Distinct Grb10 domain requirements for effects on glucose uptake and insulin signaling.

The adapter protein Grb10 binds to phosphotyrosine residues in insulin receptors via its C-terminal region and regulates insulin signaling. This study investigated Grb10 regulation of glucose uptake and the importance of the Grb10 N-terminal region using 3T3-L1 adipocytes overexpressing full-length (FL-Grb10) or N-terminally truncated Grb10 (BPS-SH2). Overexpression of FL-Grb10 inhibited insulin-stimulated receptor autophosphorylation and glucose uptake. In contrast, the BPS-SH2 fragment of Grb10 had no effect on receptor phosphorylation or glucose uptake. In spite of these differences, both FL-Grb10 and the BPS-SH2 fragment inhibited insulin-stimulated phosphorylation of IRS1, IRS2, Akt/PKB, Shc, ERK1/2, APS, and c-Cbl to a similar extent. Co-precipitation studies demonstrated more sustained binding of the BPS-SH2 fragment than FL-Grb10 to insulin receptors. Although receptor binding domains of Grb10 are sufficient to inhibit insulin effects on proximal post-receptor signaling responses, N-terminal domains of Grb10 are essential for the effects of this adapter protein on receptor phosphorylation and glucose uptake.

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