This Article Full Text Full Text (PDF) An erratum has been published Alert me when this article is cited 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 Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Letiges, M. Articles by Farese, R. V. Search for Related Content PubMed PubMed Citation Articles by Letiges, M. Articles by Farese, R. V.

Knockout of PKC Enhances Insulin Signaling Through PI3K

Max-Planck Institute for Experimental Endocrinology (M.L.), 30625 Hannover, Germany; Institute for Biochemistry II (M.P.), Medical Faculty, University of Cologne, D-50931 Cologne, Germany; and James A. Haley Hospital (M.L.S., G.B., M.P.S., Y.K., R.V.F.), University of South Florida College of Medicine, Tampa, Florida 33612

Address all correspondence and requests for reprints to: Dr. Robert Farese, J. A. Haley Veterans Hospital, University of South Florida College of Medicine, 13000 Bruce B. Downs Boulevard, Tampa, Florida 33612. E-mail: rfarese{at}com1 med.usf.edu.

Insulin stimulates glucose transport and certain other metabolic processes by activating atypical PKC isoforms (, , ) and protein kinase B (PKB) through increases in D3-polyphosphoinositides derived from the action of PI3K. The role of diacylglycerol-sensitive PKC isoforms is less clear as they have been suggested to be both activated by insulin and yet inhibit insulin signaling to PI3K. Presently, we found that insulin signaling to insulin receptor substrate 1-dependent PI3K, PKB, and PKC, and downstream processes, glucose transport and activation of ERK, were enhanced in skeletal muscles and adipocytes of mice in which the ubiquitous conventional diacylglycerol-sensitive PKC isoform, PKC, was knocked out by homologous recombination. On the other hand, insulin provoked wortmannin-insensitive increases in immunoprecipitable PKC activity in adipocytes and skeletal muscles of wild-type mice and rats. We conclude that 1) PKC is not required for insulin-stimulated glucose transport, and 2) PKC is activated by insulin at least partly independently of PI3K, and largely serves as a physiological feedback inhibitor of insulin signaling to the insulin receptor substrate 1/PI3K/PKB/PKC// complex and dependent metabolic processes.

This article has been cited by other articles:

				T. E. Jensen, S. J. Maarbjerg, A. J. Rose, M. Leitges, and E. A. Richter Knockout of the predominant conventional PKC isoform, PKC{alpha}, in mouse skeletal muscle does not affect contraction-stimulated glucose uptake Am J Physiol Endocrinol Metab, August 1, 2009; 297(2): E340 - E348. [Abstract] [Full Text] [PDF]

				M. P. Sajan, M. L. Standaert, S. Nimal, U. Varanasi, T. Pastoor, S. Mastorides, U. Braun, M. Leitges, and R. V. Farese The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NF{kappa}B in obesity J. Lipid Res., June 1, 2009; 50(6): 1133 - 1145. [Abstract] [Full Text] [PDF]

				S. Boura-Halfon and Y. Zick Phosphorylation of IRS proteins, insulin action, and insulin resistance Am J Physiol Endocrinol Metab, April 1, 2009; 296(4): E581 - E591. [Abstract] [Full Text] [PDF]

				J. Mattila, J. Kallijarvi, and O. Puig RNAi screening for kinases and phosphatases identifies FoxO regulators PNAS, September 30, 2008; 105(39): 14873 - 14878. [Abstract] [Full Text] [PDF]

				C. Schmitz-Peiffer and T. J. Biden Protein Kinase C Function in Muscle, Liver, and {beta}-Cells and Its Therapeutic Implications for Type 2 Diabetes Diabetes, July 1, 2008; 57(7): 1774 - 1783. [Full Text] [PDF]

				R. S. Waraich, C. Weigert, H. Kalbacher, A. M. Hennige, S. Z. Lutz, H.-U. Haring, E. D. Schleicher, W. Voelter, and R. Lehmann Phosphorylation of Ser357 of Rat Insulin Receptor Substrate-1 Mediates Adverse Effects of Protein Kinase C-{delta} on Insulin Action in Skeletal Muscle Cells J. Biol. Chem., April 25, 2008; 283(17): 11226 - 11233. [Abstract] [Full Text] [PDF]

				R. R. Bansode, W. Huang, S. K. Roy, M. Mehta, and K. D. Mehta Protein Kinase C Deficiency Increases Fatty Acid Oxidation and Reduces Fat Storage J. Biol. Chem., January 4, 2008; 283(1): 231 - 236. [Abstract] [Full Text] [PDF]

