (Greenman, 2007; Dutt, 2008; Davies, 2005; Byron, 2008; Byron, 2010, Pollock, 2007). Although functional studies on these mutations in FGFR2 in cancer cell lines is limited - only the S267P mutation identified in gastric cancer has been demonstrated biochemically to undergo ligand-independent dimerization (Anderson, 1998) - characterization of paralogous mutations in FGFR3 as well as in other mutations that create unpaired cysteine residues in FGFR2 support the notion that these mutant receptors undergo aberrant intermolecular disulphide bond formation that results in constitutive activation (Galvin, 1996; Neilson and Friesel,1995; Robertson, 1998; d'Avis, 1998)
			R-HSA-2029984 (Reactome)	FGFR2 S267P undergoes ligand-independent dimerization, and appears unable to stably bind FGF2 ligand under the conditions examined (Anderson, 1998). FGFR2b S373C and Y376C are paralogous to the FGFR3 S371C and Y373C mutations that are seen in thanatophoric dysplasia I (Rousseau, 1996; Tavormina, 1995a) and which have been shown to undergo spontaneous dimerization in the absence of ligand (d'Avis, 1998; Adar, 2002). Moreover, other FGFR2 mutations that introduce unpaired cysteine residues have been shown to support formation of intermolecular disulphide bonds (Galvin, 1996; Neilson and Friesel, 1995), supporting the notion that the FGFR2b S373C and Y376C mutants may promote spontaneous receptor dimerization and activation.
			R-HSA-2029988 (Reactome)	Overexpressed FGFR2 in gastric and breast cancer cells has been shown to undergo ligand-independent dimerization (Takeda, 2007; Kunii, 2008; Moffa, 2004; Turner, 2010). Full-length FGFR2 is weakly transforming in NIH 3T3 cells, and is thought to possess a transformation-inhibiting domain in the C-terminus (Itoh, 1994). Interestingly, many cancers with amplifications of FGFR2 show preferrential expression of C-terminally truncated FGFR2 variants, designated C2 and C3, with 788 or 769 residues instead of the wild-type 822 (Hattori, 1990; Itoh, 1994; Ueda, 1999). These variants, which lack a number of carboxy-terminal tyrosine residues, show increased transforming potency compared to the full-length receptor (Cha, 2008; Cha, 2009), and have been shown to be constitutively active and to dimerize spontaneously (Takeda, 2007).
			R-HSA-2029989 (Reactome)	Amplification of full length FGFR2 is only weakly transforming in NIH 3T3 cells, reflecting the presence of a putative transformation-inhibitory region in the c-terminus of the protein (Itoh, 1994, Cha, 2009). C-terminally truncated variants of FGFR2 that are preferrentially expressed in cancer show more potent transformation potential (Cha, 2008; Cha, 2009). These variants lack a number of carboxy-terminal tyrosine residues, including Y770 and Y773. Loss of Y770 contributes to transformation by enhancing FRS2 binding to the C-terminally truncated variant. This suggests that in the context of the full-length protein the presence of Y770 restricts access of FRS2 to the receptor. Loss or mutation of Y773 impairs internalization and degradation of the receptor and promotes sustained signaling (Cha, 2009). Gastric cancer cell lines with FGFR2 amplifications appear to undergo ligand-independent signaling and are sensitive to inhibition with ATP-competitive inhibitors (Takeda, 2007). FGFR2 amplifications identified in 4% of triple negative breast cancers have also been shown to be constitutively active and to have elevated levels of phosphorylated FRS2 in the absence of ligand. Consistent with this, shRNA knockdown or chemical inhibition restricts proliferation and induces apoptosis in these cells (Kunii, 2008; Turner, 2010)
			R-HSA-2029992 (Reactome)	Amplified FGFR2 has been shown to be a potential target for a number of ATP-competitive inhibitors, some of which are currently in clinical trials for therapeutic use (Takeda, 2007; Turner, 2010; http://clinicaltrials.gov).
