DOI: 10.1073/pnas.161259898. Critical role for the docking-protein FRS2α in FGF receptor-mediated signal transduction pathways

Critical role for the docking-protein FRS2α in FGF receptor-mediated signal transduction pathways

10.1073/pnas.161259898

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

The docking protein FRS2α has been implicated as a mediator of signaling via fibroblast growth factor receptors (FGFRs). We have demonstrated that targeted disruption of FRS2α gene causes severe impairment in mouse development resulting in embryonal lethality at E7.0–E7.5. Experiments with FRS2α-deficient fibroblasts demonstrate that FRS2α plays a critical role in FGF-induced mitogen-activated protein (MAP) kinase stimulation, phosphatidylinositol-3 (PI-3) kinase activation, chemotactic response, and cell proliferation. Following FGF stimulation, tyrosine phosphorylated FRS2α functions as a site for coordinated assembly of a multiprotein complex that includes Gab1 and the effector proteins that are recruited by this docking protein. Furthermore, we demonstrate that different tyrosine phosphorylation sites on FRS2α are responsible for mediating different FGF-induced biological responses. These experiments establish the central role of FRS2α in signaling via FGFRs and demonstrate that FRS2α mediates multiple FGFR-dependent signaling pathways critical for embryonic development.

Authors 5

Y. R. Hadari (first)
N. Gotoh (additional)
H. Kouhara (additional)
I. Lax (additional)
J. Schlessinger (additional)

References 23 Referenced 254

10.1016/S0092-8674(00)81688-8
10.1016/0960-9822(93)90350-W
10.1002/j.1460-2075.1992.tb05426.x
10.1016/S0092-8674(00)80252-4
10.1128/MCB.18.7.3966
10.1128/MCB.20.3.979-989.2000
10.2741/A321
10.1016/0167-4889(92)90136-Y
D F Johnson, L T Williams Adv Cancer Res 60, 1–41 (1993). / Adv Cancer Res by Johnson D F (1993)
10.1073/pnas.91.10.4303
10.1128/mcb.14.8.5192-5201.1994
10.1128/MCB.16.3.977
10.1128/MCB.20.4.1448-1459.2000
10.1073/pnas.96.7.3790
10.1016/0092-8674(94)90032-9
10.1038/379560a0
10.1073/pnas.111114298
10.1042/bj3340189
10.1016/S0925-4773(97)00123-8
10.1242/dev.124.14.2829
10.1101/gad.13.14.1834
10.1083/jcb.137.2.481
10.1083/jcb.146.1.149

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:34 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 1:01 a.m.)
Indexed	1 week ago (Aug. 27, 2025, 11:31 a.m.)
Issued	24 years, 1 month ago (July 10, 2001)
Published	24 years, 1 month ago (July 10, 2001)
Published Online	24 years, 1 month ago (July 10, 2001)
Published Print	24 years, 1 month ago (July 17, 2001)

Funders 0

None

BibTeX

@article{Hadari_2001, title={Critical role for the docking-protein FRS2α in FGF receptor-mediated signal transduction pathways}, volume={98}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.161259898}, DOI={10.1073/pnas.161259898}, number={15}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Hadari, Y. R. and Gotoh, N. and Kouhara, H. and Lax, I. and Schlessinger, J.}, year={2001}, month=jul, pages={8578–8583} }

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