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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 turnactivates different signaling pathways. On the basis of thelarge body of evidence concerning cross talk between the signalingpathways activated by growth factors and oxidative stress, wedecided to investigate the role of Gab1 in oxidative injury.We stimulated wild-type mouse embryo fibroblasts (MEF) or MEFwith a homozygous deletion of the Gab1 gene (-/- MEF) with H2O2.Our results show that Gab1 is phosphorylated in a dose- andtime-dependent manner after H2O2 triggering. Gab1 then recruitsmolecules such as SHP2, phosphatidylinositol 3-kinase (PI3K),and Shc. Gab1 phosphorylation is sensitive to the Src familykinase inhibitor PP2. Furthermore, we demonstrate that Gab1is required for H2O2-induced c-Jun N-terminal kinase (JNK) activationbut not for ERK2 or p38 activation. Reconstitution of Gab1 in-/- MEF rescues JNK activation, and we find that this is dependenton the SHP2 binding site in Gab1. Cell viability assays revealthat Gab1 has a dual role in cell survival: a positive one throughits interaction with PI3K and a negative one through its interactionwith SHP2. This is the first report identifying Gab1 as a componentin oxidative stress signaling and one that is required for JNKactivation.
* 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}mail.jci.tju.edu or albert.wong{at}mail.tju.edu.
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