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J. Biol. Chem., Vol. 283, Issue 25, 17731-17739, June 20, 2008

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Phosphorylation of Protein Kinase C 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, and Chaya Brodie¹

From the William and Karen Davidson Laboratory of Cell Signaling and Tumorigenesis, Hermelin Brain Tumor Center, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan 48202, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, 52900 Israel, and the ^¶Laboratory of Cancer Biology and Genetics, NCI, National Institutes of Health, Bethesda, Maryland 20892

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

Received for publication, March 4, 2008 , and in revised form, April 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA109196. This work was also supported by William and Karen Davidson Fund, Hermelin Brain Tumor Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Hermelin Brain Tumor Center, Dept. of Neurosurgery, Henry Ford Hospital, 2799 W Grand Blvd., Detroit, MI 48202. Tel.: 313-916-8619; Fax: 313-916-9855; E-mail: nscha{at}neuro.hfh.edu.

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