Journal
CELLULAR SIGNALLING
Volume 19, Issue 10, Pages 2165-2173Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2007.06.015
Keywords
PKC delta; caspase-3; cleavage; phosphorylation; apoptosis; Src; TRAIL; cisplatin
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Funding
- NCI NIH HHS [R01 CA 109196] Funding Source: Medline
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Protein kinase C delta (PKC delta plays a major role in the regulation of cell apoptosis and survival. PKC delta is cleaved by caspase 3 to generate a constitutively active catalytic domain that mediates both its apoptotic and anti-apoptotic effects. The caspase cleavage site of PKC delta in the hinge region is flanked by the two tyrosine residues, Y311 and Y332. Here, we examined the role of the phosphorylation of tyrosines 3 11 and 332 in the cleavage and apoptotic function of PKC delta using the apoptotic stimuli, TRAIL and cisplatin. Tyrosine 332 was constitutively phosphorylated in the A 172 and HeLa cells and was further phosphorylated by TRAIL and cisplatin. This phosphorylation was inhibited by the Src inhibitors, PP2 and SU6656, and by silencing of Src. Treatment of the A172 and HeLa cells with TRAIL induced cleavage of the WT PKC delta and of the PKC delta Y311F mutant, whereas a lower level of cleavage was observed in the PKC delta Y332F mutant. Similarly, a smaller degree of cleavage of the PKC delta Y332 mutant was observed in LNZ308 cells treated with cisplatin. Mutation of Y332F affected the apoptotic function of PKC delta; overexpression of the PKC delta Y332 mutant increased the apoptotic effect of TRAIL, whereas it decreased the apoptotic effect of cisplatin. Inhibition of Src decreased the cleavage of PKC delta and modified the apoptotic responses of the cells to TRAIL and cisplatin, similar to effect of the PKC delta Y332F mutant. These results demonstrate that the phosphorylation of tyrosine 332 by Src modulates the cleavage of PKC delta and the sensitivity of glioma cells to TRAIL and cisplatin. (c) 2007 Elsevier Inc. All rights reserved.
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