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J. Biol. Chem., Vol. 280, Issue 28, 26415-26424, July 15, 2005

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Direct Binding to Ceramide Activates Protein Kinase C before the Formation of a Pro-apoptotic Complex with PAR-4 in Differentiating Stem Cells^*

Guanghu Wang, Jeane Silva, Kannan Krishnamurthy, Eric Tran, Brian G. Condie, and Erhard Bieberich¶

From the Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, Augusta, Georgia 30912 and Department of Genetics, University of Georgia, Athens, Georgia 30602

We have reported that ceramide mediates binding of atypical protein kinase C (PKC) to its inhibitor protein, PAR-4 (prostate apoptosis response-4), thereby inducing apoptosis in differentiating embryonic stem cells. Using a novel method of lipid vesicle-mediated affinity chromatography, we showed here that endogenous ceramide binds directly to the PKC·PAR-4 complex. Ceramide and its analogs activated PKC prior to binding to PAR-4, as determined by increased levels of phosphorylated PKC and glycogen synthase kinase-3 and emergence of a PAR-4-to-phosphorylated PKC fluorescence resonance energy transfer signal that co-localizes with ceramide. Elevated expression and activation of PKC increased cell survival, whereas expression of PAR-4 promoted apoptosis. This suggests that PKC counteracts apoptosis, unless its ceramide-induced activation is compromised by binding to PAR-4. A luciferase reporter assay showed that ceramide analogs activate nuclear factor (NF)-B unless PAR-4-dependent inhibition of PKC suppresses NF-B activation. Taken together, our results show that direct physical association with ceramide and PAR-4 regulates the activity of PKC. They also indicate that this interaction regulates the activity of glycogen synthase kinase-3 and NF-B.

Received for publication, February 8, 2005 , and in revised form, May 10, 2005.

^* This work was supported by National Institutes of Health Grant R01NS046835 (to E. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. S1—S4.

^¶ To whom correspondence should be addressed: Institute of Molecular Medicine and Genetics, Medical College of Georgia, 1120 15th St., Rm. CB-2803, Augusta, GA 30912. Tel.: 706-721-9113; Fax: 706-721-8685; E-mail: ebieberich{at}mail.mcg.edu.

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