HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 281, Issue 6, 3075-3084, February 10, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/6/3075    most recent M511744200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hao, W. Articles by Cybulsky, A. V. Search for Related Content PubMed PubMed Citation Articles by Hao, W. Articles by Cybulsky, A. V. Social Bookmarking                      What's this?

Induction of Apoptosis by the Ste20-like Kinase SLK, a Germinal Center Kinase That Activates Apoptosis Signal-regulating Kinase and p38^*

From the Department of Medicine, McGill University Health Centre, Montreal, Quebec H3A 1A1, Canada

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 2 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.

Received for publication, October 31, 2005 , and in revised form, November 28, 2005.

Note Added in Proof—Recently, O'Reilly et al. (O'Reilly, P. G., Wagner, S., Franks, D. J., Cailliau, K., Browaeys, E., Dissous, C., and Sabourin, L. A. (2005) J. Biol. Chem. 280, 42383–42390) demonstrated that SLK is required for progression through the G₂ phase of the cell cycle.

^* This work was supported by Research Grants from the Canadian Institutes of Health Research and the Kidney Foundation of Canada. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a scholarship from the Fonds de la Recherche en Santé du Québec.

² To whom correspondence should be addressed: Division of Nephrology, Royal Victoria Hospital, 687 Pine Ave. W., Montreal, Quebec H3A 1A1, Canada. Tel.: 514-398-8148; Fax: 514-843-2815; E-mail: andrey.cybulsky{at}mcgill.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Eguchi Triple Twist Theory of Rho Inhibition by the Angiotensin II Type 2 Receptor Circ. Res., May 23, 2008; 102(10): 1143 - 1145. [Full Text] [PDF]

				A. V. Cybulsky, T. Takano, J. Papillon, W. Hao, A. Mancini, J. A. Di Battista, and M. I. Cybulsky The 3'-untranslated region of the Ste20-like kinase SLK regulates SLK expression Am J Physiol Renal Physiol, February 1, 2007; 292(2): F845 - F852. [Abstract] [Full Text] [PDF]

				J. Xie and Q. Guo Par-4 is a novel mediator of renal tubule cell death in models of ischemia-reperfusion injury Am J Physiol Renal Physiol, January 1, 2007; 292(1): F107 - F115. [Abstract] [Full Text] [PDF]

				J. Xie and Q. Guo Apoptosis Antagonizing Transcription Factor Protects Renal Tubule Cells against Oxidative Damage and Apoptosis Induced by Ischemia-Reperfusion J. Am. Soc. Nephrol., December 1, 2006; 17(12): 3336 - 3346. [Abstract] [Full Text] [PDF]

				Z. Chaar, P. O'Reilly, I. Gelman, and L. A. Sabourin v-Src-dependent Down-regulation of the Ste20-like Kinase SLK by Casein Kinase II J. Biol. Chem., September 22, 2006; 281(38): 28193 - 28199. [Abstract] [Full Text] [PDF]