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

TY - JOUR

T1 - Prostate-derived sterile 20-like kinase 1-alpha (PSK1-alpha ) induces apoptosis: JNK- and caspase-dependent nuclear localization is a requirement for membrane blebbing

AU - Zihni, C

AU - Mitsopoulos, C

AU - Tavares, I A

AU - Baum, B

AU - Ridley, A J

AU - Morris, J D H

PY - 2007/3/2

Y1 - 2007/3/2

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.M608336200

DO - 10.1074/jbc.M608336200

M3 - Article

SN - 1083-351X

VL - 282

SP - 6484

EP - 6493

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 9

ER -