Phosphorylation of protein kinase Cδ on distinct tyrosine residues induces sustained activation of Erk1/2 via down-regulation of MKP-1: Role in the apoptotic effect of etoposide

Stephanie L. Lomonaco, Sarit Kahana, Michal Blass, Yehuda Brody, Hana Okhrimenko, Cunli Xiang, Susan Finniss, Peter M. Blumberg, Hae Kyung Lee, Chaya Brodie

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The mechanism underlying the important role of protein kinase Cδ (PKCδ) in the apoptotic effect of etoposide in glioma cells is incompletely understood. Here, we examined the role of PKCδ 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 PKCδ since the phosphorylation of Erk1/2 was inhibited by a PKCδ-KD mutant and PKCδ small interfering RNA. We recently reported that phosphorylation of PKCδ on tyrosines 64 and 187 was essential for the apoptotic effect of etoposide. Using PKCδ tyrosine mutants, we found that the phosphorylation of PKCδ on these tyrosine residues, but not on tyrosine 155, was also essential for the activation of Erk1/2 by etoposide. In contrast, nuclear translocation of PKCδ 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 PKCδ. 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 PKCδ and on its tyrosine phosphorylation. These results indicate that distinct phosphorylation of PKCδ on 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.

Original languageEnglish
Pages (from-to)17731-17739
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number25
DOIs
StatePublished - 20 Jun 2008

Funding

FundersFunder number
National Cancer InstituteZ01BC005270

    Fingerprint

    Dive into the research topics of 'Phosphorylation of protein kinase Cδ on distinct tyrosine residues induces sustained activation of Erk1/2 via down-regulation of MKP-1: Role in the apoptotic effect of etoposide'. Together they form a unique fingerprint.

    Cite this