Cell Signal 2013,
PMID: 23314177
Goustin, Anton Scott; Derar, Nada; Abou-Samra, Abdul B
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 (125)I-insulin to living cells overexpressing the InsR shows a dissociation constant (KD) of 250pM, unaltered in the presence of 300 nM Ahsg. A mutant InsR cDNA encoding the signal peptide, the β-subunit and the furin processing site, but deleting the α-subunit, was stably expressed in HEK293 cells. Treatment with peroxovanadate, but not insulin, dramatically increased the 95 kD β-subunit tyrosine phosphoryation. The level of tyrosine phosphorylation of the 95-kD β-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 β-subunit in a mode that does not significantly alter the high-affinity binding of insulin to the holoreceptor's two complementing α-subunits.
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Text Mining Data
GLUT4 ⊣ Ahsg: "
Here we show that
Ahsg blocks insulin stimulated
GLUT4 translocation and Akt activation in intact cells ( mouse myoblasts )
"
Akt ⊣ Ahsg: "
Here we show that Ahsg blocks insulin stimulated GLUT4 translocation and Akt activation in intact cells ( mouse myoblasts )
"
GLUT4 → insulin: "
Here we show that Ahsg blocks insulin stimulated GLUT4 translocation and Akt activation in intact cells ( mouse myoblasts )
"
Akt → insulin: "
Here we show that Ahsg blocks insulin stimulated GLUT4 translocation and Akt activation in intact cells ( mouse myoblasts )
"
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