BioPAX pathway converted from "FRS-mediated FGFR3 signaling" in the Reactome database.

FRS-mediated FGFR3 signaling

This event has been computationally inferred from an event that has been demonstrated in another species.The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<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 FGFR3:p-FRS2:GRB2:SOS1 activates RAS nucleotide exchange

Reactome DB_ID: 29438

cytosolGO0005829

GTP [ChEBI:15996]

GTP

Guanosine 5'-triphosphate

Reactomehttp://www.reactome.orgChEBI15996

Reactome DB_ID: 10091501

plasma membraneGO0005886p21 RAS:GDP [plasma membrane]

p21 RAS:GDP

Converted from EntitySet in Reactome

Reactome DB_ID: 10090284

mature p21 RAS [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityS-Farn-Me-2xPalmS HRAS [plasma membrane]S-Farn-Me PalmS NRAS [plasma membrane]S-Farn-Me KRAS4B [plasma membrane]S-Farn-Me-PalmS KRAS4A [plasma membrane]

Sus scrofa

NCBI Taxonomy9823UniProtA0A287B4D9UniProtQ2MJK3UniProtA0A287B854

Reactome DB_ID: 29420

GDP [ChEBI:17552]

GDP

Guanosine 5'-diphosphateGuanosine diphosphate

ChEBI17552Reactome Database ID Release 7010091501Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10091501ReactomeR-SSC-109796

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-109796.1

Reactome DB_ID: 29420

Reactome DB_ID: 10090286

p21 RAS:GTP [plasma membrane]

p21 RAS:GTP

Reactome DB_ID: 29438

Converted from EntitySet in Reactome

Reactome DB_ID: 10090284

Reactome Database ID Release 7010090286Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10090286ReactomeR-SSC-109783

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-109783.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10148059

Activated FGFR3:p-FRS:GRB2:SOS1 [plasma membrane]

Activated FGFR3:p-FRS:GRB2:SOS1

Reactome DB_ID: 10148057

Ghost homologue of Activated FGFR3:p-FRS [plasma membrane]

Ghost homologue of Activated FGFR3:p-FRS

Reactome DB_ID: 10082808

GRB2-1:SOS1 [cytosol]

GRB2-1:SOS1

Reactome DB_ID: 10082806

UniProt:F1S4T0

UniProtF1S4T0

Chain Coordinates

EQUAL

1333

EQUAL

Reactome DB_ID: 10082802

UniProt:B6E241

UniProtB6E241

EQUAL

217

EQUAL

Reactome Database ID Release 7010082808Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10082808ReactomeR-SSC-109797

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-109797.1Reactome Database ID Release 7010148059Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10148059ReactomeR-SSC-5654308

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5654308.1GO0005088

GO molecular function

Reactome Database ID Release 7010148060Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10148060Reactome Database ID Release 7010148062Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10148062ReactomeR-SSC-5654413

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5654413.1SOS, recruited by GRB2:p-FRS2 to activated FGFR, activates RAS nucleotide exchange from the inactive GDP-bound to the active GTP-bound state.

8493579Pubmed1993Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2Chardin, PCamonis, JHGale, NWVan Aelst, LSchlessinger, JWigler, Michael HBar-Sagi, DafnaScience 260:1338-43inferred by electronic annotationIEAGOIEA

2.7.10

Activated FGFR3 phosphorylates PPTN11

Reactome DB_ID: 113592

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 10148218

Activated FGFR3:p-FRS:PTPN11 [plasma membrane]

Activated FGFR3:p-FRS:PTPN11

Reactome DB_ID: 10088633

UniProt:A0A287AQB6

UniProtA0A287AQB6

EQUAL

597

EQUAL

Reactome DB_ID: 10148057

Reactome Database ID Release 7010148218Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10148218ReactomeR-SSC-5654310

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5654310.1

Reactome DB_ID: 29370

ADP(3-) [ChEBI:456216]

ADP(3-)

ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADP

ChEBI456216

Reactome DB_ID: 10148220

Activated FGFR3:p-FRS:p-PTPN11 [plasma membrane]

Activated FGFR3:p-FRS:p-PTPN11

Reactome DB_ID: 10148057

Reactome DB_ID: 10084585

O4'-phospho-L-tyrosine at 546 (in Homo sapiens)

546

EQUAL

O4'-phospho-L-tyrosine [MOD:00048]

O4'-phospho-L-tyrosine at 584 (in Homo sapiens)

584

EQUAL

597

EQUAL

Reactome Database ID Release 7010148220Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10148220ReactomeR-SSC-5654312

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5654312.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 10148218

GO0004713

GO molecular function

Reactome Database ID Release 7010148221Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10148221Reactome Database ID Release 7010148223Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10148223ReactomeR-SSC-5654631

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5654631.1Tyrosine 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.

9299490Pubmed1997SHP2 associates directly with tyrosine phosphorylated p90 (SNT) protein in FGF-stimulated cellsOng, SHLim, YPLow, BCGuy, GRBiochem Biophys Res Commun 238:261-614534538Pubmed2003The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3Agazie, YMMovilla, NIschenko, IHayman, MJOncogene 22:6909-1818373495Pubmed2008Extracellular point mutations in FGFR2 elicit unexpected changes in intracellular signallingAhmed, ZSchüller, ACSuhling, KTregidgo, CLadbury, JEBiochem J 413:37-49inferred by electronic annotationIEAGOIEA

Activated FGFR3:p-FRS:p-PTPN11 activates RAS nucleotide exchange

Reactome DB_ID: 29438

Reactome DB_ID: 10091501

Reactome DB_ID: 29420

Reactome DB_ID: 10090286

Reactome Database ID Release 7010169678Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10169678ReactomeR-SSC-8941628

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-8941628.1RAS nucleotide is stimulated downstream of activated FGFR3 in a p-PTPN11-dependent manner. The phosphatase activity of PTPN11 is required for activation of the RAS-MAP kinase pathway, although the mechanism for RAS pathway activation is not yet clear (Hadari et al, 1998; reviewed in Mohi et al, 2007; Gotoh et al, 2008).

9632781Pubmed1998Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiationHadari, YRKouhara, HLax, ISchlessinger, JMol Cell Biol 18:3966-7317227708Pubmed2007The role of Shp2 (PTPN11) in cancerMohi, M GolamNeel, Benjamin GCurr. Opin. Genet. Dev. 17:23-3018452557Pubmed2008Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteinsGotoh, NCancer Sci 99:1319-25inferred by electronic annotationIEAGOIEA

ACTIVATION

Reactome Database ID Release 7010169679Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10169679

Reactome DB_ID: 10148220

Reactome Database ID Release 7010177396Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10177396ReactomeR-SSC-5654706

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-SSC-5654706.1The 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.

15863030Pubmed2005Cellular signaling by fibroblast growth factor receptorsEswarakumar, VPLax, ISchlessinger, JCytokine Growth Factor Rev 16:139-4916682955Pubmed2006Expression 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 cellsManuvakhova, MThottassery, JVHays, SQu, ZRentz, SSWestbrook, LKern, FGOncogene 25:6003-1411447289Pubmed2001Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathwaysHadari, YRGotoh, NKouhara, HLax, ISchlessinger, JProc Natl Acad Sci U S A 98:8578-8310377388Pubmed1999Comparison of the intracellular signaling responses by three chimeric fibroblast growth factor receptors in PC12 cellsRaffioni, SThomas, DFoehr, EDThompson, LMBradshaw, RAProc Natl Acad Sci U S A 96:7178-839182757Pubmed1997A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathwayKouhara, HHadari, YRSpivak-Kroizman, TSchilling, JBar-Sagi, DafnaLax, ISchlessinger, JCell 89:693-702inferred by electronic annotationIEAGOIEA