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Q8C180 (FRS2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 99. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Fibroblast growth factor receptor substrate 2

Short name=FGFR substrate 2
Alternative name(s):
FGFR-signaling adaptor SNT
FRS2-alpha
Suc1-associated neurotrophic factor target 1
Short name=SNT-1
Gene names
Name:Frs2
Synonyms:Frs2a
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length508 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Adapter protein that links activated FGR and NGF receptors to downstream signaling pathways. Plays an important role in the activation of MAP kinases and in the phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, in response to ligand-mediated activation of FGFR1. Modulates signaling via SHC1 by competing for a common binding site on NTRK1. Ref.3 Ref.5 Ref.8 Ref.10 Ref.11

Subunit structure

Part of a complex containing FRS2, GRB2, GAB1, PIK3R1 and SOS1. Part of a complex containing GRB2 and CBL. Binds ALK, CKS2, FGFR1, RET, MAPK1/ERK2, MAPK3/ERK1 and SRC. The tyrosine-phosphorylated protein binds the SH2 domains of GRB2 and PTPN11. Interacts with NTRK1, NTRK2 and NTRK3 (phosphorylated upon ligand-binding) By similarity. Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1, FRS2, SRC, SHC1, GAP43 and CTTN. Ref.3 Ref.4 Ref.5 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12

Subcellular location

Membrane; Lipid-anchor Ref.4.

Tissue specificity

Ubiquitous. Expression is highest in brain, kidney, lung and testis. Ref.3

Post-translational modification

Phosphorylated on tyrosine residues upon stimulation by FGF2 or NGFB. Phosphorylated by ULK2 (in vitro). Phosphorylated on tyrosine residues by activated ALK and FGFR1. Phosphorylated on tyrosine residues upon activation of FGFR2 and FGFR3. Phosphorylated on threonine residues by MAP kinases; this inhibits tyrosine phosphorylation, and thereby down-regulates FRS2-mediated activation of MAP kinases. Ref.3 Ref.4 Ref.5 Ref.6 Ref.8 Ref.10 Ref.11 Ref.13

Ubiquitinated when tyrosine phosphorylated and in a complex with GRB2. The unphosphorylated form is not subject to ubiquitination. Ref.3 Ref.4 Ref.5 Ref.6 Ref.8 Ref.10 Ref.11 Ref.13

Sequence similarities

Contains 1 IRS-type PTB domain.

Ontologies

Keywords
   Cellular componentMembrane
   PTMLipoprotein
Myristate
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of MAPK activity

Inferred from mutant phenotype PubMed 15569927PubMed 15870281PubMed 18184727. Source: MGI

anterior/posterior axis specification, embryo

Inferred from mutant phenotype PubMed 15870281. Source: MGI

fibroblast growth factor receptor signaling pathway

Inferred from mutant phenotype PubMed 23136392. Source: MGI

forebrain development

Inferred from mutant phenotype PubMed 16239343. Source: MGI

gastrulation with mouth forming second

Inferred from mutant phenotype PubMed 15870281. Source: MGI

lens development in camera-type eye

Inferred from mutant phenotype PubMed 23136392. Source: MGI

lens fiber cell development

Inferred from mutant phenotype PubMed 23136392. Source: MGI

neuroblast proliferation

Inferred from mutant phenotype PubMed 16239343. Source: MGI

optic placode formation involved in camera-type eye formation

Inferred from mutant phenotype PubMed 15569927. Source: MGI

organ induction

Inferred from mutant phenotype PubMed 15569927. Source: MGI

prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis

Inferred from mutant phenotype PubMed 18184727. Source: MGI

regulation of ERK1 and ERK2 cascade

Inferred from mutant phenotype PubMed 23782834. Source: MGI

regulation of apoptotic process

Inferred from mutant phenotype PubMed 23782834. Source: MGI

regulation of epithelial cell proliferation

Inferred from mutant phenotype PubMed 18184727. Source: MGI

transmembrane receptor protein tyrosine kinase signaling pathway

Inferred from direct assay Ref.3. Source: MGI

ventricular septum development

Inferred from mutant phenotype PubMed 17868091. Source: MGI

   Cellular_componentcell-cell junction

Inferred from direct assay PubMed 23782834. Source: MGI

cytoplasm

Inferred from direct assay PubMed 15736129Ref.3. Source: MGI

plasma membrane

Inferred from direct assay PubMed 15736129Ref.3. Source: MGI

   Molecular_functionprotein binding

Inferred from physical interaction PubMed 23452850Ref.3. Source: IntAct

transmembrane receptor protein tyrosine kinase adaptor activity

Inferred from direct assay Ref.3. Source: MGI

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Grb2Q606315EBI-6880000,EBI-1688

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Potential
Chain2 – 508507Fibroblast growth factor receptor substrate 2
PRO_0000087345

Regions

Domain13 – 115103IRS-type PTB

Amino acid modifications

Modified residue1961Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.5 Ref.8 Ref.10
Modified residue2111Phosphoserine Ref.4 Ref.8 Ref.16
Modified residue2211Phosphoserine By similarity
Modified residue3061Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.5 Ref.8 Ref.10
Modified residue3491Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.5 Ref.8 Ref.10 Ref.17
Modified residue3921Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.5 Ref.8 Ref.10
Modified residue4361Phosphotyrosine; by FGFR1 Ref.4 Ref.5 Ref.8 Ref.10
Modified residue4711Phosphotyrosine; by FGFR1 Ref.4 Ref.8 Ref.10
Lipidation21N-myristoyl glycine Ref.3

Experimental info

Mutagenesis21G → A: Abolishes myristoylation and membrane association. Ref.3
Mutagenesis1961Y → F: Abolishes tyrosine phosphorylation and interactions with GRB2 and PTPN11; when associated with F-306; F-349; F-392 and F-436. Ref.3
Mutagenesis3061Y → F: Abolishes tyrosine phosphorylation and interactions with GRB2 and PTPN11; when associated with F-196; F-349; F-392 and F-436. Ref.3
Mutagenesis3491Y → F: Abolishes tyrosine phosphorylation and interactions with GRB2 and PTPN11; when associated with F-196; F-306; F-392 and F-436. Ref.3
Mutagenesis3921Y → F: Abolishes tyrosine phosphorylation and interactions with GRB2 and PTPN11; when associated with F-196; F-306; F-349 and F-436. Ref.3
Mutagenesis4361Y → F: Abolishes tyrosine phosphorylation and interactions with GRB2 and PTPN11; when associated with F-196; F-306; F-349 and F-392. Ref.5

Sequences

Sequence LengthMass (Da)Tools
Q8C180 [UniParc].

Last modified January 23, 2007. Version 3.
Checksum: DFFE8A818BFF8631

FASTA50856,794
        10         20         30         40         50         60 
MGSCCSCPDK DTVPDNHRNK FKVINVDDDG NELGSGVMEL TDTELILYTR KRDSVKWHYL 

        70         80         90        100        110        120 
CLRRYGYDSN LFSFESGRRC QTGQGIFAFK CARAEELFNM LQEIMQNNSI NVVEEPVVER 

       130        140        150        160        170        180 
SSHQTELEVP RTPRTPTTPG LGAQNLPNGY PRYPSFGDAS SHPSSRHPSV GSARLPSVGE 

       190        200        210        220        230        240 
ESTHPLLVAE EQVHTYVNTT GVQEERKNRA SVHVPPEARV SNAESNTPKE EPSNPEDRDP 

       250        260        270        280        290        300 
QVLLKPEGVR FVLGPTPVQK QLMEKEKLEQ LGKDPVSGSG AGNTEWDTGY DSDERRDVPP 

       310        320        330        340        350        360 
VNKLVYENIN GLSIPSASGV RRGRLTSTST SDTQNINNSA QRRPALLNYE NLPSLPPVWE 

       370        380        390        400        410        420 
ARKLSRDEDD NLGPKTPSLN GYHNNLDPMH NYVNTENVTV PASAHKIDYS KRRDCTPTVF 

       430        440        450        460        470        480 
NFDIRRPSLE HRQLNYIQVD LEGGSDSDNP QTPKTPTTPL PQTPTRRTEL YAVIDIERTA 

