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J. Biol. Chem., Vol. 279, Issue 51, 53653-53664, December 17, 2004

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Identification and Characterization of PS-GAP as a Novel Regulator of Caspase-activated PAK-2^*

Mark A. Koeppel, Corine C. McCarthy, Erin Moertl, and Rolf Jakobi¶||

From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226 and the ^¶Department of Biochemistry, Kansas City University of Medicine and Biosciences, Kansas City, Missouri 64106

p21-activated protein kinase (PAK)-2 is a member of the PAK family of serine/threonine kinases. PAKs are activated by the p21 G-proteins Rac and Cdc42 in response to a variety of extracellular signals and act in pathways controlling cell growth, shape, motility, survival, and death. PAK-2 is unique among the PAK family members because it is also activated through proteolytic cleavage by caspase-3 or similar proteases to generate the constitutively active PAK-2p34 fragment. Activation of full-length PAK-2 by Rac or Cdc42 stimulates cell survival and protects cells from cell death, whereas caspase-activated PAK-2p34 induces a cell death response. Caspase-activated PAK-2p34 is rapidly degraded by the 26 S proteasome, but full-length PAK-2 is not. Stabilization of PAK-2p34 by preventing its polyubiquitination and degradation results in a dramatic stimulation of cell death. Although many proteins have been shown to interact with and regulate full-length PAK-2, little is known about the regulation of caspase-activated PAK-2p34. Here, we identify PS-GAP as a regulator of caspase-activated PAK-2p34. PS-GAP is a GTPase-activating protein for Cdc42 and RhoA that was originally identified by its interaction with the tyrosine kinase PYK-2. PS-GAP interacts specifically with caspase-activated PAK-2p34, but not active or inactive full-length PAK-2, through a region between the GAP and SH3 domains. The interaction with PS-GAP inhibits the protein kinase activity of PAK-2p34 and changes the localization of PAK-2p34 from the nucleus to the perinuclear region. Furthermore, PS-GAP decreases the stimulation of cell death induced by stabilization of PAK-2p34.

Received for publication, September 13, 2004 , and in revised form, October 4, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY179965, AY179966, and AY179967.

^* This work was supported by a grant from the Research Affairs Committee of the Medical College of Wisconsin and by Susan G. Komen Breast Cancer Foundation Grant BCTR0100185. 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.

Present address: Invitrogen, Madison, WI 53719.

^|| To whom correspondence should be addressed: Dept. of Biochemistry, Kansas City University of Medicine and Biosciences, 1750 Independence Ave., Kansas City, MO 64106. Tel.: 816-283-2273; Fax: 816-283-2357; E-mail: rjakobi{at}kcumb.edu.

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