			R-HSA-2033472 (Reactome)	Mutations in the highly conserved Pro-Ser dipeptide repeat of FGFR2 have been identified both in Apert syndrome and in endometrial and ovarian cancers (Wilkie, 1995; Dutt, 2008; Pollock, 2007; Byron, 2010). Missense S252W or P253R mutations affect both the 'b' and 'c' isoforms, although mutation in the FGFR2c isoform is believed to be more clinically relevant to the development of Apert syndrome (Lomri, 1998). In the context of endometrial cancer, these mutations are mutually exclusive with KRAS mutations, but are associated at high frequency with PTEN mutations (Byron, 2008). The S252W and P253R mutations allow the receptor to bind to an expanded range of ligands, such that the mesenchymal splice form (FGFR2c) is anomalously activated by the mesenchymal ligands FGF7 and FGF10, establishing an autocrine signaling loop. These mutations also increase the binding affinity for the receptor's normal epithelial ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).
			R-HSA-2033474 (Reactome)	Apert sydrome is the most severe of the craniosynostosis syndromes and results almost entirely from two missense mutations in the conserved Ser252 and Pro253 residues in the IgII-IgIII linker of FGFR2 (Wilkie, 1995). These mutations affect both the 'b' and 'c' isoforms, although mutation in the FGFR2c isoform is believed to be more clinically relevant to the development of Apert syndrome (Lomri, 1998). More recently, the same mutations arising somatically have been identified in endometrial and ovarian cancer (Dutt, 2008; Byron, 2008; Pollock, 2007). The IgII and IgIII domains and the intervening linker of the FGF receptor constitute a binding site for FGFs (Chellaiah, 1999; Stauber, 2000; Plotnikov, 1999). The epithelial isoform FGFR2b binds only to mesenchymally expressed ligands including FGF7 and FGF10 and does not respond to epithelial ligands FGF2, 4, 6, 8 and 9 (Ornitz, 1996). Introduction of the P252W and P252R mutations into FGFR2b allows the aberrant binding and activation by the epithelially expressed ligands FGF 2, 6 and 9, establishing an autocrine signaling loop in epithelial cells. These mutations also increase the binding affinity for the receptor's normal mesenchymal ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).
			R-HSA-2033479 (Reactome)	Several missense mutations in the tyrosine kinase domain of FGFR2 have been identified in Crouzon syndrome and similar craniosynostosis disorders (Kan, 2002; Cunningham, 2007). The N549H and K660N mutations are paralogous to FGFR3 N540K and K650N/E mutations identified in hypochondroplasia and thanatophoric dysplasia II (Bellus, 2000). In FGFR3, these mutations have been demonstrated to have weak ligand-independent autophosphorylation and enhanced kinase activity mediated by disruption of a hydrogen-bonding network that holds the receptor in an inactive conformation (Chen, 2007; Bellus, 2000, Raffioni, 1998). Due to the highly conserved nature of these residues across all four FGF receptors, it is generally believed that these germline mutations in FGFR2 are also activating, though this remains to be demonstrated experimentally. As further support of this notion, activating point mutations in the kinase domain of FGFR2 have also been identified in endometrial, uterine and cervical cancers (Pollock, 2007; Dutt, 2008), and in some cases have been shown to have enhanced kinase activity and to support anchorage-independent growth in NIH 3T3 cells (Dutt, 2008). Knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival (Dutt, 2008; Byron, 2008). Kinase-domain mutants show elevated levels of activity relative to the wild-type even in the absence of receptor phosphorylation, and although their kinase activity is further enhanced upon trans-autophosphorylation, the extent of this is less than that seen in the wild-type, suggesting that the mutant alleles are capable of of supporting ligand-independent activation (Chen, 2007)
			R-HSA-2033486 (Reactome)	After aberrantly dimerizing in response to mesenchymally expressed ligands, FGFR2c S252W and P253R mutants are assumed to undergo transautophosphorylation analagous to the wild-type receptor, although this has not been explicitly demonstrated. Knock-down or chemical inhibition of other FGFR2-activating mutations identified in endometrial cancer cells has been shown to cause cell death (Byron, 2008).
