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Screening and Identification of Small Peptides Targeting Fibroblast Growth Factor Receptor2 using a Phage Display Peptide Library
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Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways

Y R Hadari1, N Gotoh, H Kouhara

  • 1Department of Pharmacology and The Skirball Institute, New York University Medical School, New York, NY 10016, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 12, 2001
PubMed

Insights

The docking protein FRS2 alpha is essential for embryonic development, mediating fibroblast growth factor receptor (FGFR) signaling. Its absence causes severe developmental defects and embryonic lethality, highlighting its critical role in cell growth and response.

Area of Science:

  • Cellular Biology
  • Developmental Biology
  • Molecular Signaling

Background:

  • Fibroblast growth factor receptors (FGFRs) are crucial for embryonic development.
  • The docking protein FRS2 alpha is a known mediator of FGFR signaling pathways.
  • Understanding FRS2 alpha's precise role is vital for comprehending developmental processes.

Purpose of the Study:

  • To investigate the essential role of FRS2 alpha in embryonic development.
  • To elucidate the specific signaling pathways regulated by FRS2 alpha downstream of FGFRs.
  • To determine how FRS2 alpha mediates FGF-induced cellular responses.

Main Methods:

  • Gene targeting to create FRS2 alpha-deficient mice and fibroblasts.
  • Analysis of embryonic development and viability.
  • Biochemical assays to assess FGF-induced signaling pathways (MAP kinase, PI-3 kinase).
  • Investigation of protein complex assembly and tyrosine phosphorylation sites on FRS2 alpha.

Main Results:

  • Targeted disruption of the FRS2 alpha gene led to severe impairment in mouse development and embryonic lethality at E7.0--E7.5.
  • FRS2 alpha-deficient fibroblasts showed impaired FGF-induced mitogen-activated protein (MAP) kinase and phosphatidylinositol-3 (PI-3) kinase activation.
  • FRS2 alpha acts as a scaffold for assembling signaling complexes, with distinct tyrosine phosphorylation sites mediating different biological responses.
  • FRS2 alpha is critical for FGF-induced chemotaxis and cell proliferation.

Conclusions:

  • FRS2 alpha plays a central and indispensable role in signaling via FGFRs.
  • FRS2 alpha mediates multiple FGFR-dependent signaling pathways essential for embryonic development.
  • Specific tyrosine phosphorylation sites on FRS2 alpha differentially regulate FGF-induced biological outcomes.

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