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Originally published In Press as doi:10.1074/jbc.M212557200 on January 30, 2003

J. Biol. Chem., Vol. 278, Issue 15, 13101-13109, April 11, 2003
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Localization of p21-activated Protein Kinase gamma -PAK/Pak2 in the Endoplasmic Reticulum Is Required for Induction of Cytostasis*

Zhongdong HuangDagger , Jun Ling, and Jolinda A. Traugh§

From the Department of Biochemistry, University of California, Riverside, California 92521

The intracellular localization and physiological functions of the p21-activated protein kinase gamma -PAK have been examined in human embryonic kidney 293T and COS-7 cells. At 1-4 days post-transfection, cell division is inhibited by the expression of wild type (WT) gamma -PAK and the mutant S490A, whereas cells expressing S490D and the inactive mutants K278R and T402A grow exponentially, indicating a role for gamma -PAK in the induction of cytostasis. WT gamma -PAK and S490A are localized in a region surrounding the nucleus identified as the endoplasmic reticulum (ER), as determined by immunofluorescence, whereas K278R, T402A, and S490D lack localization. As shown by sucrose density gradient centrifugation, WT gamma -PAK, S490A, and endogenous gamma -PAK are distributed among the high density (ER-associated), intermediate density, and low density fractions, whereas the mutants that do not inhibit cell division are present only as soluble enzyme. The amount of endogenous gamma -PAK associated with the particulate fractions is increased 4-fold when cell division is inhibited by ionizing radiation. gamma -PAK in the ER and intermediate density fractions has high specific activity and is active, whereas the soluble form of gamma -PAK has low activity and is activable. The importance of localization of gamma -PAK is supported by data with the C-terminal mutants S490D and Delta 488; these mutants have high levels of protein kinase activity but do not induce cytostasis and are not bound to the ER. A model for the induction of cytostasis by gamma -PAK through targeting of gamma -PAK to the ER is presented in which gamma -PAK activity and Ser-490 are implicated in the regulation of cytostasis.

* This research was supported by United States Public Health Service Grant GM26738 from the National Institutes of Health.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: G. W. Hooper Foundation, University of California, 513 Parnassus Ave. HSW1501, San Francisco, CA 94143-0552.

§ To whom correspondence should be addressed. Fax: 909-787-3590; E-mail: jolinda.traugh@ucr.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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