			R-HSA-2033488 (Reactome)	After aberrantly dimerizing in response to epithelially expressed ligands, FGFR2b S252W and P253R mutants are assumed to undergo transautophosphorylation analagous to both the wild-type receptor, although this has not been explicitly demonstrated. Transformation of NIH 3T3 cells with the FGFR2b S252W mutant confers anchorage independent growth and results in increased phosphorylation of FRS2 in a manner that depends on a functional kinase domain (Dutt, 2008). Knock-down or chemical inhibition of other FGFR2-activating mutations identified in endometrial cancer cells has been shown to cause cell death (Byron, 2008).
			R-HSA-2033490 (Reactome)	Several missense mutations in the tyrosine kinase domain of FGFR2 have been identified in Crouzon syndrome and similar craniosynostosis disorders (Kan, 2002; Cunningham, 2007). The N549H and K660N mutations identified in FGFR2 in craniosynostosis disorders are paralogous to FGFR3 N540K and K650N/E mutations identified in hypochondroplasia and thanatophoric dysplasia II (Bellus, 2000). In FGFR3, these mutations have been demonstrated to have weak ligand-independent autophosphorylation and enhanced kinase activity mediated by disruption of a hydrogen-bonding network that holds the receptor in an inactive conformation (Chen, 2007; Bellus, 2000, Raffioni, 1998). Characterization of FGFR2 proteins containing somatic mutations at these residues support the notion that they have elevated levels of kinase activity. FRS2 is constitutively phosphorylated in the FGFR2 N549K kinase mutant identified in endometrial tumors and knockdown of N549K with short hairpin RNAs or the pan-FGFR inhibitor PD170734 inhibits cell survival in endometrial cancer cells lines, suggesting that FGFR2 activity is required for tumor cell survival. FGFR2 knockdown also results in a significant decrease in the levels of phosphorylated Erk1/2 (Dutt, 2008; Byron, 2008; Pollock, 2007). Crystal structures of FGFR2 kinase mutants N549H and K650N show that the mutations disengage an 'auto-inhibitory brake' on the kinase domain of the receptor. Biochemically, the FGFR2 N549K and K660E mutants show elevated kinase activity relative to the unphosphorylated wild-type protein and have increased activity towards peptide substrates; this activity is stimulated upon receptor phosphorylation, but to a lesser extent than seen with the wild-type receptor (Chen, 2007).
			R-HSA-2067713 (Reactome)	Treatment of FGFR2-amplified gastric and breast cancer cell lines with the antibody GP369 inhibits FGFR2 phosphorylation and downstream signaling and suppresses cell proliferation. Treatment of mice with GP369 inhibits the growth of human cancer xenografts carrying activating FGFR2 mutations. The GP369-binding epitope is contained in the ligand-binding region of the receptor, suggesting that the antibody works by disrupting the ligand-dependent activation of amplified FGFR2 (Bai, 2010).
			R-HSA-2077421 (Reactome)	FP-1039 is a soluble fusion protein consisting of the extracellular region of FGFR1c bound to the Fc region of human IgG1. It is capable of binding to a wide range of FGF ligands and thereby prevents activation of multiple FGF receptors. FP-1039 is in Phase I clinical trials in solid malignancies and in Phase II trials for patients with endometrial cancers harbouring the activating mutations S252W and P253R (reviewed in Wesche, 2011).
			R-HSA-2077424 (Reactome)	FGFR2 is inhibited by a range of in vitro tyrosine kinase inhibitors, including PD170734 and SU5402 (reviewed in Greulich and Pollock, 2010; Wesche, 2011). In addition, there are a number of FGFR2 inhibitors currently in clinical trials that for treatment of solid malignancies (http://ClinicalTrials.gov).
			R-HSA-5654147 (Reactome)	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.
			R-HSA-5654157 (Reactome)	Dissociation from the activated receptor quickly follows phosphorylation of PLC-gamma. Phosphorylated PLC-gamma catalyzes the hydrolysis of phosphatidylinositol(4, 5)bisphosphate to generate two second messengers, diacylglycerol and inositol (1,4,5) triphosphate.
