Prostate-derived sterile 20-like kinase 2 (PSK2) regulates apoptotic morphology via C-Jun N-terminal kinase and Rho kinase-1.
We have reported previously that human prostate-derived sterile 20-like kinase (PSK) 1 alters actin cytoskeletal organization and binds to microtubules, regulating their organization and stability. We have shown a structurally related protein kinase PSK2, which lacks a microtubule-binding site, activated c-Jun N-terminal kinase (JNK), and induced apoptotic morphological changes that include cell contraction, membrane blebbing, and apoptotic body formation. Apoptotic stimuli increased the catalytic activity of endogenous PSK2 and JNK, and dominant negative JNK or a physiological inhibitor of JNK blocked these apoptotic morphological responses to PSK2, demonstrating a requirement for JNK. PSK2 also stimulated the cleavage of Rho kinase-1 (ROCK-I), and the activity of ROCK-I was required for PSK2 to induce cell contraction and membrane blebbing. The activation of caspases was also needed for the induction of membrane blebbing by PSK2, which was itself a substrate for caspase 3. PSK2 therefore regulates apoptotic morphology associated with the execution phase of apoptosis, which involves dynamic reorganization of the actin cytoskeleton, via downstream targets that include JNK and ROCK-I. Our findings suggest that PSKs form a subgroup of sterile 20 (STE20)-like kinases that regulate different cytoskeletal processes.
Zihni
Ceniz
C
KCL School of Medicine and Dentistry, Rayne Institute, Kings College London, 123 Coldharbour Lane, London SE5 9NU, UK.
Mitsopoulos
Costas
C
Tavares
Ignatius A
IA
Ridley
Anne J
AJ
Morris
Jonathan D H
JD
D051339:Actin Depolymerizing Factors / Q000737:chemistry; D000199:Actins / Q000378:metabolism; D017209:Apoptosis; D001665:Binding Sites; D015152:Blotting, Northern; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002384:Catalysis; D002462:Cell Membrane / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D053938:DNA Fragmentation; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000378:metabolism; D008957:Models, Genetic; D010957:Plasmids / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D013012:Sorbitol / Q000494:pharmacology; D019311:Staurosporine / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D054460:rho-Associated Kinases
D051339:Actin Depolymerizing Factors; D000199:Actins; D047908:Intracellular Signaling Peptides and Proteins; D013012:Sorbitol; D011494:Protein Kinases; C404957:TAOK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C505407:CASP3 protein, human; D053143:Caspase 2; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine