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J. Biol. Chem., Vol. 282, Issue 9, 6484-6493, March 2, 2007

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Prostate-derived Sterile 20-like Kinase 1- Induces Apoptosis

JNK- AND CASPASE-DEPENDENT NUCLEAR LOCALIZATION IS A REQUIREMENT FOR MEMBRANE BLEBBING^*

Ceniz Zihni¹, Costas Mitsopoulos¹, Ignatius A. Tavares, Buzz Baum^¶, Anne J. Ridley^¶, and Jonathan D. H. Morris²

From the Kings College London, Rayne Institute, 123 Coldharbour Lane, London SE5 9NU, ^¶The Ludwig Institute for Cancer Research (University College London Branch), 91 Riding House Street, London W1W 7BS, and Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom

We have demonstrated previously that full-length prostate-derived sterile 20-like kinase 1- (PSK1-) binds to microtubules via its C terminus and regulates their organization and stability independently of its catalytic activity. Here we have shown that apoptotic and microtubule-disrupting agents promote catalytic activation, C-terminal cleavage, and nuclear translocation of endogenous phosphoserine 181 PSK1- and activated N-terminal PSK1--induced apoptosis. PSK1-, unlike its novel isoform PSK1-, stimulated the c-Jun N-terminal kinase (JNK) pathway, and the nuclear localization of PSK1- and its induction of cell contraction, membrane blebbing, and apoptotic body formation were dependent on JNK activity. PSK1- was also a caspase substrate, and the broad spectrum caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone or mutation of a putative caspase recognition motif (⁹¹⁶DPGD⁹¹⁹) blocked nuclear localization of PSK1- and its induction of membrane blebs. Additional inhibition of caspase 9 was needed to prevent cell contraction. PSK1- is therefore a bifunctional kinase that associates with microtubules, and JNK- and caspase-mediated removal of its C-terminal microtubule-binding domain permits nuclear translocation of the N-terminal region of PSK1- and its induction of apoptosis.

Received for publication, August 31, 2006 , and in revised form, November 30, 2006.

^* This work was supported by the Biotechnology and Biological Science Research Council UK, the Association for International Cancer Research, St. Andrews, Scotland, the Ludwig Institute for Cancer Research, and a donation from Laura Price. 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 These authors contributed equally toward this work.

² To whom correspondence should be addressed. Fax: 44-20-78485873; E-mail: jonathan.morris{at}kcl.ac.uk.

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