			R-HSA-5654159 (Reactome)	Recruitment of PLC-gamma by FGF receptors has been best studied in FGFR1c signaling, where it has been shown that autophosphorylation of Tyr766 in the C-terminal tail of FGFR1c creates a specific binding site for the SH2 domain of PLC-gamma. A mutant FGFR1c in which Y766 is replaced by phenylalanine is unable to activate PI hydrolysis and Ca2+ release in response to FGF stimulation. Membrane recruitment of PLC-gamma is also aided by binding of the Pleckstrin homology (PH) domain of this enzyme to PtIns(3,4,5) P3 molecules that are generated in response to PI-3 kinase stimulation. By sequence comparison, Y766 is conserved in all FGFR isoforms, and PLC-gamma signaling is observed, to a greater or lesser extent, downstream of all FGFR receptors upon stimulation with FGFs.
			R-HSA-5654397 (Reactome)	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.
			R-HSA-5654399 (Reactome)	FRS2 (also known as FRS2alpha) is broadly expressed in adult and fetal tissues. Membrane-bound FRS2 interacts with FGFR as a first step in the phosphorylation of this docking protein. The juxtamembrane binding site for FRS2 does not contain tyrosine, so binding may be independent of receptor activation and/or constitutive. Activation of the FGFR receptor is required for FRS2 phosphorylation and subsequent recruitment of downstream effectors.
			R-HSA-5654402 (Reactome)	SOS, recruited by GRB2:p-FRS2 to activated FGFR, activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state.
			R-HSA-5654404 (Reactome)	Although a role for SHC1 in FGF signalling has been implicated in many studies, it is not clear that SHC1 interacts directly with the receptor.
			R-HSA-5654406 (Reactome)	Phosphorylated SHC1 links FGFR to Grb2 (Klint et al. 1995) leading to the formation of a signaling complex including Shc, Grb2 and Sos. Transformation of NIH 3T3 cells with v-Src produced a strong constitutive association of FGFR1 with Shc, Grb2 and Sos (Curto et al. 1998) suggesting Src involvement. Recruitment of Grb2-Sos links FGFR to the Ras pathway.
			R-HSA-5654407 (Reactome)	The p46 and p53 isoforms of SHC1 have been shown to be phosphorylated upon FGF stimulation. Three consensus RTK phosphoryation sites are present in SHC1, although phosphorylation of these specific tyrosine residues has not been explicitly demonstrated in response to FGF stimulation. In contrast, the p66 isoform of SHC1 does not appear to undergo FGF-dependent phosphorylation.
			R-HSA-5654562 (Reactome)	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.
			R-HSA-5654603 (Reactome)	FRS3 (also known as FRS2beta) is predominantly expressed in the developing and adult neuroepithelium. As is the case for FRS2 (also known as FRS2alpha), binding of FRS3 to FGFR may be constitutive and/or independent of receptor activation. Elements of the downstream signaling mediated by the two FRS family members appear to be at least partially conserved, as FRS3 is phosphorylated upon FGF stimulation, binds PPTN11/SHP2 and GRB2 and results in ERK activation. Moreover, expression of FRS3 in FRS2-/- MEFs restores ERK activation.
			R-HSA-5654605 (Reactome)	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.
			R-HSA-5654607 (Reactome)	Tyrosine phosphorylation of PPTN11/SHP2 by FGFR kinase is required for activation of the phosphatase activity of PPTN11 and for downstream signaling. Tyrosine phosphorylated PPTN11 plays a major role in the activation of RAS-MAP kinase pathway, although the precise role is not yet clear.
			R-HSA-5654608 (Reactome)	p-FRS2 has two PPTN11/SHP2-binding sites at pY436 and pY471.
			R-HSA-5654612 (Reactome)	The direct GRB2-binding sites of FRS2 have a major role in activation of the PI3K pathway.
			R-HSA-5654614 (Reactome)	The 110 kDa catalytic subunit (PIK3CA) binds to the 85 kDa regulatory subunit (PIK3R1) to create the active PIK3.
			R-HSA-5654615 (Reactome)	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.
			R-HSA-5654618 (Reactome)	SOS, recruited by GRB2:p-FRS2 to activated FGFR, activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state.
