Zihni, C and Mitsopoulos, C and Tavares, IA and Baum, B and Ridley, AJ and Morris, JDH (2007) 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 , 282 (9) 6484 - 6493. 10.1074/jbc.M608336200.
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-a and activated N-terminal PSK1-alpha-induced apoptosis. PSK1-a, unlike its novel isoform PSK1-beta, stimulated the c-jun N-terminal kinase (JNK) pathway, and the nucleajr 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-a and its induction of membrane blebs. Additional inhibition of caspase 9 was needed to prevent cell contraction. PSK1-a 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.
|Title:||Prostate-derived sterile 20-like kinase 1-alpha induces apoptosis - JNK- and caspase-dependent nuclear localization is a requirement for membrane blebbing|
|Open access status:||An open access publication|
|Keywords:||FOCAL ADHESION KINASE, N-TERMINAL KINASE, PROTEIN-KINASE, STE20-RELATED KINASE, MEDIATED ACTIVATION, SCAFFOLD PROTEINS, HISTONE H2B, ROCK-I, CLEAVAGE, PHOSPHORYLATION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of)|
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Laboratory for Molecular Cell Biology
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