TNF-{alpha}-Induced Repression of GKAP42 Protein Levels through cGK-I{alpha} Causes Insulin Resistance in 3T3-L1 Adipocytes [Molecular Bases of Disease]

January 13th, 2015 by Ando, Y., Shinozawa, Y., Iijima, Y., Yu, B.-C., Sone, M., Ooi, Y., Watanaka, Y., Chida, K., Hakuno, F., Takahashi, S.-I.

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-α, which induced insulin resistance, significantly decreased the GKAP42 protein level. We then investigated the roles of cGMP-dependent kinase (cGK)-Iα that bound to GKAP42, in these changes. cGK-Iα knockdown partially rescued TNF-α-induced decrease in GKAP42 and impairment of insulin signals. These data indicated that TNF-α-induced repression of GKAP42 via cGK-Iα caused reduction of insulin-induced IRS-1 tyrosine phosphorylation at least in a part. The present study describes analysis of the novel TNF-α-induced pathway, cGKIα-GKAP42, which regulates insulin-dependent signals and GLUT4 translocation.
  • Posted in Journal of Biological Chemistry, Publications
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