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J. Biol. Chem., Vol. 281, Issue 51, 39033-39040, December 22, 2006

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Control of Death-associated Protein Kinase (DAPK) Activity by Phosphorylation and Proteasomal Degradation^*

Yijun Jin, Emily K. Blue, and Patricia J. Gallagher¹

From the Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, Louisiana 71103 and the Department of Cellular and Integrated Physiology, Indiana University School of Medicine, Indianapolis, Indiana 46202

Activation of death-associated protein kinase (DAPK) occurs via dephosphorylation of Ser-308 and subsequent association of calcium/calmodulin. In this study, we confirmed the existence of the alternatively spliced human DAPK-, and we examined the levels of DAPK autophosphorylation and DAPK catalytic activity in response to tumor necrosis factor or ceramide. It was found that DAPK is rapidly dephosphorylated in response to tumor necrosis factor or ceramide and then subsequently degraded via proteasome activity. Dephosphorylation and activation of DAPK are shown to temporally precede its subsequent degradation. This results in an initial increase in kinase activity followed by a decrease in DAPK expression and activity. The decline in DAPK expression is paralleled with increased caspase activity and cell apoptosis. These results suggest that the apoptosis regulatory activities mediated by DAPK are controlled both by phosphorylation status and protein stability.

Received for publication, May 30, 2006 , and in revised form, September 11, 2006.

^* This work was supported by National Institutes of Health Grant NHLBIHL54118 (to P. J. G.), American Heart Association Scientist Development Grant 0435064N (to Y. J.), and Indiana University Diabetes and Obesity Research Training Grant DK064466 (to E. K. B.). 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.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) EF090258 [GenBank] .

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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