Phosphorylation of protein kinase Cdelta on distinct tyrosine residues induces sustained activation of Erk1/2 via down-regulation of MKP-1: role in the apoptotic effect of etoposide
| Autor: | Stephanie L, Lomonaco, Sarit, Kahana, Michal, Blass, Yehuda, Brody, Hana, Okhrimenko, Cunli, Xiang, Susan, Finniss, Peter M, Blumberg, Hae-Kyung, Lee, Chaya, Brodie |
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| Rok vydání: | 2008 |
| Předmět: |
Mitogen-Activated Protein Kinase 1
Microscopy Confocal Mitogen-Activated Protein Kinase 3 Mechanisms of Signal Transduction Apoptosis Dual Specificity Phosphatase 1 environment and public health Antineoplastic Agents Phytogenic Gene Expression Regulation Enzymologic Protein Kinase C-delta Mutation Mutagenesis Site-Directed Humans Tyrosine Phosphorylation Etoposide Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 283(25) |
| ISSN: | 0021-9258 |
| Popis: | The mechanism underlying the important role of protein kinase Cdelta (PKCdelta) in the apoptotic effect of etoposide in glioma cells is incompletely understood. Here, we examined the role of PKCdelta in the activation of Erk1/2 by etoposide. We found that etoposide induced persistent activation of Erk1/2 and nuclear translocation of phospho-Erk1/2. MEK1 inhibitors decreased the apoptotic effect of etoposide, whereas inhibitors of p38 and JNK did not. The activation of Erk1/2 by etoposide was downstream of PKCdelta since the phosphorylation of Erk1/2 was inhibited by a PKCdelta-KD mutant and PKCdelta small interfering RNA. We recently reported that phosphorylation of PKCdelta on tyrosines 64 and 187 was essential for the apoptotic effect of etoposide. Using PKCdeltatyrosine mutants, we found that the phosphorylation of PKCdeltaon these tyrosine residues, but not on tyrosine 155, was also essential for the activation of Erk1/2 by etoposide. In contrast, nuclear translocation of PKCdelta was independent of its tyrosine phosphorylation and not necessary for the phosphorylation of Erk1/2. Etoposide induced down-regulation of kinase phosphatase-1 (MKP-1), which correlated with persistent phosphorylation of Erk1/2 and was dependent on the tyrosine phosphorylation of PKCdelta. Moreover, silencing of MKP-1 increased the phosphorylation of Erk1/2 and the apoptotic effect of etoposide. Etoposide induced polyubiquitylation and degradation of MKP-1 that was dependent on PKCdelta and on its tyrosine phosphorylation. These results indicate that distinct phosphorylation of PKCdeltaon tyrosines 64 and 187 specifically activates the Erk1/2 pathway by the down-regulation of MKP-1, resulting in the persistent phosphorylation of Erk1/2 and cell apoptosis. |
| Databáze: | OpenAIRE |
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