Prostate-derived sterile 20-like kinase 1-alpha induces apoptosis. JNK- and caspase-dependent nuclear localization is a requirement for membrane blebbing.
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Zihni C, Mitsopoulos C, Tavares IA, Baum B, Ridley AJ, Morris JD
Prostate-derived sterile 20-like kinase 1-alpha induces apoptosis. JNK- and caspase-dependent nuclear localization is a requirement for membrane blebbing.
J Biol Chem. 2007 Mar 2;282(9):6484-93. Epub 2006 Dec 11.
- PubMed ID
- 17158878 [ View in PubMed]
- Abstract
We have demonstrated previously that full-length prostate-derived sterile 20-like kinase 1-alpha (PSK1-alpha) 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-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 benzyloxycarbonyl-VAD-fluoromethyl ketone 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 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-alpha and its induction of apoptosis.