Role of Gab1 in UV-Induced c-Jun NH₂-Terminal Kinase Activation and Cell Apoptosis

Abstract

Exposure of mammalian cells to UV irradiation leads to activation of the c-Jun NH₂-terminal protein kinase (JNK) pathway, which is associated with cell apoptosis. However, the molecular mechanism for JNK activation by UV exposure is not fully understood. We show here an essential role of a multisubstrate adapter, Gab1, in this signaling cascade. Gab1-deficient mouse fibroblast cells were defective in induction of JNK activity by UV exposure or heat shock, and this defect was rescued by reintroduction of Gab1 into Gab1^−/− cells. Consistently, Gab1^−/− cells displayed reduced caspase 3 induction and apoptotic cell death in response to UV irradiation. Gab1 was constitutively complexed with JNK and became tyrosine phosphorylated in UV-irradiated cells. Genetic and pharmaceutical analyses suggest the involvement of c-Met and the Src family tyrosine kinases in mediating UV-induced Gab1 phosphorylation as well as JNK activation. In aggregate, these observations identify a new function of Gab1 in the response of mammalian cells to UV light.

We thank Robert Abraham, Morag Park, George Vande Woude, Masahiko Hibi, and Toshio Hirano for cell lines, reagents, or helpful discussion.

This work was supported by a postdoctoral fellowship award (5FB-0087) from the Breast Cancer Research Program of California (to Y.S.), by NIH grants R01GM53660 and R01HL66208 (to G.-S.F.), and by NNSFC (39928009).