			R-HSA-5654620 (Reactome)	p-PPTN11 recruits GRB2-GAB1 to the activated receptor.
			R-HSA-5654622 (Reactome)	The 110 kDa catalytic subunit (PIK3CA) binds to the 85 kDa regulatory subunit (PIK3R1) to create the active PIK3.
			R-HSA-5654677 (Reactome)	Grb2 bound to tyrosine phosphorylated FRS2 forms a ternary complex with Cbl through the binding of the SH3 domains of Grb2 to a proline rich region in Cbl. Grb2-mediated recruitment of Cbl results in ubiquitination of FGFR and FRS2. Cbl is a multidomain protein that posses an intrinsic ubiquitin ligase activity and also functions as a platform for recruitment of a variety of signaling proteins. Multiple mechanisms appear to be required for downregulation of FGFR, as internalization of the receptor is reduced but not abolished if recruitment of CBL to FRS2 is compromised by mutation of GRB2-binding sites.
			R-HSA-5654697 (Reactome)	Once recruited to the activated receptor, PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling. PI3K signaling has been demonstrated in ZMYM2-, FOP- and BCR-FGFR1 fusions (Chen, 2004; Demiroglu, 2001; Guasch, 2001), as well as downstream of a number of other FGFR mutants (see for instance, Byron, 2008; Kunii, 2008; Agazie, 2003; Takeda, 2007).
			R-HSA-5654701 (Reactome)	Once recruited to the membrane, PI3K catalyzes the phosphorylation of PI(4,5)P2 to PI(3,4,5)P3.
			R-HSA-5654729 (Reactome)	The ubiquitin ligase CBL exists in a complex with GRB2 and is recruited to tyrosine-phosphorylated FRS2 after FGF stimulation. In addition to promoting the ubiquitination, endocytosis, and degradation of the activated receptor complex, recruitment of the p-CBL:GRB2 complex seems to attenuate FGFR signaling by competing with GRB2:SOS1 for binding to the direct GRB2-binding sites on p-FRS2.
			R-HSA-5654748 (Reactome)	Dissociation from the activated receptor quickly follows phosphorylation of PLC-gamma. Phosphorylated PLC-gamma catalyzes the hydrolysis of phosphatidylinositol(4, 5)bisphosphate to generate two second messengers, diacylglycerol and inositol (1,4,5) triphosphate.
			R-HSA-5655233 (Reactome)	Activation of FGFR mutants has in some cases been shown to result in phosphorylation of both FRS2 (also known as FRS2alpha) and ERK1/2, suggesting activation of the MAPK pathway through wild-type like recruitment of the GRB2-SOS1 complex (reviewed in Wesche, 2011; see for instance, Weiss, 2010; Dutt, 2011; Raffioni, 1998; Hart, 2000).
			R-HSA-5655241 (Reactome)	Activation of Erk1/2 downstream of FGFR mutants suggests that, as is the case for WT FGFR, FGFR mutant-associated SOS1 activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state (see for instance, Weiss, 2010; Dutt, 2011; Raffioni, 1998; Cha, 2009; Hart, 2000; Turner, 2010; Kunii, 2008; Byron, 2008; Roidl, 2010; Chesi, 2001; Ronchetti, 2001; reviewed in Wesche, 2011).
			R-HSA-5655245 (Reactome)	Activation of the PI3K pathway has been demonstrated downstream of a number of FGFR mutants (reviewed in Wesche, 2001; see for instance, Agazie, 2003; Kunii, 2008; Takeda, 2007; Chen, 2004; Demiroglu, 2001; Guasch, 2001; Byron, 2008), and is presumed to occur in a manner analogous to the wild-type receptor.
			R-HSA-5655268 (Reactome)	After recruitment to activated FGFR mutants, FRS2 is believed to be phosphorylated, potentially on all 6 of the tyrosines phosphorylated by wild-type FGFRs. Phosphorylation of FRS2 by FGFR has been demonstrated in some cases (see for instance Qing, 2009; Bai, 2010; Ahmed, 2008; Raffioni, 1998) and is inferred to occur in others based on activation of downstream signaling modules (reviewed in Wesche, 2011; Turner and Grose, 2010).
