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J. Biol. Chem., Vol. 276, Issue 42, 38417-38425, October 19, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/42/38417    most recent M103471200v1 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 Kruidering, M. Articles by Vreugdenhil, E. Search for Related Content PubMed PubMed Citation Articles by Kruidering, M. Articles by Vreugdenhil, E. Social Bookmarking                      What's this?

Caspase-mediated Cleavage of the Ca²⁺/Calmodulin-dependent Protein Kinase-like Kinase Facilitates Neuronal Apoptosis^*

Marieke Kruidering^§, Theo Schouten, Gerard I. Evan, and Erno Vreugdenhil^¶

From the Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research/Leiden University Medical Center, Leiden University, P.O. Box 9503, 2300 RA, Leiden, The Netherlands and  University of California San Francisco Cancer Center, San Francisco, California 94115

This study was designed to identify the role of a recently identified Ca²⁺/calmodulin-dependent protein kinase (CaMK)-like kinase (CaMKLK) in neuronal apoptosis. For this purpose, we studied proteolytic cleavage of CaMKLK by caspases in vitro and in neuronal NG108 cells. In addition, we have investigated the effect of overexpression of wild type and mutant CaMKLK proteins on staurosporine- and serum deprivation-induced apoptosis of NG108 cells. We found that CaMKLK is a substrate for caspase-3 and -8, both in vitro and in NG108 cells during staurosporine- and serum withdrawal-induced apoptosis. Substitution of an aspartic acid residue at position 62 in an asparagine residue within a putative caspase cleavage site completely blocked cleavage of CaMKLK, strongly indicating that ⁵⁹DEND⁶² is the caspase recognition site. Overexpression of an Asp⁶²  Asn CaMKLK mutant protected NG108 cells from staurosporine-induced apoptosis to a similar extent as Bcl-x_L. In contrast, overexpression of wild type CaMKLK did not lead to protection. Moreover, microinjection of Asp⁶²  Asn CaMKLK protected NG108 cells from serum deprivation-induced apoptosis, while overexpression of a caspase-generated noncatalytic N-terminal CaMKLK fragment exacerbated apoptosis. Together, our data suggest that cleavage of CaMKLK and generation of the noncatalytic N-terminal domain of CaMKLK facilitate neuronal apoptosis.

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