Reviewed, UniProtKB/Swiss-Prot Q8C180 (FRS2_MOUSE)

Names and origin

Protein names

Recommended name:
    Fibroblast growth factor receptor substrate 2
      Short name=FGFR substrate 2
Alternative name(s):
    Suc1-associated neurotrophic factor target 1
      Short name=SNT-1
    FGFR-signaling adaptor SNT
    FRS2 alpha

Gene names

Name:	Frs2
Synonyms:	Frs2a

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › 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 FGR and NGF receptors to downstream signaling pathways. Involved in the activation of MAP kinases. Modulates signaling via SHC1 by competing for a common binding site on NTRK1. Ref.3 Ref.7
Subunit structure	Binds NTRK2 and NTRK3. Part of a complex containing GRB2 and CBL By similarity. Binds FGFR1, SUC1, RET and phosphorylated NTRK1. The tyrosine-phosphorylated protein binds the SH2 domains of GRB2 and PTPN11. Part of a complex containing FRS2, GRB2 and SOS1.
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 BFGF or NGFB. Ref.3 Ref.7 Ref.4 Ref.9 Ubiquitinated when tyrosine phosphorylated and in a complex with GRB2. The unphosphorylated form is not subject to ubiquitination. Ref.3 Ref.7 Ref.4 Ref.9
Sequence similarities	Contains 1 IRS-type PTB domain.

Ontologies

Keywords
Cellular component	Membrane
PTM	Lipoprotein Myristate Phosphoprotein Ubl conjugation
Technical term	Direct protein sequencing
Gene Ontology (GO)
Biological process	activation of MAPK activity Inferred from mutant phenotype. Source: MGI determination of anterior/posterior axis, embryo Inferred from mutant phenotype. Source: MGI fibroblast growth factor receptor signaling pathway Inferred from genetic interaction. Source: MGI forebrain development Inferred from mutant phenotype. Source: MGI gastrulation with mouth forming second Inferred from mutant phenotype. Source: MGI induction of an organ Inferred from mutant phenotype. Source: MGI neuroblast proliferation Inferred from genetic interaction. Source: MGI optic placode formation involved in camera-type eye Inferred from mutant phenotype. Source: MGI
Cellular component	cytoplasm Ref.3 Inferred from direct assay. Source: MGI plasma membrane Ref.3 Inferred from direct assay. Source: MGI
Molecular function	insulin receptor binding Inferred from electronic annotation. Source: InterPro transmembrane receptor protein tyrosine kinase docking protein activity Ref.3 Inferred from direct assay. 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
	Modified residue	172	1	Phosphoserine
	Modified residue	211	1	Phosphoserine
	Modified residue	288	1	Phosphothreonine Ref.3 Ref.7 Ref.4 Ref.9
	Modified residue	349	1	Phosphotyrosine
	Lipidation	2	1	N-myristoyl glycine
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)
	Q8C180-1 [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: 16141072] [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: 15489334] [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: 9182757] [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: 8780727] [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: 9632781] [Abstract] Cited for: INTERACTION WITH PTPN11, MUTAGENESIS OF TYR-436.
[6]	"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: 10629055] [Abstract] Cited for: INTERACTION WITH FGFR1 AND NTRK1.
[7]	"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: 11390647] [Abstract] Cited for: FUNCTION, INTERACTION WITH RET, PHOSPHORYLATION AT TYROSINE RESIDUES.
[8]	"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: 11997436] [Abstract] Cited for: IDENTIFICATION IN A COMPLEX WITH GRB2 AND CBL, UBIQUITINATION.
[9]	"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: 17242355] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-288, MASS SPECTROMETRY. Tissue: Liver.
[10]	"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: 19144319] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-169; SER-172 AND SER-211, MASS SPECTROMETRY. Tissue: Macrophage.
[11]	"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: 19131326] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-349, MASS SPECTROMETRY.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBLGenBankDDBJ	AK028813 mRNA. Translation: BAC26132.1. BC043109 mRNA. Translation: AAH43109.1. BC055334 mRNA. Translation: AAH55334.1.
IPI	IPI00224112.
RefSeq	NP_808466.1.
UniGene	Mm.135965
3D structure databases
HSSP	HSSP built from PDB template 1J0W based on UniProtKB Q9P104.
SMR	Q8C180. Positions 10-135, 11-136.
ModBase	Search...
PTM databases
PhosphoSite	Q8C180.
Genome annotation databases
Ensembl	ENSMUSG00000020170. Mus musculus. [Contig view]
GeneID	327826.
KEGG	mmu:327826.
Organism-specific databases
MGI	MGI:1100860. Frs2.
Phylogenomic databases
HOGENOM	Q8C180.
HOVERGEN	Q8C180.
OMA	Q8C180. AFKCARA.
Gene expression databases
ArrayExpress	Q8C180.
Bgee	Q8C180.
CleanEx	MM_FRS2.
GermOnline	ENSMUSG00000020170. Mus musculus.
Family and domain databases
InterPro	IPR002404. Insln_rcpt_S1. IPR011993. PH_type. [Graphical view]
Gene3D	G3DSA:2.30.29.30. PH_type. 1 hit.
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 Resources
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:	June 16, 2009
This is version 55 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)