title: Induction of apoptosis by the Ste20-like kinase SLK, a germinal center kinase that activates apoptosis signal-regulating kinase and p38.
abstract: Expression and activity of the germinal center kinase, Ste20-like kinase (SLK), are increased during kidney development and recovery from ischemic acute renal failure. In this study, we characterize the activation and functional role of SLK. SLK underwent dimerization via the C-terminal domain, and dimerization enhanced SLK activity. In contrast, the C-terminal domain of SLK did not dimerize with a related kinase, Mst1, and did not affect Mst1 activity. Phosphorylation/dephosphorylation of SLK were not associated with changes in kinase activity. SLK induced phosphorylation of apoptosis signal-regulating kinase-1 (ASK1) and increased ASK1 activity, indicating that ASK1 is a substrate of SLK. Moreover, SLK stimulated phosphorylation of p38 mitogen-activated protein kinase via ASK1, but not c-Jun N-terminal kinase nor extracellular signal-regulated kinase. Chemical anoxia and recovery during re-exposure to glucose (ischemia-reperfusion injury in cell culture) stimulated SLK activity. Overexpression of SLK enhanced anoxia/recovery-induced apoptosis, release of cytochrome c, and activities of caspase-8 and -9, and apoptosis was reduced significantly with p38 and caspase-9 inhibitors. Induction of the endoplasmic reticulum stress response by anoxia/recovery or tunicamycin (monitored by induction of Bip or Grp94 expression, phosphorylation of eukaryotic translation initiation factor 2alpha subunit, expression of CHOP, and activation of caspase-12) was attenuated in cells that overexpress SLK. Thus, SLK is an anoxia/recovery-dependent kinase that is activated via homodimerization and that signals via ASK1 and p38 to promote apoptosis. Attenuation of the protective aspects of the endoplasmic reticulum stress response by SLK may contribute to its proapoptotic effect.
authors.affiliation: Department of Medicine, McGill University Health Centre, Montreal, Quebec H3A 1A1, Canada.
authors.forename: Wen
authors.initials: W
authors.lastname: Hao
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takano
authors.forename: Julie
authors.initials: J
authors.lastname: Guillemette
authors.forename: Joan
authors.initials: J
authors.lastname: Papillon
authors.forename: Guohui
authors.initials: G
authors.lastname: Ren
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Cybulsky
mesh_terms: D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D053454:Caspase 12; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis; D020134:Catalytic Domain; D002453:Cell Cycle; D002460:Cell Line; D002522:Chlorocebus aethiops; D045304:Cytochromes c / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D003720:Densitometry; D019281:Dimerization; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D000081410:Germinal Center Kinases; D005947:Glucose / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D015151:Immunoblotting; D047468:Immunoprecipitation; D007476:Ionophores / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury; D014415:Tunicamycin / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D002118:Calcium; D053454:Caspase 12; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases; D045304:Cytochromes c; D018076:DNA, Complementary; D015852:Eukaryotic Initiation Factor-2; D000081410:Germinal Center Kinases; D005947:Glucose; D018840:HSP70 Heat-Shock Proteins; D017228:Hepatocyte Growth Factor; D007476:Ionophores; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D014415:Tunicamycin; D048051:p38 Mitogen-Activated Protein Kinases; C018551:glucose-regulated proteins; C082332:macrophage stimulating protein; C109163:STK24 protein, human; D000099317:Hippo Kinases; C506444:CASP12 protein, human; C506433:CASP9 protein, human; C506443:Casp12 protein, rat; C506435:Casp9 protein, rat