			R-HSA-5655301 (Reactome)	By analogy with the wild-type pathway, PLC-gamma is presumed to be phosphorylated by activated FGFR mutants, resulting in PLC-gamma activation, stimulation of phosphatidyl inositol hydrolysis and generation of two second messengers, diacylglycerol and inositol (1,4,5) P3.
			R-HSA-5655320 (Reactome)	FGFR1-amplified cells derived from lung cancer patients show phosphorylation of AKT and S6, demonstrating the activation of the PI3K signaling pathway in these lines. Inhibition of FGFR1 phosphorylation by treatment with the in vitro reagent PD173074 did not abrogate the phosphorylation of these substrates, however, indicating that the PI3K pathway is not the major signaling pathway activated by amplified FGFR1 (Weiss, 2010; Dutt, 2011). Activation of the PI3K pathway has also been demonstrated downstream of other FGFR mutants (see for instance, Agazie, 2003; Kunii, 2008, Takeda, 2007; Byron, 2008; Demiroglu, 2001; Guasch, 2001; Chen, 2004); however not all mutants activate the PI3K pathway to the same extent and in the case of the rhabdomyosarcoma FGFR4 mutants K535 and E550, phosphorylation of AKT is actually reduced compared to wild-type signaling (Taylor, 2009).
			R-HSA-5655323 (Reactome)	Once recruited to the activated receptor, PI3K phosphorylates PIP2 to PIP3, leading to activation of AKT signaling. PI3K signaling has been demonstrated in ZMYM2-, FOP- and BCR-FGFR1 fusions (Chen, 2004; Demiroglu, 2001; Guasch, 2001), as well as downstream of a number of other FGFR mutants (see for instance, Byron, 2008; Kunii, 2008; Agazie, 2003; Takeda, 2007).
			R-HSA-5655339 (Reactome)	After activation, FGFR mutants are presumed to recruit FRS2 (also known as FRS2alpha). This has been demonstrated in some cases (see for instance Ahmed, 2008; Weiss, 2010; Dutt, 2008; Dutt, 2011; Cha, 2009; Qing, 2009; Bai, 2010 ) and is inferred to occur in others by analogy with the wild-type receptor.
			R-HSA-5655343 (Reactome)	Although it has not been rigourously established, there is some evidence that PLC-gamma signaling may be activated after autophosphorylation of some FGFR mutants, analagous to the wild type receptor (see for instance, Hart, 2000; Chen, 2005; Cha, 2008; di Martino, 2009; Gartside, 2009; Cross, 2000; Hatch, 2006). The extent to which each of the mutants activates this pathway and to which proliferation and tumorigenesis relies on PLC-gamma dependent signaling, remains to be more firmly established.
			R-HSA-5656070 (Reactome)	Fibroblast growth factor binding proteins (FGFBPs) are extracellular proteins that bind to FGFs and extract them from the extracellular matrix, thereby increasing their mitogenic potential (Wu et al, 1991; Tassi et al, 2001; Beer et al, 2005; reviewed in Abuharbeid et al, 2005). FGFBP1 has been shown to bind to FGF1, 2, 7, 10 and 22 by co-immunoprecipitation and enhances the proliferation of FGFR2b-expressing cells in response to ligand stimulation (Tassi et al, 2001; Beer et al, 2005). FGFBP expression is upregulated in some cancers and contributes to tumor growth and angiogenesis (reviewed in Abuharbeid et al, 2005).
			R-HSA-934559 (Reactome)	In humans, the phosphorylated MNK1 kinase phosphorylates the adaptor protein Sprouty2 on Ser112 and Ser121, and also at some other serine and threonine residues. MNK1 appears not to form a complex with Sprouty2. Some of these (including the two main sites mentioned above) conform to the serine-containing consensus sites for phosphorylation by MNK1 kinase (K/R-X-X-S, R-X-S). It appears that serine phosphorylation is required to protect Sprouty2 from degradation. In the absence of serine phosphorylation, phosphorylation of Tyr55 and subsequent binding to E3 ubiquitin ligase, CBL, is enhanced. Serine phosphorylation of Sprouty2 appears to stabilise the protein by interfering with its potential phosphorylation of Tyr55 (Sprouty2 appears to be a poor substrate for c-Src kinase) in response to growth factor stimulation.