				R. A. Fenton and M. A. Knepper Mouse Models and the Urinary Concentrating Mechanism in the New Millennium Physiol Rev, October 1, 2007; 87(4): 1083 - 1112. [Abstract] [Full Text] [PDF]

				M. P Corcoran, S. Lamon-Fava, and R. A Fielding Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise Am. J. Clinical Nutrition, March 1, 2007; 85(3): 662 - 677. [Abstract] [Full Text] [PDF]

				Z. Gao, Z. Wang, X. Zhang, A. A. Butler, A. Zuberi, B. Gawronska-Kozak, M. Lefevre, D. York, E. Ravussin, H.-R. Berthoud, et al. Inactivation of PKC{theta} leads to increased susceptibility to obesity and dietary insulin resistance in mice Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E84 - E91. [Abstract] [Full Text] [PDF]

				R. Nawaratne, A. Gray, C. H. Jorgensen, C. P. Downes, K. Siddle, and J. K. Sethi Regulation of Insulin Receptor Substrate 1 Pleckstrin Homology Domain by Protein Kinase C: Role of Serine 24 Phosphorylation Mol. Endocrinol., August 1, 2006; 20(8): 1838 - 1852. [Abstract] [Full Text] [PDF]

				H. Oster and M. Leitges Protein Kinase C {alpha} but not PKC{zeta} Suppresses Intestinal Tumor Formation in ApcMin/+ Mice. Cancer Res., July 15, 2006; 66(14): 6955 - 6963. [Abstract] [Full Text] [PDF]

				C. Pfeifhofer, T. Gruber, T. Letschka, N. Thuille, C. Lutz-Nicoladoni, N. Hermann-Kleiter, U. Braun, M. Leitges, and G. Baier Defective IgG2a/2b Class Switching in PKC{alpha}-/- Mice J. Immunol., May 15, 2006; 176(10): 6004 - 6011. [Abstract] [Full Text] [PDF]

				E. D. Labonte, R. J. Kirby, N. M. Schildmeyer, A. M. Cannon, K. W. Huggins, and D. Y. Hui Group 1B Phospholipase A2-Mediated Lysophospholipid Absorption Directly Contributes to Postprandial Hyperglycemia. Diabetes, April 1, 2006; 55(4): 935 - 941. [Abstract] [Full Text] [PDF]

				L. Li, K. Sampat, N. Hu, J. Zakari, and S. H. Yuspa Protein Kinase C Negatively Regulates Akt Activity and Modifies UVC-induced Apoptosis in Mouse Keratinocytes J. Biol. Chem., February 10, 2006; 281(6): 3237 - 3243. [Abstract] [Full Text] [PDF]

				R. Nakagawa, J. W. Soh, and A. M. Michie Subversion of Protein Kinase C{alpha} Signaling in Hematopoietic Progenitor Cells Results in the Generation of a B-Cell Chronic Lymphocytic Leukemia-Like Population In vivo Cancer Res., January 1, 2006; 66(1): 527 - 534. [Abstract] [Full Text] [PDF]

				R. C. Hresko and M. Mueckler mTOR{middle dot}RICTOR Is the Ser473 Kinase for Akt/Protein Kinase B in 3T3-L1 Adipocytes J. Biol. Chem., December 9, 2005; 280(49): 40406 - 40416. [Abstract] [Full Text] [PDF]

				F. Oriente, F. Andreozzi, C. Romano, G. Perruolo, A. Perfetti, F. Fiory, C. Miele, F. Beguinot, and P. Formisano Protein Kinase C-{alpha} Regulates Insulin Action and Degradation by Interacting with Insulin Receptor Substrate-1 and 14-3-3{epsilon} J. Biol. Chem., December 9, 2005; 280(49): 40642 - 40649. [Abstract] [Full Text] [PDF]

				T. Hara, Y. Saito, T. Hirai, K. Nakamura, K. Nakao, M. Katsuki, and K. Chida Deficiency of Protein Kinase C{alpha} in Mice Results in Impairment of Epidermal Hyperplasia and Enhancement of Tumor Formation in Two-Stage Skin Carcinogenesis Cancer Res., August 15, 2005; 65(16): 7356 - 7362. [Abstract] [Full Text] [PDF]

