Regulation of death-associated protein kinase: Stabilization by HSP90 heterocomplexes

Liguo Zhang, Kenneth Nephew, Patricia Gallagher

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)11795-11804
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number16
DOIs
StatePublished - Apr 20 2007

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Death-Associated Protein Kinases
Stabilization
Degradation
Proteolysis
Ubiquitination
Proteins
Phosphorylation
Proteasome Inhibitors
Ubiquitin-Protein Ligases
Proteasome Endopeptidase Complex
Ubiquitin
Antigen-Antibody Complex

ASJC Scopus subject areas

  • Biochemistry

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Regulation of death-associated protein kinase : Stabilization by HSP90 heterocomplexes. / Zhang, Liguo; Nephew, Kenneth; Gallagher, Patricia.

In: Journal of Biological Chemistry, Vol. 282, No. 16, 20.04.2007, p. 11795-11804.

Research output: Contribution to journalArticle

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