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J. Biol. Chem., Vol. 275, Issue 42, 32482-32490, October 20, 2000
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From the Current evidence suggests that the mixed lineage
kinase family member dual leucine zipper-bearing kinase (DLK)
might play a significant role in the regulation of cell growth and
differentiation, particularly during the process of tissue remodeling.
To further explore this working model, we have investigated the
regulation of host and recombinant DLK in NIH3T3 and COS-1 cells
undergoing apoptosis. Using calphostin C, a potent and selective
inhibitor of protein kinase C and a recognized apoptosis inducer for
various cell types, we demonstrate, by immunoblot analysis, that DLK
protein levels are rapidly and dramatically down-regulated during the early phases of apoptosis. Down-regulation in calphostin C-treated cells was also accompanied by the appearance of SDS- and
mercaptoethanol-resistant high molecular weight DLK immunoreactive
oligomers. Experiments aimed at elucidating the mechanism(s) underlying
DLK oligomerization revealed that the tissue transglutaminase (tTG)
inhibitor monodansylcadaverine antagonized the effects of calphostin C
almost completely, thereby suggesting the involvement of a
tTG-catalyzed reaction as the root cause of DLK down-regulation and
accumulation as high molecular weight species. In support of this
notion, we also show that DLK can serve as a substrate for
tTG-dependent cross-linking in vitro and that
this covalent post-translational modification leads to the functional
inactivation of DLK. Taken together, these observations suggest that
transglutamination and oligomerization may constitute a relevant
physiological mechanism for the regulation of DLK activity.
The Mixed Lineage Kinase DLK Is Oligomerized by Tissue
Transglutaminase during Apoptosis*
,,,,¶
Centre de Recherche sur les Mécanismes
d'Expression Génétique, Département de Biologie,
Faculté des Sciences, Université de Sherbrooke, Sherbrooke,
Québec J1K 2R1 and § Santé Canada, Programme des
Produits Thérapeutiques/Bureau des Produits Biologiques et
Radiopharmaectiques/Division des Services de Recherche-Biotechnologie,
Centre de Recherche Sir F. G. Banting, Parc Tunney, Ottawa,
Ontario K1A OL2, Canada
*
This work was supported by grants from the Natural Sciences
and Engineering Research Council of Canada and by the "Fonds pour la
Formation de Chercheurs et l'Aide à la Recherche" of the
Province of Quebec.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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