Protein Kinase C theta (PKC theta)-dependent Phosphorylation of PDK1 at Ser(504) and Ser(532) Contributes to Palmitate-induced Insulin Resistance

	Protein Kinase C theta (PKC theta)-dependent Phosphorylation of PDK1 at Ser(504) and Ser(532) Contributes to Palmitate-induced Insulin Resistance
	Wang, CH; Liu, ML; Riojas, RA; Xin, XB; Gao, ZG; Zeng, R; Wu, JR; Dong, LQ; Liu, F
刊名	JOURNAL OF BIOLOGICAL CHEMISTRY
	2009
卷号	284 期号:4 页码:2038-2044
通讯作者	Liu, F (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA.,liuf@uthscsa.edu
英文摘要	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 Thr(308) in the activation loop is reduced in C2C12 myotubes treated with palmitate or overexpressing protein kinase C theta (PKC theta), 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 PKC theta-deficient mouse embryonic fibroblasts (MEFs) by treating C2C12 myotubes with PKC theta pseudosubstrates. In vivo labeling studies revealed that PDK1 undergoes palmitate-induced phosphorylation at two novel sites, Ser(504) and Ser(532). Replacing Ser(504/532) with alanine disrupted PKC theta-catalyzed PDK1 phosphorylation in vitro and palmitate-induced PDK1 phosphorylation in cells. PDK1-deficient MEFs transiently expressing PDK1(S504A/S532A) but not PDK1(S504E/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 PKC theta as the kinase mediating the negative regulation.
学科主题	Biochemistry & Molecular Biology
类目[WOS]	Biochemistry & Molecular Biology
关键词[WOS]	FREE FATTY-ACID ; PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY ; SKELETAL-MUSCLE CELLS ; PKC-THETA ; RECEPTOR SUBSTRATE-1 ; SIGNALING CASCADE ; ACTIVATION ; INHIBITION ; EXPRESSION ; LOCALIZATION
收录类别	SCI
语种	英语
WOS记录号	WOS:000262545600011
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/1185]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Wang, CH,Liu, ML,Riojas, RA,et al. Protein Kinase C theta (PKC theta)-dependent Phosphorylation of PDK1 at Ser(504) and Ser(532) Contributes to Palmitate-induced Insulin Resistance[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2009,284(4):2038-2044.
APA	Wang, CH.,Liu, ML.,Riojas, RA.,Xin, XB.,Gao, ZG.,...&Liu, F.(2009).Protein Kinase C theta (PKC theta)-dependent Phosphorylation of PDK1 at Ser(504) and Ser(532) Contributes to Palmitate-induced Insulin Resistance.JOURNAL OF BIOLOGICAL CHEMISTRY,284(4),2038-2044.
MLA	Wang, CH,et al."Protein Kinase C theta (PKC theta)-dependent Phosphorylation of PDK1 at Ser(504) and Ser(532) Contributes to Palmitate-induced Insulin Resistance".JOURNAL OF BIOLOGICAL CHEMISTRY 284.4(2009):2038-2044.