FRS2 explained

Fibroblast growth factor receptor substrate 2 is a protein that in humans is encoded by the FRS2 gene.^{[1] [2] [3] [4]}

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.^[5] It is overexpressed and amplified in several cancer types, including prostate cancer.^{[6] [7]}

Interactions

FRS2 has been shown to interact with:

• • CBL FGFR1^{[8] [9] [10]}
• GRB2^{[11] [12] [13] [14]}
• PRKCI^[15]
• PTPN11^{[16] [17] [18]}
• SOS1^{[11] [14] [19]}
• TrkA^[13]
• ALK^[20]

Further reading

• Ong SH, Goh KC, Lim YP, Low BC, Klint P, Claesson-Welsh L, Cao X, Tan YH, Guy GR . 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 . 1996 . 8780727 . 10.1006/bbrc.1996.1288 .
• Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J . A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. . Cell . 89 . 5 . 693–702 . 1997 . 9182757 . 10.1016/S0092-8674(00)80252-4 . 2187363 . free .
• Hadari YR, Kouhara H, Lax I, Schlessinger J . Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation. . Mol. Cell. Biol. . 18 . 7 . 3966–73 . 1998 . 9632781 . 108981 . 10.1128/mcb.18.7.3966.
• Meakin SO, MacDonald JI, Gryz EA, Kubu CJ, Verdi JM . 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 . 1999 . 10092678 . 10.1074/jbc.274.14.9861 . free .
• Lim YP, Low BC, Lim J, Wong ES, Guy GR . Association of atypical protein kinase C isotypes with the docker protein FRS2 in fibroblast growth factor signaling. . J. Biol. Chem. . 274 . 27 . 19025–34 . 1999 . 10383403 . 10.1074/jbc.274.27.19025 . free .
• Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J, Lax I . 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 . 2000 . 10629055 . 85215 . 10.1128/MCB.20.3.979-989.2000 .
• Delahaye L, Rocchi S, Van Obberghen E . Potential involvement of FRS2 in insulin signaling. . Endocrinology . 141 . 2 . 621–8 . 2000 . 10650943 . 10.1210/endo.141.2.7298 . free .
• Foehr ED, Tatavos A, Tanabe E, Raffioni S, Goetz S, Dimarco E, De Luca M, Bradshaw RA . 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 . 2000 . 10783152 . 10.1096/fasebj.14.7.973. free . 43317719 .
• Wang X, Weng LP, Yu Q . Specific inhibition of FGF-induced MAPK activation by the receptor-like protein tyrosine phosphatase LAR. . Oncogene . 19 . 19 . 2346–53 . 2000 . 10822386 . 10.1038/sj.onc.1203558 . free .
• Dhalluin C, Yan KS, Plotnikova O, Lee KW, Zeng L, Kuti M, Mujtaba S, Goldfarb MP, Zhou MM . Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors. . Mol. Cell . 6 . 4 . 921–9 . 2000 . 11090629 . 10.1016/S1097-2765(05)00087-0 . 5155437 .
• Kao S, Jaiswal RK, Kolch W, Landreth GE . 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 . 2001 . 11278445 . 10.1074/jbc.M008870200 . free .
• Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I . 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 . 2001 . 11353842 . 33424 . 10.1073/pnas.111114298 . 2001PNAS...98.6074O . free .
• Kurokawa K, Iwashita T, Murakami H, Hayashi H, Kawai K, Takahashi M . Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction. . Oncogene . 20 . 16 . 1929–38 . 2001 . 11360177 . 10.1038/sj.onc.1204290 . free .
• Melillo RM, Santoro M, Ong SH, Billaud M, Fusco A, Hadari YR, Schlessinger J, Lax I . 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 . 2001 . 11390647 . 87079 . 10.1128/MCB.21.13.4177-4187.2001 .
• Hadari YR, Gotoh N, Kouhara H, Lax I, Schlessinger J . 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 . 2001 . 11447289 . 37478 . 10.1073/pnas.161259898 . 2001PNAS...98.8578H . free .
• Yan KS, Kuti M, Yan S, Mujtaba S, Farooq A, Goldfarb MP, Zhou MM . FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors. . J. Biol. Chem. . 277 . 19 . 17088–94 . 2002 . 11877385 . 10.1074/jbc.M107963200 . free .
• Wong A, Lamothe B, Lee A, Schlessinger J, Lax I, Li A . 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 . 2002 . 11997436 . 124463 . 10.1073/pnas.052138899 . 2002PNAS...99.6684W . free .
• Stoletov KV, Ratcliffe KE, Terman BI . Fibroblast growth factor receptor substrate 2 participates in vascular endothelial growth factor-induced signaling. . FASEB J. . 16 . 10 . 1283–5 . 2002 . 12154000 . 10.1096/fj.01-0835fje . free . 35161062 .

Notes and References

1. Rabin SJ, Cleghon V, Kaplan DR . 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 . April 1993 . 7681142 . 359541 . 10.1128/mcb.13.4.2203 .
2. Wang JK, Xu H, Li HC, Goldfarb M . Broadly expressed SNT-like proteins link FGF receptor stimulation to activators of Ras . Oncogene . 13 . 4 . 721–9 . October 1996 . 8761293 .
3. Xu H, Lee KW, Goldfarb M . Novel recognition motif on fibroblast growth factor receptor mediates direct association and activation of SNT adapter proteins . J Biol Chem . 273 . 29 . 17987–90 . August 1998 . 9660748 . 10.1074/jbc.273.29.17987 . free .
4. Web site: Entrez Gene: FRS2 Fibroblast growth factor receptor substrate 2.
5. Pawson T, Scott JD . Signaling through scaffold, anchoring, and adaptor proteins. . Science . 278 . 5346 . 2075–80 . December 1997 . 9405336 . 10.1126/science.278.5346.2075 . 1997Sci...278.2075P .
6. Valencia T, Joseph A, Kachroo N, Darby S, Meakin S, Gnanapragasam VJ . Role and expression of FRS2 and FRS3 in prostate cancer. . BMC Cancer . 11 . 484 . Nov 11, 2011 . 22078327 . 3231952 . 10.1186/1471-2407-11-484 . free .
7. 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 . Identification of Druggable Cancer Driver Genes Amplified across TCGA Datasets. . PLOS ONE . 9 . 5 . e98293 . 2014 . 24874471 . 4038530 . 10.1371/journal.pone.0098293 . 2014PLoSO...998293C . free .
8. Yan KS, Kuti M, Yan S, Mujtaba S, Farooq A, Goldfarb MP, Zhou MM . FRS2 PTB domain conformation regulates interactions with divergent neurotrophic receptors . J. Biol. Chem. . 277 . 19 . 17088–94 . May 2002 . 11877385 . 10.1074/jbc.M107963200 . free .
9. Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J, Lax I . 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 . February 2000 . 10629055 . 85215 . 10.1128/mcb.20.3.979-989.2000.
10. Dhalluin C, Yan KS, Plotnikova O, Lee KW, Zeng L, Kuti M, Mujtaba S, Goldfarb MP, Zhou MM . Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors . Mol. Cell . 6 . 4 . 921–9 . October 2000 . 11090629 . 10.1016/S1097-2765(05)00087-0 . 5155437 .
11. Wong A, Lamothe B, Lee A, Schlessinger J, Lax I, Li A . 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 . May 2002 . 11997436 . 124463 . 10.1073/pnas.052138899 . 2002PNAS...99.6684W . free .
12. Ong SH, Goh KC, Lim YP, Low BC, Klint P, Claesson-Welsh L, Cao X, Tan YH, Guy GR . 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 . August 1996 . 8780727 . 10.1006/bbrc.1996.1288 .
13. Meakin SO, MacDonald JI, Gryz EA, Kubu CJ, Verdi JM . 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 . April 1999 . 10092678 . 10.1074/jbc.274.14.9861. free .
14. Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I, Schlessinger J . A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway . Cell . 89 . 5 . 693–702 . May 1997 . 9182757 . 10.1016/s0092-8674(00)80252-4. 2187363 . free .
15. Lim YP, Low BC, Lim J, Wong ES, Guy GR . Association of atypical protein kinase C isotypes with the docker protein FRS2 in fibroblast growth factor signaling . J. Biol. Chem. . 274 . 27 . 19025–34 . July 1999 . 10383403 . 10.1074/jbc.274.27.19025. free .
16. Delahaye L, Rocchi S, Van Obberghen E . Potential involvement of FRS2 in insulin signaling . Endocrinology . 141 . 2 . 621–8 . February 2000 . 10650943 . 10.1210/endo.141.2.7298 . free .
17. Kurokawa K, Iwashita T, Murakami H, Hayashi H, Kawai K, Takahashi M . Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction . Oncogene . 20 . 16 . 1929–38 . April 2001 . 11360177 . 10.1038/sj.onc.1204290 . free .
18. Hadari YR, Kouhara H, Lax I, Schlessinger J . Binding of Shp2 tyrosine phosphatase to FRS2 is essential for fibroblast growth factor-induced PC12 cell differentiation . Mol. Cell. Biol. . 18 . 7 . 3966–73 . July 1998 . 9632781 . 108981 . 10.1128/mcb.18.7.3966.
19. Foehr ED, Tatavos A, Tanabe E, Raffioni S, Goetz S, Dimarco E, De Luca M, Bradshaw RA . 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 . May 2000 . 10783152 . 10.1096/fasebj.14.7.973. free . 43317719 .
20. Degoutin J, Vigny M, Gouzi JY . ALK activation induces Shc and FRS2 recruitment: Signaling and phenotypic outcomes in PC12 cells differentiation . FEBS Letters . 581 . 4 . 727–34 . February 2007 . 17274988 . 10.1016/j.febslet.2007.01.039 . 40978851 . free .