HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/28/26415    most recent M501492200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, G. Articles by Bieberich, E. Search for Related Content PubMed PubMed Citation Articles by Wang, G. Articles by Bieberich, E. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. S. Brooks, G. Wang, Z. Yang, K. K. Smith, E. Bieberich, and L. Ko Functional Pre- mRNA trans-Splicing of Coactivator CoAA and Corepressor RBM4 during Stem/Progenitor Cell Differentiation J. Biol. Chem., July 3, 2009; 284(27): 18033 - 18046. [Abstract] [Full Text] [PDF]

				G. Wang, K. Krishnamurthy, N. S. Umapathy, A. D. Verin, and E. Bieberich The Carboxyl-terminal Domain of Atypical Protein Kinase C{zeta} Binds to Ceramide and Regulates Junction Formation in Epithelial Cells J. Biol. Chem., May 22, 2009; 284(21): 14469 - 14475. [Abstract] [Full Text] [PDF]

				N. Bartke and Y. A. Hannun Bioactive sphingolipids: metabolism and function J. Lipid Res., April 1, 2009; 50(Supplement): S91 - S96. [Abstract] [Full Text] [PDF]

				A. Mukhopadhyay, S. A. Saddoughi, P. Song, I. Sultan, S. Ponnusamy, C. E. Senkal, C. F. Snook, H. K. Arnold, R. C. Sears, Y. A. Hannun, et al. Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling FASEB J, March 1, 2009; 23(3): 751 - 763. [Abstract] [Full Text] [PDF]

				L. Xia, H. Wang, S. Munk, J. Kwan, H. J. Goldberg, I. G. Fantus, and C. I. Whiteside High glucose activates PKC-{zeta} and NADPH oxidase through autocrine TGF-{beta}1 signaling in mesangial cells Am J Physiol Renal Physiol, December 1, 2008; 295(6): F1705 - F1714. [Abstract] [Full Text] [PDF]

				C. Lu, J.-Q. Chen, G.-P. Zhou, S.-H. Wu, Y.-F. Guan, and C.-S. Yuan Multimolecular complex of Par-4 and E2F1 binding to Smac promoter contributes to glutamate-induced apoptosis in human- bone mesenchymal stem cells Nucleic Acids Res., September 1, 2008; 36(15): 5021 - 5032. [Abstract] [Full Text] [PDF]

				Y. Sun, T. Fox, G. Adhikary, M. Kester, and E. Pearlman Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide J. Leukoc. Biol., June 1, 2008; 83(6): 1512 - 1521. [Abstract] [Full Text] [PDF]

				L. Leseux, G. Laurent, C. Laurent, M. Rigo, A. Blanc, D. Olive, and C. Bezombes PKC {zeta} mTOR pathway: a new target for rituximab therapy in follicular lymphoma Blood, January 1, 2008; 111(1): 285 - 291. [Abstract] [Full Text] [PDF]

				H.-F. Bao, Z.-R. Zhang, Y.-Y. Liang, J. J. Ma, D. C. Eaton, and H.-P. Ma Ceramide mediates inhibition of the renal epithelial sodium channel by tumor necrosis factor-{alpha} through protein kinase C Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1178 - F1186. [Abstract] [Full Text] [PDF]

				T. E. Fox, K. L. Houck, S. M. O'Neill, M. Nagarajan, T. C. Stover, P. T. Pomianowski, O. Unal, J. K. Yun, S. J. Naides, and M. Kester Ceramide Recruits and Activates Protein Kinase C {zeta} (PKC{zeta}) within Structured Membrane Microdomains J. Biol. Chem., April 27, 2007; 282(17): 12450 - 12457. [Abstract] [Full Text] [PDF]

				K. Krishnamurthy, S. Dasgupta, and E. Bieberich Development and characterization of a novel anti-ceramide antibody J. Lipid Res., April 1, 2007; 48(4): 968 - 975. [Abstract] [Full Text] [PDF]

				N. Ghosh, N. Patel, K. Jiang, J. E. Watson, J. Cheng, C. E. Chalfant, and D. R. Cooper Ceramide-Activated Protein Phosphatase Involvement in Insulin Resistance via Akt, Serine/Arginine-Rich Protein 40, and Ribonucleic Acid Splicing in L6 Skeletal Muscle Cells Endocrinology, March 1, 2007; 148(3): 1359 - 1366. [Abstract] [Full Text] [PDF]

				K. Krishnamurthy, G. Wang, J. Silva, B. G. Condie, and E. Bieberich Ceramide Regulates Atypical PKC{zeta}/{lambda}-mediated Cell Polarity in Primitive Ectoderm Cells: A NOVEL FUNCTION OF SPHINGOLIPIDS IN MORPHOGENESIS J. Biol. Chem., February 2, 2007; 282(5): 3379 - 3390. [Abstract] [Full Text] [PDF]

				J. S. Heo, Y. J. Lee, and H. J. Han EGF stimulates proliferation of mouse embryonic stem cells: involvement of Ca2+ influx and p44/42 MAPKs Am J Physiol Cell Physiol, January 1, 2006; 290(1): C123 - C133. [Abstract] [Full Text] [PDF]