FRS2

Fibroblast growth factor receptor substrate 2

PDB rendering based on 1xr0.

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1XR0, 2MFQ

Identifiers

Symbols

FRS2 ; FRS2A; FRS2alpha; SNT; SNT-1; SNT1

External IDs

OMIM: 607743 MGI: 1100860 HomoloGene: 4846 GeneCards: FRS2 Gene

Gene ontology
Molecular function	• transmembrane receptor protein tyrosine kinase adaptor activity • fibroblast growth factor receptor binding • insulin receptor binding • neurotrophin TRKA receptor binding • protein binding • phosphatase activator activity
Cellular component	• endosome • plasma membrane • integral component of plasma membrane • membrane
Biological process	• activation of MAPKK activity • activation of MAPK activity • gastrulation with mouth forming second • organ induction • ventricular septum development • epidermal growth factor receptor signaling pathway • transmembrane receptor protein tyrosine phosphatase signaling pathway • G-protein coupled receptor signaling pathway • neuroblast proliferation • insulin receptor signaling pathway • fibroblast growth factor receptor signaling pathway • anterior/posterior axis specification, embryo • forebrain development • Fc-epsilon receptor signaling pathway • innate immune response • optic placode formation involved in camera-type eye formation • neurotrophin TRK receptor signaling pathway • phosphatidylinositol-mediated signaling • regulation of epithelial cell proliferation • prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 12:
69.86 – 69.97 Mb

Chr 10:
117.07 – 117.15 Mb

PubMed search

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

FRS2 is overexpressed and amplified in several cancer types, including prostate cancer.^[4]^[5]

Interactions

FRS2 has been shown to interact with:

CBL,^[6]
FGFR1,^[2]^[7]^[8]^[9]
GRB2,^[6]^[10]^[11]^[12]
PRKCI,^[13]
PTPN11,^[14]^[15]^[16]
SOS1,^[6]^[12]^[17] and
TrkA.^[11]

References

↑ 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.
↑ 2.0 2.1 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.
↑ "Entrez Gene: FRS2 Fibroblast growth factor receptor substrate 2".
↑ 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.
↑ Chen Y, McGee J, Chen X, Doman TN, Gong X, Zhang Y et al. (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.
↑ 6.0 6.1 6.2 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.
↑ Yan KS, Kuti M, Yan S, Mujtaba S, Farooq A, Goldfarb MP et al. (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.
↑ Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J et al. (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.
↑ Dhalluin C, Yan KS, Plotnikova O, Lee KW, Zeng L, Kuti M et al. (October 2000). "Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors". Mol. Cell 6 (4): 921–9. doi:10.1016/s1097-2765(00)00089-7. PMID 11090629.
↑ Ong SH, Goh KC, Lim YP, Low BC, Klint P, Claesson-Welsh L et al. (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.
↑ 11.0 11.1 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.
↑ 12.0 12.1 Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I et al. (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.
↑ 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.
↑ 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.
↑ 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.
↑ 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. PMC 108981. PMID 9632781.
↑ Foehr ED, Tatavos A, Tanabe E, Raffioni S, Goetz S, Dimarco E et al. (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. PMID 10783152.

Ong SH, Goh KC, Lim YP, Low BC, Klint P, Claesson-Welsh L et al. (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 et al. (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.
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. 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 et al. (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 et al. (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. PMID 10783152.
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 et al. (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. 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 et al. (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 et al. (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.

PDB gallery

1xr0: Structural Basis of SNT PTB Domain Interactions with Distinct Neurotrophic Receptors

FRS2

Interactions

References

Further reading