Sci. STKE, 24 June 2003
OXIDATIVE STRESS A Life or Death Choice
Gab1, a docking protein that is tyrosine-phosphorylated in response to various growth factors, activates signaling pathways involved in cell growth and in protection from apoptosis. Holgado-Madruga and Wong investigated the role of Gab1 in the response to oxidative stress and uncovered evidence implicating Gab1 in mediating positive and negative survival signals through distinct signaling pathways. The authors used Western analysis of Gab1 immunoprecipitates to demonstrate that H2O2 elicited tyrosine phosphorylation of Gab1 in several cell lines. Pharmacological analysis revealed that phosphorylation depended on activity of Src family tyrosine kinases. Experiments comparing wild-type mouse embryo fibroblasts (MEFs) to MEFs that lacked Gab1 (Gab1–/–) showed that Gab1 was necessary for H2O2-dependent activation of JNK (c-Jun N-terminal kinase) but not for JNK activation after other stimuli or for H2O2-dependent activation of other mitogen-activated protein kinases (MAPKs). Expression of Gab1 in Gab-deficient MEFs rescued H2O2-dependent activation of JNK; this depended on the presence of an intact SHP2 [Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2] binding domain. In cell viability assays, Gab1–/– cells were more sensitive than wild-type MEF to H2O2-triggered apoptosis. Gab1 expression in Gab-deficient MEFs enhanced viability; however, cells expressing a GAB1 mutant that could not bind SHP2 showed improved survival over those expressing wild-type Gab1. Mutational analyses indicated that, after exposure to H2O2, Gab1 interactions with phosphatidylinositol 3-kinase promoted cell survival, whereas interactions with SHP2 promoted cell death. Thus, in addition to its roles in the response to growth factors, Gab1 appears to integrate positive and negative survival signals in response to oxidative stress.
Citation: A Life or Death Choice. Sci. STKE 2003, tw239 (2003).
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