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J. Biol. Chem., Vol. 280, Issue 26, 24698-24705, July 1, 2005

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p21-activated Kinase 1 (Pak1)-dependent Phosphorylation of Raf-1 Regulates Its Mitochondrial Localization, Phosphorylation of BAD, and Bcl-2 Association^*

Shenghao Jin, Ya Zhuo, Weining Guo, and Jeffrey Field

From the Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104

Raf-1 protects cells from apoptosis, independently of its signals to MEK and ERK, by translocating to the mitochondria where it binds Bcl-2 and displaces BAD. However, the answer to the question of how Raf-1 is normally lured to the mitochondria and becomes activated remains elusive. p21-activated protein kinases (Paks) are serine/threonine protein kinases that phosphorylate Raf-1 at Ser-338 and Ser-339. Here we elucidate the molecular mechanism through which Pak1 signals to BAD through a Raf-1-activated pathway. Upon phosphorylation by Pak1, Raf-1 translocates to mitochondria and phosphorylates BAD at Ser-112. Moreover, the mitochondrial translocation of Raf-1 and the interaction between Raf-1 and Bcl-2 are regulated by Raf-1 phosphorylation at Ser-338/Ser-339. Notably, we show that formation of a Raf-1-Bcl-2 complex coincides with loss of an interaction between Bcl-2 and BAD. These signals are specific for Pak1, because Src-activated Raf-1 only stimulates the MAP kinase cascade. Thus, our data identify the molecular connections of a Pak1-Raf-1-BAD pathway that is involved in cell survival signaling.

Received for publication, November 29, 2004 , and in revised form, April 21, 2005.

^* This work was supported by National Institutes of Health Grant GM48241 and the Department of Defense Neurofibromatosis Program Grant DAMD17-01-1-07190. 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.

To whom correspondence should be addressed: Dept. of Pharmacology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104. Tel.: 215-898-1912; Fax: 215-573-2236; E-mail: field{at}pharm.med.upenn.edu.

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