| First Author | Ando Y | Year | 2015 |
| Journal | J Biol Chem | Volume | 290 |
| Issue | 9 | Pages | 5881-92 |
| PubMed ID | 25586176 | Mgi Jnum | J:265598 |
| Mgi Id | MGI:6201784 | Doi | 10.1074/jbc.M114.624759 |
| Citation | Ando Y, et al. (2015) Tumor necrosis factor (TNF)-alpha-induced repression of GKAP42 protein levels through cGMP-dependent kinase (cGK)-Ialpha causes insulin resistance in 3T3-L1 adipocytes. J Biol Chem 290(9):5881-92 |
| abstractText | 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. |