				L. Q. Dong and F. Liu PDK2: the missing piece in the receptor tyrosine kinase signaling pathway puzzle Am J Physiol Endocrinol Metab, August 1, 2005; 289(2): E187 - E196. [Abstract] [Full Text] [PDF]

				C. S Reddy Protein kinase C and chemical-induced abnormal palate development Human and Experimental Toxicology, April 1, 2005; 24(4): 203 - 214. [Abstract] [PDF]

				P. Kempna, E. Reiter, M. Arock, A. Azzi, and J.-M. Zingg Inhibition of HMC-1 Mast Cell Proliferation by Vitamin E: INVOLVEMENT OF THE PROTEIN KINASE B PATHWAY J. Biol. Chem., December 3, 2004; 279(49): 50700 - 50709. [Abstract] [Full Text] [PDF]

				Z. Gao, X. Zhang, A. Zuberi, D. Hwang, M. J. Quon, M. Lefevre, and J. Ye Inhibition of Insulin Sensitivity by Free Fatty Acids Requires Activation of Multiple Serine Kinases in 3T3-L1 Adipocytes Mol. Endocrinol., August 1, 2004; 18(8): 2024 - 2034. [Abstract] [Full Text] [PDF]

				J. Menne, J.-K. Park, M. Boehne, M. Elger, C. Lindschau, T. Kirsch, M. Meier, F. Gueler, A. Fiebeler, F. H. Bahlmann, et al. Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-{alpha}--Deficient Diabetic Mice Diabetes, August 1, 2004; 53(8): 2101 - 2109. [Abstract] [Full Text] [PDF]

				S. Redling, I. L. Pfaff, M. Leitges, and V. Vallon Immunolocalization of protein kinase C isoenzymes {alpha}, {beta}I, {beta}II, {delta}, and {varepsilon} in mouse kidney Am J Physiol Renal Physiol, August 1, 2004; 287(2): F289 - F298. [Abstract] [Full Text] [PDF]

				L. Yao, D.-Y. Huang, I. L. Pfaff, X. Nie, M. Leitges, and V. Vallon Evidence for a role of protein kinase C-{alpha} in urine concentration Am J Physiol Renal Physiol, August 1, 2004; 287(2): F299 - F304. [Abstract] [Full Text] [PDF]

				G. Vigliotta, C. Miele, S. Santopietro, G. Portella, A. Perfetti, M. A. Maitan, A. Cassese, F. Oriente, A. Trencia, F. Fiory, et al. Overexpression of the ped/pea-15 Gene Causes Diabetes by Impairing Glucose-Stimulated Insulin Secretion in Addition to Insulin Action Mol. Cell. Biol., June 1, 2004; 24(11): 5005 - 5015. [Abstract] [Full Text] [PDF]

				P. Cogram, A. Hynes, L. P.E. Dunlevy, N. D.E. Greene, and A. J. Copp Specific isoforms of protein kinase C are essential for prevention of folate-resistant neural tube defects by inositol Hum. Mol. Genet., January 1, 2004; 13(1): 7 - 14. [Abstract] [Full Text] [PDF]

				C. Lindschau, P. Quass, J. Menne, F. Guler, A. Fiebeler, M. Leitges, F. C. Luft, and H. Haller Glucose-Induced TGF-{beta}1 and TGF-{beta} Receptor-1 Expression in Vascular Smooth Muscle Cells Is Mediated by Protein Kinase C-{alpha} Hypertension, September 1, 2003; 42(3): 335 - 341. [Abstract] [Full Text] [PDF]

				K. Chida, T. Hara, T. Hirai, C. Konishi, K. Nakamura, K. Nakao, A. Aiba, M. Katsuki, and T. Kuroki Disruption of Protein Kinase C{eta} Results in Impairment of Wound Healing and Enhancement of Tumor Formation in Mouse Skin Carcinogenesis Cancer Res., May 15, 2003; 63(10): 2404 - 2408. [Abstract] [Full Text] [PDF]

				Y. Kanoh, M. P. Sajan, G. Bandyopadhyay, A. Miura, M. L. Standaert, and R. V. Farese Defective Activation of Atypical Protein Kinase C {zeta} and {lambda} by Insulin and Phosphatidylinositol-3,4,5-(PO4)3 in Skeletal Muscle of Rats Following High-Fat Feeding and Streptozotocin-Induced Diabetes Endocrinology, March 1, 2003; 144(3): 947 - 954. [Abstract] [Full Text] [PDF]