PMID- 25586176 OWN - NLM STAT- MEDLINE DCOM- 20150511 LR - 20210205 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 290 IP - 9 DP - 2015 Feb 27 TI - Tumor necrosis factor (TNF)-alpha-induced repression of GKAP42 protein levels through cGMP-dependent kinase (cGK)-Ialpha causes insulin resistance in 3T3-L1 adipocytes. PG - 5881-92 LID - 10.1074/jbc.M114.624759 [doi] AB - Insulin receptor substrates (IRSs) have been shown to be major mediators of insulin signaling. Recently, we found that IRSs form high-molecular weight complexes, and here, we identify by yeast two-hybrid screening a novel IRS-1-associated protein: a 42-kDa cGMP-dependent protein kinase-anchoring protein (GKAP42). GKAP42 knockdown in 3T3-L1 adipocytes suppressed insulin-dependent IRS-1 tyrosine phosphorylation and downstream signaling, resulting in suppression of GLUT4 translocation to plasma membrane induced by insulin. In addition, GLUT4 translocation was also suppressed in cells overexpressing GKAP42-N (the IRS-1 binding region of GKAP42), which competed with GKAP42 for IRS-1, indicating that GKAP42 binding to IRS-1 is required for insulin-induced GLUT4 translocation. Long term treatment of 3T3-L1 adipocytes with TNF-alpha, which induced insulin resistance, significantly decreased the GKAP42 protein level. We then investigated the roles of cGMP-dependent kinase (cGK)-Ialpha, which bound to GKAP42, in these changes. cGK-Ialpha knockdown partially rescued TNF-alpha-induced decrease in GKAP42 and impairment of insulin signals. These data indicated that TNF-alpha-induced repression of GKAP42 via cGK-Ialpha caused reduction of insulin-induced IRS-1 tyrosine phosphorylation at least in part. The present study describes analysis of the novel TNF-alpha-induced pathway, cGK-Ialpha-GKAP42, which regulates insulin-dependent signals and GLUT4 translocation. CI - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Ando, Yasutoshi AU - Ando Y AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Shinozawa, Yusuke AU - Shinozawa Y AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Iijima, Yumi AU - Iijima Y AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Yu, Bu-Chin AU - Yu BC AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Sone, Meri AU - Sone M AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Ooi, Yuko AU - Ooi Y AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Watanaka, Yusuke AU - Watanaka Y AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Chida, Kazuhiro AU - Chida K AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. FAU - Hakuno, Fumihiko AU - Hakuno F AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan ahakuno@mail.ecc.u-tokyo.ac.jp. FAU - Takahashi, Shin-Ichiro AU - Takahashi S AD - From the Departments of Animal Sciences and Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150113 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (Gkap1 protein, mouse) RN - 0 (Glucose Transporter Type 4) RN - 0 (Hypoglycemic Agents) RN - 0 (Insulin) RN - 0 (Insulin Receptor Substrate Proteins) RN - 0 (Irs1 protein, mouse) RN - 0 (Slc2a4 protein, mouse) RN - 0 (Tumor Necrosis Factor-alpha) RN - 42HK56048U (Tyrosine) RN - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I) SB - IM MH - 3T3-L1 Cells MH - Adaptor Proteins, Signal Transducing/genetics/*metabolism MH - Adipocytes/cytology/*drug effects/metabolism MH - Animals MH - CHO Cells MH - Cricetinae MH - Cricetulus MH - Cyclic GMP-Dependent Protein Kinase Type I/genetics/*metabolism MH - Drug Resistance MH - Glucose Transporter Type 4/metabolism MH - HEK293 Cells MH - Humans MH - Hypoglycemic Agents/pharmacology MH - Immunoblotting MH - Insulin/*pharmacology MH - Insulin Receptor Substrate Proteins/genetics/metabolism MH - Mice MH - Microscopy, Confocal MH - Phosphorylation/drug effects MH - Protein Binding MH - Protein Transport/drug effects MH - RNA Interference MH - Tumor Necrosis Factor-alpha/*pharmacology MH - Two-Hybrid System Techniques MH - Tyrosine/genetics/metabolism PMC - PMC4342495 OTO - NOTNLM OT - Adipocyte OT - Glucose Metabolism OT - Glucose Transporter Type 4 (GLUT4) OT - Insulin Receptor Substrate 1 (IRS-1) OT - Tumor Necrosis Factor (TNF) OT - Type 2 Diabetes EDAT- 2015/01/15 06:00 MHDA- 2015/05/12 06:00 PMCR- 2016/02/27 CRDT- 2015/01/15 06:00 PHST- 2015/01/15 06:00 [entrez] PHST- 2015/01/15 06:00 [pubmed] PHST- 2015/05/12 06:00 [medline] PHST- 2016/02/27 00:00 [pmc-release] AID - S0021-9258(19)46856-7 [pii] AID - M114.624759 [pii] AID - 10.1074/jbc.M114.624759 [doi] PST - ppublish SO - J Biol Chem. 2015 Feb 27;290(9):5881-92. doi: 10.1074/jbc.M114.624759. Epub 2015 Jan 13.