期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 9, 页码 5881-5892出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.624759
关键词
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资金
- Japan Society for the Promotion of Science [24380152, 16208028, 22248030, 25221204]
- Program for Promotion of Basic Research Activities for Innovative Biosciences
- Program for Basic and Applied Research for Innovations in Bio-oriented Industry
- Grants-in-Aid for Scientific Research [22248030, 13F03089] Funding Source: KAKEN
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)-I alpha, which bound to GKAP42, in these changes. cGK-I alpha 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-I alpha 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-I alpha-GKAP42, which regulates insulin-dependent signals and GLUT4 translocation.
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