			R-HSA-934604 (Reactome)	In humans, the phosphorylated adaptor protein Sprouty2 is ubiquitinated by the E3 ubiquitin ligase CBL, marking it for degradation by the 26S proteasome.
	S111/S120 p-SPRY2:B-RAF	Arrow	R-HSA-1295634 (Reactome)
S111/S120 p-SPRY2:B-RAF			R-HSA-1295604 (Reactome)
SHC1 p46,p52			R-HSA-5654404 (Reactome)
SPRY2:B-RAF			R-HSA-1295634 (Reactome)
SRC-1		mim-catalysis	R-HSA-1295609 (Reactome)
Tyrosine kinase inhibitors of overexpressed FGFR2			R-HSA-2029992 (Reactome)
Tyrosine kinase inhibitors of FGFR2 mutants			R-HSA-2077424 (Reactome)
	Ub-(Y55/Y227)p-SPRY2	Arrow	R-HSA-1295621 (Reactome)
	Ub-Activated FGFR2 complex:Ub-p-FRS2	Arrow	R-HSA-5654677 (Reactome)
	Ub:Y55/Y227-pSPRY2:CBL	Arrow	R-HSA-934604 (Reactome)
Ub:Y55/Y227-pSPRY2:CBL			R-HSA-1295621 (Reactome)
Ub			R-HSA-5654677 (Reactome)
Ub			R-HSA-934604 (Reactome)
	Y55/Y227-pSPRY2:CBL	Arrow	R-HSA-1295622 (Reactome)
Y55/Y227-pSPRY2:CBL			R-HSA-934604 (Reactome)
Y55/Y227-pSPRY2:CBL		mim-catalysis	R-HSA-934604 (Reactome)
	activated FGFR2:PLCG1	Arrow	R-HSA-5654159 (Reactome)
activated FGFR2:PLCG1			R-HSA-5654147 (Reactome)
activated FGFR2:PLCG1		mim-catalysis	R-HSA-5654147 (Reactome)
	activated FGFR2:p-4Y-PLCG1	Arrow	R-HSA-5654147 (Reactome)
activated FGFR2:p-4Y-PLCG1			R-HSA-5654157 (Reactome)
	p-4Y-PLCG1	Arrow	R-HSA-5654157 (Reactome)
	p-4Y-PLCG1	Arrow	R-HSA-5654748 (Reactome)
p-MEK:ERK			R-HSA-1268210 (Reactome)
p-MEK:ERK		mim-catalysis	R-HSA-1268210 (Reactome)
	p-MEK:p-ERK	Arrow	R-HSA-1268210 (Reactome)
p-MEK:p-ERK			R-HSA-1268206 (Reactome)
	p-S111,S120-SPRY2	Arrow	R-HSA-1295604 (Reactome)
	p-T,Y MAPK dimers	Arrow	R-HSA-1295628 (Reactome)
p-T,Y MAPK dimers		Arrow	R-HSA-1295634 (Reactome)
p-T,Y MAPK dimers		mim-catalysis	R-HSA-5654562 (Reactome)
	p-T,Y MAPKs	Arrow	R-HSA-1268206 (Reactome)
p-T,Y MAPKs			R-HSA-1295628 (Reactome)
p-T250,T255,T385,S437-MKNK1		mim-catalysis	R-HSA-934559 (Reactome)
p-Y371-CBL:GRB2			R-HSA-5654729 (Reactome)
p21 RAS:GDP			R-HSA-5654402 (Reactome)
p21 RAS:GDP			R-HSA-5654618 (Reactome)
p21 RAS:GDP			R-HSA-5655241 (Reactome)
	p21 RAS:GTP	Arrow	R-HSA-5654402 (Reactome)
	p21 RAS:GTP	Arrow	R-HSA-5654618 (Reactome)
	p21 RAS:GTP	Arrow	R-HSA-5655241 (Reactome)

Signaling by FGFR2 (Homo sapiens)

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