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Prostate-derived sterile 20-like kinase 1-alpha (PSK1-alpha ) induces apoptosis: JNK- and caspase-dependent nuclear localization is a requirement for membrane blebbing

Research output: Contribution to journalArticle

C Zihni, C Mitsopoulos, I A Tavares, B Baum, A J Ridley, J D H Morris

Original languageEnglish
Pages (from-to)6484 - 6493
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number9
DOIs
Published2 Mar 2007

King's Authors

Abstract

We have demonstrated previously that full-length prostate-derived sterile 20-like kinase (PSK) 1-alpha binds to microtubules via its C terminus and regulates their organization and stability independently of its catalytic activity. Here we show that apoptotic and microtubule-disrupting agents promoted catalytic activation, C-terminal cleavage and nuclear translocation of endogenous phospho-serine181 PSK1-alpha and activated N-terminal PSK1-alpha induced apoptosis. PSK1-alpha, unlike its novel isoform PSK1-beta, stimulated the c-Jun N-terminal kinase (JNK) pathway and the nuclear localization of PSK1-alpha and its induction of cell contraction, membrane blebbing and apoptotic body formation were dependent on JNK activity. PSK1-alpha was also a caspase substrate and the broad-spectrum caspase inhibitor Z-VAD-FMK, or mutation of a putative caspase recognition motif ((916)DPGD(919)), blocked nuclear localization of PSK1-alpha and its induction of membrane blebs. Additional inhibition of caspase 9 was needed to prevent cell contraction. PSK1-alpha is therefore a bi-functional 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-alpha and its induction of apoptosis.

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