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Gab1 is an integrator of cell death versus cell survival signals in oxidative stress

Marina Holgado-Madruga1, Albert J Wong

  • 1Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. M_Holgado_Madruga@mail.jci.tju.edu

Molecular and Cellular Biology
|June 17, 2003
PubMed

Insights

Growth factor adaptor Gab1 (also known as Gab1) plays a critical role in oxidative stress response. Gab1 is essential for hydrogen peroxide-induced c-Jun N-terminal kinase (JNK) activation and influences cell survival.

Area of Science:

  • Cellular signaling
  • Oxidative stress response
  • Molecular biology

Background:

  • Growth factors and cytokines activate signaling pathways via Gab1 phosphorylation.
  • Cross-talk exists between growth factor signaling and oxidative stress pathways.
  • The role of Gab1 in oxidative injury was previously unexplored.

Purpose of the Study:

  • To investigate the role of Gab1 in oxidative stress signaling.
  • To determine if Gab1 is involved in hydrogen peroxide (H(2)O(2))-induced cellular responses.
  • To elucidate the specific signaling pathways regulated by Gab1 during oxidative stress.

Main Methods:

  • Stimulation of wild-type and Gab1-deficient mouse embryo fibroblasts (MEFs) with H(2)O(2).
  • Analysis of Gab1 phosphorylation and recruitment of signaling molecules (SHP2, PI3K, Shc).
  • Assessment of JNK, ERK2, and p38 activation using kinase assays and inhibitor studies.
  • Cell viability assays to evaluate Gab1's role in cell survival.

Main Results:

  • Gab1 is dose- and time-dependently phosphorylated upon H(2)O(2) stimulation.
  • Gab1 recruits SHP2, PI3K, and Shc, and its phosphorylation is sensitive to Src family kinase inhibition.
  • Gab1 is essential for H(2)O(2)-induced JNK activation, but not ERK2 or p38.
  • Gab1 exhibits a dual role in cell survival, promoting it via PI3K interaction and inhibiting it via SHP2 interaction.

Conclusions:

  • Gab1 is a key component of the oxidative stress signaling network.
  • Gab1 is required for H(2)O(2)-induced JNK activation, mediated by its SHP2 binding site.
  • Gab1 modulates cell viability through differential interactions with PI3K and SHP2.

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