Induction of apoptosis by SLK, a germinal center kinase that activates apoptosis signal-regulating kinase and p38

doi:10.1074/jbc.M511744200

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Papers In Press, published online ahead of print November 29, 2005
J. Biol. Chem, 10.1074/jbc.M511744200
Submitted on October 31, 2005
Accepted on November 29, 2005

Induction of apoptosis by SLK, a germinal center kinase that activates apoptosis signal-regulating kinase and p38

Wen Hao, Tomoko Takano, Julie Guillemette, Joan Papillon, Guohui Ren, and Andrey V. Cybulsky

Dept. of Medicine, McGill University Health Centre, Montreal, Quebec H3A 1A1

Corresponding Author: andrey.cybulsky{at}mcgill.ca

Expression and activity of the germinal center kinase, SLK (Ste20-like kinase), 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, as well as activities of caspases-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 2-alpha 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.

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