Q8C180 (FRS2_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	508 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 component	Membrane
PTM	Lipoprotein Myristate Phosphoprotein Ubl conjugation
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	activation 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 genetic interaction PubMed 15870281PubMed 17868091. 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 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 epithelial cell proliferation Inferred from mutant phenotype PubMed 18184727. Source: MGI ventricular septum development Inferred from mutant phenotype PubMed 17868091. Source: MGI
Cellular_component	cytoplasm Inferred from direct assay PubMed 15736129Ref.3. Source: MGI plasma membrane Inferred from direct assay PubMed 15736129Ref.3. Source: MGI
Molecular_function	transmembrane receptor protein tyrosine kinase adaptor activity Inferred from direct assay Ref.3. Source: MGI
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Initiator methionine	1	1	Removed Potential
	Chain	2 – 508	507	Fibroblast growth factor receptor substrate 2		PRO_0000087345
Regions
	Domain	13 – 115	103	IRS-type PTB
Amino acid modifications
	Modified residue	169	1	Phosphoserine Ref.3 Ref.4 Ref.8 Ref.16
	Modified residue	172	1	Phosphoserine Ref.3 Ref.4 Ref.8 Ref.16
	Modified residue	196	1	Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.5 Ref.8 Ref.10
	Modified residue	211	1	Phosphoserine Ref.3 Ref.4 Ref.8 Ref.16
	Modified residue	221	1	Phosphoserine By similarity
	Modified residue	288	1	Phosphothreonine Ref.3 Ref.4 Ref.8 Ref.14
	Modified residue	306	1	Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.5 Ref.8 Ref.10
	Modified residue	349	1	Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.5 Ref.8 Ref.10 Ref.17
	Modified residue	392	1	Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.5 Ref.8 Ref.10
	Modified residue	436	1	Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.5 Ref.8 Ref.10
	Modified residue	471	1	Phosphotyrosine; by FGFR1 Ref.3 Ref.4 Ref.8 Ref.10
	Lipidation	2	1	N-myristoyl glycine Ref.3
Experimental info
	Mutagenesis	2	1	G → A: Abolishes myristoylation and membrane association. Ref.3
	Mutagenesis	196	1	Y → F: Abolishes tyrosine phosphorylation and interactions with GRB2 and PTPN11; when associated with F-306; F-349; F-392 and F-436. Ref.3
	Mutagenesis	306	1	Y → F: Abolishes tyrosine phosphorylation and interactions with GRB2 and PTPN11; when associated with F-196; F-349; F-392 and F-436. Ref.3
	Mutagenesis	349	1	Y → F: Abolishes tyrosine phosphorylation and interactions with GRB2 and PTPN11; when associated with F-196; F-306; F-392 and F-436. Ref.3
	Mutagenesis	392	1	Y → F: Abolishes tyrosine phosphorylation and interactions with GRB2 and PTPN11; when associated with F-196; F-306; F-349 and F-436. Ref.3
	Mutagenesis	436	1	Y → 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		Length	Mass (Da)
	Q8C180 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: DFFE8A818BFF8631	FASTA	508	56,794
	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

References

	« Hide 'large scale' referencesShow '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. , 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 TYROSINE RESIDUES, 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: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-288, MASS SPECTROMETRY. 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-169; SER-172 AND SER-211, MASS SPECTROMETRY. Tissue: Macrophage.
[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, MASS SPECTROMETRY. 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.
IPI	IPI00224112.
RefSeq	NP_808466.1. NM_177798.3.
UniGene	Mm.135965.
3D structure databases
ProteinModelPortal	Q8C180.
SMR	Q8C180. Positions 11-136.
ModBase	Search...
Protein-protein interaction databases
STRING	10090.ENSMUSP00000020381.
PTM databases
PhosphoSite	Q8C180.
Proteomic databases
PRIDE	Q8C180.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000020381; ENSMUSP00000020381; ENSMUSG00000020170.
GeneID	327826.
KEGG	mmu:327826.
UCSC	uc007hct.1. mouse.
Organism-specific databases
CTD	10818.
MGI	MGI:1100860. Frs2.
Phylogenomic databases
eggNOG	NOG316561.
GeneTree	ENSGT00510000046707.
HOGENOM	HOG000290694.
HOVERGEN	HBG062705.
InParanoid	Q8C180.
KO	K12461.
OMA	RKNRASV.
OrthoDB	EOG4M398C.
Gene expression databases
Bgee	Q8C180.
CleanEx	MM_FRS2.
Genevestigator	Q8C180.
GermOnline	ENSMUSG00000020170. Mus musculus.
Family and domain databases
Gene3D	2.30.29.30. 1 hit.
InterPro	IPR002404. Insln_rcpt_S1. IPR011993. PH_like_dom. [Graphical view]
Pfam	PF02174. IRS. 1 hit. [Graphical view]
SMART	SM00310. PTBI. 1 hit. [Graphical view]
PROSITE	PS51064. IRS_PTB. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	397981.
SOURCE	Search...

Entry information

Entry name

FRS2_MOUSE

Accession

Primary (citable) accession number: Q8C180

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 19, 2005
Last sequence update:	January 23, 2007
Last modified:	April 3, 2013
This is version 88 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program