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Protein kinase C theta (PKCtheta)-dependent phosphorylation of PDK1 at Ser504 and Ser532 contributes to palmitate-induced insulin resistance.
J Biol Chem. 2009 Jan 23; 284(4):2038-44.JB

Abstract

Clinical, epidemiological, and biochemical studies have highlighted the role of obesity-induced insulin resistance in various metabolic diseases. However, the underlying molecular mechanisms remain to be established. In the present study, we show that palmitate-induced serine phosphorylation of phosphoinositide-dependent protein kinase-1 (PDK1) negatively regulates insulin signaling. PDK1-mediated Akt phosphorylation at Thr308 in the activation loop is reduced in C2C12 myotubes treated with palmitate or overexpressing protein kinase C theta (PKCtheta), a kinase that has been implicated in hyperlipidemia-induced insulin resistance. Palmitate treatment also inhibited platelet-derived growth factor-stimulated Akt phosphorylation, suggesting that the inhibition could occur at a site independent of IRS1/2. The inhibitory effect of palmitate on PDK1 and Akt was diminished in PKCtheta-deficient mouse embryonic fibroblasts (MEFs) by treating C2C12 myotubes with PKCtheta pseudosubstrates. In vivo labeling studies revealed that PDK1 undergoes palmitate-induced phosphorylation at two novel sites, Ser504 and Ser532. Replacing Ser504/532 with alanine disrupted PKCtheta-catalyzed PDK1 phosphorylation in vitro and palmitate-induced PDK1 phosphorylation in cells. PDK1-deficient MEFs transiently expressing PDK1S504A/S532A but not PDK1S504E/S532D showed increased basal and insulin-stimulated Akt phosphorylation at Thr308 when compared with MEFs expressing wild-type PDK1. Taken together, our results identify PDK1 as a novel target in free fatty acid-induced insulin resistance and PKCtheta as the kinase mediating the negative regulation.

Authors+Show Affiliations

Department of Pharmacology, Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX 78229, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19047061

Citation

Wang, Changhua, et al. "Protein Kinase C Theta (PKCtheta)-dependent Phosphorylation of PDK1 at Ser504 and Ser532 Contributes to Palmitate-induced Insulin Resistance." The Journal of Biological Chemistry, vol. 284, no. 4, 2009, pp. 2038-44.
Wang C, Liu M, Riojas RA, et al. Protein kinase C theta (PKCtheta)-dependent phosphorylation of PDK1 at Ser504 and Ser532 contributes to palmitate-induced insulin resistance. J Biol Chem. 2009;284(4):2038-44.
Wang, C., Liu, M., Riojas, R. A., Xin, X., Gao, Z., Zeng, R., Wu, J., Dong, L. Q., & Liu, F. (2009). Protein kinase C theta (PKCtheta)-dependent phosphorylation of PDK1 at Ser504 and Ser532 contributes to palmitate-induced insulin resistance. The Journal of Biological Chemistry, 284(4), 2038-44. https://doi.org/10.1074/jbc.M806336200
Wang C, et al. Protein Kinase C Theta (PKCtheta)-dependent Phosphorylation of PDK1 at Ser504 and Ser532 Contributes to Palmitate-induced Insulin Resistance. J Biol Chem. 2009 Jan 23;284(4):2038-44. PubMed PMID: 19047061.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein kinase C theta (PKCtheta)-dependent phosphorylation of PDK1 at Ser504 and Ser532 contributes to palmitate-induced insulin resistance. AU - Wang,Changhua, AU - Liu,Meilian, AU - Riojas,Ramon A, AU - Xin,Xiaoban, AU - Gao,Zhanguo, AU - Zeng,Rong, AU - Wu,Jiarui, AU - Dong,Lily Q, AU - Liu,Feng, Y1 - 2008/12/01/ PY - 2008/12/3/pubmed PY - 2009/3/24/medline PY - 2008/12/3/entrez SP - 2038 EP - 44 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 284 IS - 4 N2 - Clinical, epidemiological, and biochemical studies have highlighted the role of obesity-induced insulin resistance in various metabolic diseases. However, the underlying molecular mechanisms remain to be established. In the present study, we show that palmitate-induced serine phosphorylation of phosphoinositide-dependent protein kinase-1 (PDK1) negatively regulates insulin signaling. PDK1-mediated Akt phosphorylation at Thr308 in the activation loop is reduced in C2C12 myotubes treated with palmitate or overexpressing protein kinase C theta (PKCtheta), a kinase that has been implicated in hyperlipidemia-induced insulin resistance. Palmitate treatment also inhibited platelet-derived growth factor-stimulated Akt phosphorylation, suggesting that the inhibition could occur at a site independent of IRS1/2. The inhibitory effect of palmitate on PDK1 and Akt was diminished in PKCtheta-deficient mouse embryonic fibroblasts (MEFs) by treating C2C12 myotubes with PKCtheta pseudosubstrates. In vivo labeling studies revealed that PDK1 undergoes palmitate-induced phosphorylation at two novel sites, Ser504 and Ser532. Replacing Ser504/532 with alanine disrupted PKCtheta-catalyzed PDK1 phosphorylation in vitro and palmitate-induced PDK1 phosphorylation in cells. PDK1-deficient MEFs transiently expressing PDK1S504A/S532A but not PDK1S504E/S532D showed increased basal and insulin-stimulated Akt phosphorylation at Thr308 when compared with MEFs expressing wild-type PDK1. Taken together, our results identify PDK1 as a novel target in free fatty acid-induced insulin resistance and PKCtheta as the kinase mediating the negative regulation. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/19047061/Protein_kinase_C_theta__PKCtheta__dependent_phosphorylation_of_PDK1_at_Ser504_and_Ser532_contributes_to_palmitate_induced_insulin_resistance_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=19047061 DB - PRIME DP - Unbound Medicine ER -