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J. Biol. Chem., Vol. 280, Issue 50, 41192-41200, December 16, 2005

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PAK4 Functions in Tumor Necrosis Factor (TNF) -induced Survival Pathways by Facilitating TRADD Binding to the TNF Receptor^*

From the Department of Biological Sciences, Columbia University, New York, New York 10027

PAK4 is a member of the group B family of p21-activated kinases. Its expression is elevated in many cancer cell lines, and activated PAK4 is highly transforming, suggesting that it plays an important role in tumorigenesis. Although most previous work was carried out with overexpressed PAK4, here we used RNA interference to knock down endogenous PAK4 in cancer cells. By studying PAK4 knockdown HeLa cells, we demonstrated that endogenous PAK4 is required for anchorage-independent growth. Because cell survival is a key part of tumorigenesis and anchorage-independent growth, we studied whether PAK4 has a role in protecting cells from cell death. To address this, we studied the role for PAK4 downstream to the tumor necrosis factor (TNF) receptor. Although overexpressed PAK4 was previously shown to abrogate proapoptotic pathways, here we demonstrate that endogenous PAK4 is required for the full activation of prosurvival pathways induced by TNF. Our results indicate that PAK4 is required for optimal binding of the scaffold protein TRADD to the activated TNF receptor through both kinase-dependent and kinase-independent mechanisms. Consequently, activation of several prosurvival pathways, including the NFB and ERK pathways, is reduced in the absence of PAK4. Interestingly, constitutive activation of the NFB and ERK pathways could compensate for the lack of PAK4, indicating that these pathways function downstream to PAK4. The role for PAK4 in regulating prosurvival pathways is a completely new function for this protein, and the connection between PAK4 and cell survival under stress helps explain its role in tumorigenesis and development.

Received for publication, June 24, 2005 , and in revised form, October 14, 2005.

^* This work was supported by National Institutes of Health Grant R01CA076342 (to A. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biological Sciences MC 2460, Columbia University, Sherman Fairchild Center, Rm. 813, New York, NY 10027. Tel.: 212-854-5632; Fax: 212-854-1559; E-mail: agm24{at}columbia.edu.

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