       490        500 
AMSNLQKALP RDDGTSRKTR HNSTDLPM 

« Hide

References

« Hide 'large scale' references
[1]"The transcriptional landscape of the mammalian genome."
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. expand/collapse author list , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6J.
Tissue: Skin.
[2]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Strain: C57BL/6.
Tissue: Brain.
[3]"A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway."
Kouhara H., Hadari Y.R., Spivak-Kroizman T., Schilling J., Bar-Sagi D., Lax I., Schlessinger J.
Cell 89:693-702(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF 251-260; 305-320; 344-361 AND 468-480, FUNCTION, INTERACTION WITH GRB2, IDENTIFICATION IN A COMPLEX WITH GRB2 AND SOS1, MYRISTOYLATION AT GLY-2, MUTAGENESIS OF GLY-2; TYR-196; TYR-306; TYR-349 AND TYR-392, PHOSPHORYLATION AT TYR-196; TYR-306; TYR-349 AND TYR-392, TISSUE SPECIFICITY.
[4]"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 S.-H., Goh K.C., Lim Y.P., Low B.C., Klint P., Claesson-Welsh L., Cao X., Tan Y.H., Guy G.R.
Biochem. Biophys. Res. Commun. 225:1021-1026(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH SUC1 AND GRB2, PHOSPHORYLATION AT TYROSINE RESIDUES, SUBCELLULAR LOCATION.
[5]"Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation."
Hadari Y.R., Kouhara H., Lax I., Schlessinger J.
Mol. Cell. Biol. 18:3966-3973(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH PTPN11, FUNCTION, PHOSPHORYLATION AT TYR-196; TYR-306; TYR-349; TYR-392 AND TYR-436, MUTAGENESIS OF TYR-436.
[6]"Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts."
Mansukhani A., Bellosta P., Sahni M., Basilico C.
J. Cell Biol. 149:1297-1308(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION IN RESPONSE TO FRFR2 AND FGFR3 ACTIVATION.
[7]"FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors."
Ong S.-H., Guy G.R., Hadari Y.R., Laks S., Gotoh N., Schlessinger J., Lax I.
Mol. Cell. Biol. 20:979-989(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH FGFR1 AND NTRK1.
[8]"Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade."
Melillo R.M., Santoro M., Ong S.-H., Billaud M., Fusco A., Hadari Y.R., Schlessinger J., Lax I.
Mol. Cell. Biol. 21:4177-4187(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH RET, PHOSPHORYLATION AT TYROSINE RESIDUES.
[9]"N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor signalling."
Cavallaro U., Niedermeyer J., Fuxa M., Christofori G.
Nat. Cell Biol. 3:650-657(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A COMPLEX WITH NCAM1; CDH2; PLCG1; FRS2; SRC; SHC1; GAP43 AND CTTN.
[10]"Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins."
Ong S.H., Hadari Y.R., Gotoh N., Guy G.R., Schlessinger J., Lax I.
Proc. Natl. Acad. Sci. U.S.A. 98:6074-6079(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH GRB2 AND GAB1, PHOSPHORYLATION AT TYR-196; TYR-306; TYR-349; TYR-392; TYR-436 AND TYR-471.
[11]"The Shb adaptor protein binds to tyrosine 766 in the FGFR-1 and regulates the Ras/MEK/MAPK pathway via FRS2 phosphorylation in endothelial cells."
Cross M.J., Lu L., Magnusson P., Nyqvist D., Holmqvist K., Welsh M., Claesson-Welsh L.
Mol. Biol. Cell 13:2881-2893(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN ACTIVATION OF SIGNALING VIA RAS AND MAP KINASES, INTERACTION WITH PTPN11, PHOSPHORYLATION.
[12]"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. 99:6684-6689(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION IN A COMPLEX WITH GRB2 AND CBL, UBIQUITINATION.
[13]"UNC-51-like kinase regulation of fibroblast growth factor receptor substrate 2/3."
Avery A.W., Figueroa C., Vojtek A.B.
Cell. Signal. 19:177-184(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION BY ULK2.
[14]"Large-scale phosphorylation analysis of mouse liver."
Villen J., Beausoleil S.A., Gerber S.A., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 104:1488-1493(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Liver.
[15]"Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins."
Gotoh N.
Cancer Sci. 99:1319-1325(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION; SUBUNIT AND PHOSPHORYLATION.
[16]"The phagosomal proteome in interferon-gamma-activated macrophages."
Trost M., English L., Lemieux S., Courcelles M., Desjardins M., Thibault P.
Immunity 30:143-154(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-211, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[17]"Large scale localization of protein phosphorylation by use of electron capture dissociation mass spectrometry."
Sweet S.M., Bailey C.M., Cunningham D.L., Heath J.K., Cooper H.J.
Mol. Cell. Proteomics 8:904-912(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-349, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Embryonic fibroblast.
[18]"Fibroblast growth factor signalling: from development to cancer."
Turner N., Grose R.
Nat. Rev. Cancer 10:116-129(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION IN FGF SIGNALING.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AK028813 mRNA. Translation: BAC26132.1.
BC043109 mRNA. Translation: AAH43109.1.
BC055334 mRNA. Translation: AAH55334.1.
CCDSCCDS24190.1.
RefSeqNP_808466.1. NM_177798.3.
UniGeneMm.135965.

3D structure databases

ProteinModelPortalQ8C180.
SMRQ8C180. Positions 11-136.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid236497. 6 interactions.
IntActQ8C180. 2 interactions.
MINTMINT-8013548.
STRING10090.ENSMUSP00000020381.

PTM databases

PhosphoSiteQ8C180.

Proteomic databases

PRIDEQ8C180.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000020381; ENSMUSP00000020381; ENSMUSG00000020170.
GeneID327826.
KEGGmmu:327826.
UCSCuc007hct.1. mouse.

Organism-specific databases

CTD10818.
MGIMGI:1100860. Frs2.

Phylogenomic databases

eggNOGNOG316561.
GeneTreeENSGT00510000046707.
HOGENOMHOG000290694.
HOVERGENHBG062705.
InParanoidQ8C180.
KOK12461.
OMATRRRDCT.
OrthoDBEOG7QG43P.
PhylomeDBQ8C180.
TreeFamTF324994.

Gene expression databases

BgeeQ8C180.
CleanExMM_FRS2.
GenevestigatorQ8C180.

Family and domain databases

Gene3D2.30.29.30. 1 hit.
InterProIPR002404. Insln_rcpt_S1.
IPR011993. PH_like_dom.
[Graphical view]
PfamPF02174. IRS. 1 hit.
[Graphical view]
SMARTSM00310. PTBI. 1 hit.
[Graphical view]
PROSITEPS51064. IRS_PTB. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

NextBio397981.
PROQ8C180.
SOURCESearch...

Entry information

Entry nameFRS2_MOUSE
AccessionPrimary (citable) accession number: Q8C180
Entry history
Integrated into UniProtKB/Swiss-Prot: July 19, 2005
Last sequence update: January 23, 2007
Last modified: July 9, 2014
This is version 99 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot