FRS2

Fibroblast growth factor receptor substrate 2 is a protein that in humans is encoded by the FRS2 gene.[4][5][6][7]

FRS2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1XR0, 2MFQ
Identifiers
Aliases	FRS2, FRS2A, FRS2alpha, SNT, SNT-1, SNT1, FRS1A, fibroblast growth factor receptor substrate 2
External IDs	OMIM: 607743 MGI: 1100860 HomoloGene: 4846 GeneCards: FRS2
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q15 Start 69,470,349 bp[1] End 69,579,789 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • transmembrane receptor protein tyrosine kinase adaptor activity • fibroblast growth factor receptor binding • neurotrophin TRKA receptor binding • GO:0001948 protein binding • phosphatase activator activity • 1-phosphatidylinositol-3-kinase activity • phosphatidylinositol-4,5-bisphosphate 3-kinase activity • Ras guanyl-nucleotide exchange factor activity Cellular component • cytoplasm • endosome • membrane • cell membrane • integral component of plasma membrane • endomembrane system • intercellular junction • cytosol Biological process • regulation of apoptotic process • G-protein coupled receptor signaling pathway • ventricular septum development • organ induction • activation of MAPKK activity • transmembrane receptor protein tyrosine kinase signaling pathway • gastrulation with mouth forming second • MAPK cascade • optic placode formation involved in camera-type eye formation • fibroblast growth factor receptor signaling pathway • transmembrane receptor protein tyrosine phosphatase signaling pathway • activation of MAPK activity • lens development in camera-type eye • prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis • regulation of ERK1 and ERK2 cascade • neuroblast proliferation • forebrain development • regulation of epithelial cell proliferation • anterior/posterior axis specification, embryo • lens fiber cell development • phosphatidylinositol phosphorylation • phosphatidylinositol-3-phosphate biosynthetic process • axon guidance • negative regulation of cardiac muscle cell differentiation • positive regulation of protein kinase B signaling • neurotrophin TRK receptor signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	10818	327826
Ensembl	ENSG00000166225	ENSMUSG00000020170
UniProt	Q8WU20	Q8C180
RefSeq (mRNA)	NM_006654 NM_001042555 NM_001278351 NM_001278353 NM_001278354 NM_001278355 NM_001278356 NM_001278357	NM_177798
RefSeq (protein)	NP_001036020 NP_001265280 NP_001265282 NP_001265283 NP_001265284 NP_001265285 NP_001265286 NP_006645	NP_808466
Location (UCSC)	Chr 12: 69.47 – 69.58 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

FRS2 is an 80 kDa membrane-anchored signal transducing adaptor protein (STAP) that links specific activated Receptor Tyrosine Kinases (RTKs) to multiple downstream signaling pathways, most notably the MAPK/ERK, PI3K/AKT/mTOR and PLCγ pathways.[8] It is overexpressed and amplified in several cancer types, including prostate cancer.[9][10]

Interactions

FRS2 has been shown to interact with:

• CBL[11]
• FGFR1[6][12][13][14]
• GRB2[11][15][16][17]
• PRKCI[18]
• PTPN11[19][20][21]
• SOS1[11][17][22]
• TrkA[16]
• ALK[23]

References

1. GRCh38: Ensembl release 89: ENSG00000166225 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Rabin SJ, Cleghon V, Kaplan DR (April 1993). "SNT, a differentiation-specific target of neurotrophic factor-induced tyrosine kinase activity in neurons and PC12 cells". Molecular and Cellular Biology. 13 (4): 2203–13. doi:10.1128/mcb.13.4.2203. PMC 359541. PMID 7681142.
5. Wang JK, Xu H, Li HC, Goldfarb M (October 1996). "Broadly expressed SNT-like proteins link FGF receptor stimulation to activators of Ras". Oncogene. 13 (4): 721–9. PMID 8761293.
6. Xu H, Lee KW, Goldfarb M (August 1998). "Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteins". J Biol Chem. 273 (29): 17987–90. doi:10.1074/jbc.273.29.17987. PMID 9660748.
7. "Entrez Gene: FRS2 Fibroblast growth factor receptor substrate 2".
8. Pawson T, Scott JD (December 1997). "Signaling through scaffold, anchoring, and adaptor proteins". Science. 278 (5346): 2075–80. doi:10.1126/science.278.5346.2075. PMID 9405336.
9. Valencia T, Joseph A, Kachroo N, Darby S, Meakin S, Gnanapragasam VJ (Nov 11, 2011). "Role and expression of FRS2 and FRS3 in prostate cancer". BMC Cancer. 11: 484. doi:10.1186/1471-2407-11-484. PMC 3231952. PMID 22078327.
10. Chen Y, McGee J, Chen X, Doman TN, Gong X, Zhang Y, Hamm N, Ma X, Higgs RE, Bhagwat SV, Buchanan S, Peng SB, Staschke KA, Yadav V, Yue Y, Kouros-Mehr H (2014). "Identification of Druggable Cancer Driver Genes Amplified across TCGA Datasets". PLOS ONE. 9 (5): e98293. doi:10.1371/journal.pone.0098293. PMC 4038530. PMID 24874471.
11. Wong A, Lamothe B, Lee A, Schlessinger J, Lax I, Li A (May 2002). "FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl". Proc. Natl. Acad. Sci. U.S.A. 99 (10): 6684–9. doi:10.1073/pnas.052138899. PMC 124463. PMID 11997436.
12. Yan KS, Kuti M, Yan S, Mujtaba S, Farooq A, Goldfarb MP, Zhou MM (May 2002). "FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors". J. Biol. Chem. 277 (19): 17088–94. doi:10.1074/jbc.M107963200. PMID 11877385.
13. Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J, Lax I (February 2000). "FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors". Mol. Cell. Biol. 20 (3): 979–89. doi:10.1128/mcb.20.3.979-989.2000. PMC 85215. PMID 10629055.
14. Dhalluin C, Yan KS, Plotnikova O, Lee KW, Zeng L, Kuti M, Mujtaba S, Goldfarb MP, Zhou MM (October 2000). "Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors". Mol. Cell. 6 (4): 921–9. doi:10.1016/S1097-2765(05)00087-0. PMC 5155437. PMID 11090629.
15. Ong SH, Goh KC, Lim YP, Low BC, Klint P, Claesson-Welsh L, Cao X, Tan YH, Guy GR (August 1996). "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". Biochem. Biophys. Res. Commun. 225 (3): 1021–6. doi:10.1006/bbrc.1996.1288. PMID 8780727.
16. Meakin SO, MacDonald JI, Gryz EA, Kubu CJ, Verdi JM (April 1999). "The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation". J. Biol. Chem. 274 (14): 9861–70. doi:10.1074/jbc.274.14.9861. PMID 10092678.
17. Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J (May 1997). "A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway". Cell. 89 (5): 693–702. doi:10.1016/s0092-8674(00)80252-4. PMID 9182757. S2CID 2187363.
18. Lim YP, Low BC, Lim J, Wong ES, Guy GR (July 1999). "Association of atypical protein kinase C isotypes with the docker protein FRS2 in fibroblast growth factor signaling". J. Biol. Chem. 274 (27): 19025–34. doi:10.1074/jbc.274.27.19025. PMID 10383403.
19. Delahaye L, Rocchi S, Van Obberghen E (February 2000). "Potential involvement of FRS2 in insulin signaling". Endocrinology. 141 (2): 621–8. doi:10.1210/endo.141.2.7298. PMID 10650943.
20. Kurokawa K, Iwashita T, Murakami H, Hayashi H, Kawai K, Takahashi M (April 2001). "Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction". Oncogene. 20 (16): 1929–38. doi:10.1038/sj.onc.1204290. PMID 11360177.
21. Hadari YR, Kouhara H, Lax I, Schlessinger J (July 1998). "Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation". Mol. Cell. Biol. 18 (7): 3966–73. doi:10.1128/mcb.18.7.3966. PMC 108981. PMID 9632781.
22. Foehr ED, Tatavos A, Tanabe E, Raffioni S, Goetz S, Dimarco E, De Luca M, Bradshaw RA (May 2000). "Discoidin domain receptor 1 (DDR1) signaling in PC12 cells: activation of juxtamembrane domains in PDGFR/DDR/TrkA chimeric receptors". FASEB J. 14 (7): 973–81. doi:10.1096/fasebj.14.7.973. PMID 10783152. S2CID 43317719.
23. Degoutin J, Vigny M, Gouzi JY (February 2007). "ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation". FEBS Letters. 581 (4): 727–34. doi:10.1016/j.febslet.2007.01.039. PMID 17274988. S2CID 40978851.

Further reading

• Ong SH, Goh KC, Lim YP, Low BC, Klint P, Claesson-Welsh L, Cao X, Tan YH, Guy GR (1996). "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". Biochem. Biophys. Res. Commun. 225 (3): 1021–6. doi:10.1006/bbrc.1996.1288. PMID 8780727.
• Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J (1997). "A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway". Cell. 89 (5): 693–702. doi:10.1016/S0092-8674(00)80252-4. PMID 9182757. S2CID 2187363.
• Hadari YR, Kouhara H, Lax I, Schlessinger J (1998). "Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation". Mol. Cell. Biol. 18 (7): 3966–73. doi:10.1128/mcb.18.7.3966. PMC 108981. PMID 9632781.
• Meakin SO, MacDonald JI, Gryz EA, Kubu CJ, Verdi JM (1999). "The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation". J. Biol. Chem. 274 (14): 9861–70. doi:10.1074/jbc.274.14.9861. PMID 10092678.
• Lim YP, Low BC, Lim J, Wong ES, Guy GR (1999). "Association of atypical protein kinase C isotypes with the docker protein FRS2 in fibroblast growth factor signaling". J. Biol. Chem. 274 (27): 19025–34. doi:10.1074/jbc.274.27.19025. PMID 10383403.
• Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J, Lax I (2000). "FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors". Mol. Cell. Biol. 20 (3): 979–89. doi:10.1128/MCB.20.3.979-989.2000. PMC 85215. PMID 10629055.
• Delahaye L, Rocchi S, Van Obberghen E (2000). "Potential involvement of FRS2 in insulin signaling". Endocrinology. 141 (2): 621–8. doi:10.1210/endo.141.2.7298. PMID 10650943.
• Foehr ED, Tatavos A, Tanabe E, Raffioni S, Goetz S, Dimarco E, De Luca M, Bradshaw RA (2000). "Discoidin domain receptor 1 (DDR1) signaling in PC12 cells: activation of juxtamembrane domains in PDGFR/DDR/TrkA chimeric receptors". FASEB J. 14 (7): 973–81. doi:10.1096/fasebj.14.7.973. PMID 10783152. S2CID 43317719.
• Wang X, Weng LP, Yu Q (2000). "Specific inhibition of FGF-induced MAPK activation by the receptor-like protein tyrosine phosphatase LAR". Oncogene. 19 (19): 2346–53. doi:10.1038/sj.onc.1203558. PMID 10822386.
• Dhalluin C, Yan KS, Plotnikova O, Lee KW, Zeng L, Kuti M, Mujtaba S, Goldfarb MP, Zhou MM (2000). "Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors". Mol. Cell. 6 (4): 921–9. doi:10.1016/S1097-2765(05)00087-0. PMC 5155437. PMID 11090629.
• Kao S, Jaiswal RK, Kolch W, Landreth GE (2001). "Identification of the mechanisms regulating the differential activation of the mapk cascade by epidermal growth factor and nerve growth factor in PC12 cells". J. Biol. Chem. 276 (21): 18169–77. doi:10.1074/jbc.M008870200. PMID 11278445.
• Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I (2001). "Stimulation of phosphatidylinositol 3-kinase by fibroblast growth factor receptors is mediated by coordinated recruitment of multiple docking proteins". Proc. Natl. Acad. Sci. U.S.A. 98 (11): 6074–9. doi:10.1073/pnas.111114298. PMC 33424. PMID 11353842.
• Kurokawa K, Iwashita T, Murakami H, Hayashi H, Kawai K, Takahashi M (2001). "Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction". Oncogene. 20 (16): 1929–38. doi:10.1038/sj.onc.1204290. PMID 11360177.
• Melillo RM, Santoro M, Ong SH, Billaud M, Fusco A, Hadari YR, Schlessinger J, Lax I (2001). "Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade". Mol. Cell. Biol. 21 (13): 4177–87. doi:10.1128/MCB.21.13.4177-4187.2001. PMC 87079. PMID 11390647.
• Hadari YR, Gotoh N, Kouhara H, Lax I, Schlessinger J (2001). "Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways". Proc. Natl. Acad. Sci. U.S.A. 98 (15): 8578–83. doi:10.1073/pnas.161259898. PMC 37478. PMID 11447289.
• Yan KS, Kuti M, Yan S, Mujtaba S, Farooq A, Goldfarb MP, Zhou MM (2002). "FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors". J. Biol. Chem. 277 (19): 17088–94. doi:10.1074/jbc.M107963200. PMID 11877385.
• Wong A, Lamothe B, Lee A, Schlessinger J, Lax I, Li A (2002). "FRS2 alpha attenuates FGF receptor signaling by Grb2-mediated recruitment of the ubiquitin ligase Cbl". Proc. Natl. Acad. Sci. U.S.A. 99 (10): 6684–9. doi:10.1073/pnas.052138899. PMC 124463. PMID 11997436.
• Stoletov KV, Ratcliffe KE, Terman BI (2002). "Fibroblast growth factor receptor substrate 2 participates in vascular endothelial growth factor-induced signaling". FASEB J. 16 (10): 1283–5. doi:10.1096/fj.01-0835fje. PMID 12154000. S2CID 35161062.