title: Prostate-derived sterile 20-like kinase 1-alpha induces apoptosis. JNK- and caspase-dependent nuclear localization is a requirement for membrane blebbing.
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.
authors.affiliation: Kings College London, Rayne Institute, 123 Coldharbour Lane, London SE5 9NU, United Kingdom.
authors.forename: Ceniz
authors.initials: C
authors.lastname: Zihni
authors.forename: Costas
authors.initials: C
authors.lastname: Mitsopoulos
authors.forename: Ignatius A
authors.initials: IA
authors.lastname: Tavares
authors.forename: Buzz
authors.initials: B
authors.lastname: Baum
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Ridley
authors.forename: Jonathan D H
authors.initials: JD
authors.lastname: Morris
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane; D048430:Cell Shape; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011494:Protein Kinases / Q000502:physiology*; D014162:Transfection
chemical_list: D011494:Protein Kinases; C404957:TAOK2 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases