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J. Biol. Chem., Vol. 282, Issue 16, 11795-11804, April 20, 2007

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Regulation of Death-associated Protein Kinase

STABILIZATION BY HSP90 HETEROCOMPLEXES^*

Liguo Zhang, Kenneth P. Nephew, and Patricia J. Gallagher¹

From the Department of Cellular and Integrated Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202 and Medical Sciences, Indiana University School of Medicine, Bloomington, Indiana 47405

Death-associated protein kinase (DAPK) has been found associated with HSP90, and inhibition of HSP90 with 17-alkylamino-17-demethoxygeldanamycin reduced expression of DAPK. These results were extended to determine whether the degradation of DAPK in the absence of HSP90 activity is dependent on the ubiquitin-proteasome pathway. Our results show that treatment of cells with geldanamycin (GA) leads to degradation of DAPK, and this degradation is attenuated by the proteasome inhibitor, lactacystin. GA-induced DAPK degradation is also dependent on phosphorylation of DAPK at Ser³⁰⁸, and the cellular levels of phospho(Ser³⁰⁸)-DAPK dramatically increase in response to GA treatment. Expression of two distinct ubiquitin E3 ligases, carboxyl terminus of HSC70-interacting protein (CHIP) or DIP1/Mib1, enhanced DAPK degradation, and conversely, short interfering RNA depletion of either CHIP or DIP1/Mib1 attenuated DAPK degradation. In vitro ubiquitination assays confirmed that DAPK is targeted for ubiquitination by both CHIP and DIP. Consistent with these results, DAPK is found in two distinct immune complexes, one containing HSP90 and CHIP and a second complex containing only DIP1/Mib. Collectively, these results indicate that strict modulation of DAPK activities is critical for regulation of apoptosis and cellular homeostasis.

Received for publication, November 8, 2006 , and in revised form, February 26, 2007.

^* This work was supported by NHLBI, National Institutes of Health (NIH), Grants HL54118 and DK062810 (to P. J. G.), NCI, NIH, Grant CA 085289, American Cancer Society Research and Alaska Run for Woman Grant TBE-104125, and the Walther Cancer Institute (to K. P. N.). 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 Cellular and Integrated Physiology, Indiana University School of Medicine, 635 Barnhill Dr., Indianapolis, IN 46202-5120. Tel.: 317-278-2146; Fax: 317-274-3318; E-mail: pgallag{at}iupui.edu.

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