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

• Published in: The Journal of biological chemistry Vol. 282; no. 9; pp. 6484 - 6493
• Main Authors: Zihni, Ceniz, Mitsopoulos, Costas, Tavares, Ignatius A., Baum, Buzz, Ridley, Anne J., Morris, Jonathan D.H.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 02-03-2007
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M608336200

We have demonstrated previously that full-length prostate-derived sterile 20-like kinase 1-α (PSK1-α) 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-α and activated N-terminal PSK1-α-induced apoptosis. PSK1-α, unlike its novel isoform PSK1-β, stimulated the c-Jun N-terminal kinase (JNK) pathway, and the nuclear localization of PSK1-α and its induction of cell contraction, membrane blebbing, and apoptotic body formation were dependent on JNK activity. PSK1-α 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-α and its induction of membrane blebs. Additional inhibition of caspase 9 was needed to prevent cell contraction. PSK1-α 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-α and its induction of apoptosis.