Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways

Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8578-83. doi: 10.1073/pnas.161259898. Epub 2001 Jul 10.

Abstract

The docking protein FRS2 alpha has been implicated as a mediator of signaling via fibroblast growth factor receptors (FGFRs). We have demonstrated that targeted disruption of FRS2 alpha gene causes severe impairment in mouse development resulting in embryonal lethality at E7.0--E7.5. Experiments with FRS2 alpha-deficient fibroblasts demonstrate that FRS2 alpha 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 FRS2 alpha 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 FRS2 alpha are responsible for mediating different FGF-induced biological responses. These experiments establish the central role of FRS2 alpha in signaling via FGFRs and demonstrate that FRS2 alpha mediates multiple FGFR-dependent signaling pathways critical for embryonic development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Division
  • Cell Line
  • Cell Movement
  • Fibroblast Growth Factor 1
  • Fibroblast Growth Factor 2 / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Signal Transduction*

Substances

  • Adaptor Proteins, Signal Transducing
  • FRS2 protein, human
  • Gab1 protein, mouse
  • Membrane Proteins
  • Phosphoproteins
  • Receptors, Fibroblast Growth Factor
  • Fibroblast Growth Factor 2
  • Fibroblast Growth Factor 1
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinases