Proteolytic activation of PKN by caspase-3 or related protease during apoptosis.

PKN, a fatty acid- and Rho-activated serine/threonine kinase having a catalytic domain highly homologous to protein kinase C (PKC), was cleaved at specific sites in apoptotic Jurkat and U937 cells on Fas ligation and treatment with staurosporin or etoposide, respectively. The cleavage of PKN occurred with a time course similar ...
to that of PKCdelta, a known caspase substrate. This proteolysis was inhibited by a caspase inhibitor, acetyl-Asp-Glu-Val-Asp-aldehyde. The cleavage fragments were generated in vitro from PKN by treatment with recombinant caspase-3. Site-directed mutagenesis of specific aspartate residues prevented the appearance of these fragments. These results indicate that PKN is cleaved by caspase-3 or related protease during apoptosis. The major proteolysis took place between the amino-terminal regulatory domain and the carboxyl-terminal catalytic domain, and it generated a constitutively active kinase fragment. The cleavage of PKN may contribute to signal transduction, eventually leading to apoptosis.
Mesh Terms:
Amino Acid Sequence, Animals, Apoptosis, Binding Sites, COS Cells, Caspase 3, Caspases, Cell Line, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Endopeptidases, Enzyme Activation, Humans, Jurkat Cells, Kinetics, Mutagenesis, Site-Directed, Oligopeptides, Peptide Fragments, Protein Kinase C, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Recombinant Proteins, Signal Transduction
Proc. Natl. Acad. Sci. U.S.A.
Date: Sep. 29, 1998
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