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Molecular and Cellular Biology, February 2004, p. 1531-1539, Vol. 24, No. 4
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.4.1531-1539.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Yingqing Sun,¹ Jing Yuan,¹ Houqi Liu,^1, Zhongqing Shi,¹ Kelly Baker,¹ Kristiina Vuori,¹ Jie Wu,² and Gen-Sheng Feng^1*

Cancer Research Center, The Burnham Institute, La Jolla, California 92037,¹ Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612²

Received 3 November 2003/ Accepted 11 November 2003

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.

Present address: Center of Developmental Biology, and Medical School of the Army, Shanghai, People’s Republic of China.

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