Ahsg-fetuin blocks the metabolic arm of insulin action through its interaction with the 95-kD beta-subunit of the insulin receptor

作者：Goustin Anton Scott^*; Derar Nada; Abou Samra Abdul B

来源：Cellular Signalling, 2013, 25(4): 981-988.

DOI：10.1016/j.cellsig.2012.12.011

• Insulin receptor
• Insulin resistance
• Fetuin
• Ahsg

We previously have shown that Ahsg, a liver glycoprotein, inhibits insulin receptor (InsR) tyrosine kinase (TK) activity and the ERK1/2 mitogenic signaling arm of insulin signaling. Here we show that Ahsg blocks insulin-stimulated GLUT4 translocation and Akt activation in intact cells (mouse myoblasts). Furthermore, Ahsg inhibits InsR autophosphorylation of highly-purified insulin holoreceptors in a cell-free, ATP-dependent system, with an IC50 within the range of single-chain Ahsg concentrations in human serum. Binding of I-125-insulin to living cells overexpressing the InsR shows a dissociation constant (K-D) of 250 pM, unaltered in the presence of 300 nM Ahsg. A mutant InsR cDNA encoding the signal peptide, the beta-subunit and the furin processing site, but deleting the alpha-subunit, was stably expressed in HEK293 cells. Treatment with peroxovanadate, but not insulin, dramatically increased the 95 KD beta-subunit tyrosine phosphoryation. The level of tyrosine phosphorylation of the 95-KD beta-subunit can be driven down sharply by treatment of living HEK293 transfectant cells with physiological doses of Ahsg. Treatment of myogenic cells with Ahsg blunts insulin-stimulated InsR autophosphorylation and AKT phosphorylation. Taken together, we show that Ahsg antagonizes the metabolic functions initiated by InsR activation without interference in insulin binding. The experiments suggest a direct interaction of Ahsg with the InsR ectodomain beta-subunit in a mode that does not significantly alter the high-affinity binding of insulin to the holoreceptor%26apos;s two complementing alpha-subunits.

• 出版日期2013-4