The docking protein Gab1 is the primary mediator of EGF-stimulated activation of the PI-3K/Akt cell survival pathway

BMC Biol. 2004 Nov 18;2:24. doi: 10.1186/1741-7007-2-24.

Abstract

Background: Gab1 is a docking protein that recruits phosphatidylinositol-3 kinase (PI-3 kinase) and other effector proteins in response to the activation of many receptor tyrosine kinases (RTKs). As the autophosphorylation sites on EGF-receptor (EGFR) do not include canonical PI-3 kinase binding sites, it is thought that EGF stimulation of PI-3 kinase and its downstream effector Akt is mediated by an indirect mechanism.

Results: We used fibroblasts isolated from Gab1-/- mouse embryos to explore the mechanism of EGF stimulation of the PI-3 kinase/Akt anti-apoptotic cell signaling pathway. We demonstrate that Gab1 is essential for EGF stimulation of PI-3 kinase and Akt in these cells and that these responses are mediated by complex formation between p85, the regulatory subunit of PI-3 kinase, and three canonical tyrosine phosphorylation sites on Gab1. Furthermore, complex formation between Gab1 and the protein tyrosine phosphatase Shp2 negatively regulates Gab1 mediated PI-3 kinase and Akt activation following EGF-receptor stimulation. We also demonstrate that tyrosine phosphorylation of ErbB3 may lead to recruitment and activation of PI-3 kinase and Akt in Gab1-/- MEFs.

Conclusions: The primary mechanism of EGF-induced stimulation of the PI-3 kinase/Akt anti-apoptotic pathway occurs via the docking protein Gab1. However, in cells expressing ErbB3, EGF and neuroregulin can stimulate PI-3 kinase and Akt activation in a Gab1-dependent or Gab1-independent manner.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Embryo, Mammalian / cytology
  • Epidermal Growth Factor / pharmacology*
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoproteins / drug effects
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Signal Transduction*

Substances

  • Adaptor Proteins, Signal Transducing
  • Gab1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Epidermal Growth Factor
  • Proto-Oncogene Proteins c-akt
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse