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Mol. Cell. Biol. 23 (13): 4471-4484

Copyright © 2003 by the American Society for Microbiology. All rights reserved.

Gab1 Is an Integrator of Cell Death versus Cell Survival Signals in Oxidative Stress

Marina Holgado-Madruga* and Albert J. Wong*

Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Received for publication 13 August 2002. Revision received 4 October 2002. Accepted for publication 20 February 2003.

Abstract: Upon the addition of different growth factors and cytokines, the Gab1 docking protein is tyrosine phosphorylated and in turn activates different signaling pathways. On the basis of the large body of evidence concerning cross talk between the signaling pathways activated by growth factors and oxidative stress, we decided to investigate the role of Gab1 in oxidative injury. We stimulated wild-type mouse embryo fibroblasts (MEF) or MEF with a homozygous deletion of the Gab1 gene (-/- MEF) with H2O2. Our results show that Gab1 is phosphorylated in a dose- and time-dependent manner after H2O2 triggering. Gab1 then recruits molecules such as SHP2, phosphatidylinositol 3-kinase (PI3K), and Shc. Gab1 phosphorylation is sensitive to the Src family kinase inhibitor PP2. Furthermore, we demonstrate that Gab1 is required for H2O2-induced c-Jun N-terminal kinase (JNK) activation but not for ERK2 or p38 activation. Reconstitution of Gab1 in -/- MEF rescues JNK activation, and we find that this is dependent on the SHP2 binding site in Gab1. Cell viability assays reveal that Gab1 has a dual role in cell survival: a positive one through its interaction with PI3K and a negative one through its interaction with SHP2. This is the first report identifying Gab1 as a component in oxidative stress signaling and one that is required for JNK activation.

* Corresponding author. Mailing address: Kimmel Cancer Institute, Thomas Jefferson University, 233 S. 10th St., BLSB 1002, Philadelphia, PA 19107. Phone: (215) 503-4650. Fax: (215) 503-0567. E-mail for Marina Holgado-Madruga: M_Holgado_Madruga{at} or albert.wong{at}

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