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.
Mesh Terms:
3T3-L1 Cells, Adaptor Proteins, Signal Transducing, Adipocytes, Animals, GRB10 Adaptor Protein, Glucose, Glucose Transporter Type 4, Insulin, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Mice, Monosaccharide Transport Proteins, Muscle Proteins, Phosphoproteins, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-cbl, Receptor, Insulin, Shc Signaling Adaptor Proteins, Signal Transduction, Transfection, Ubiquitin-Protein Ligases
Mol. Cell. Endocrinol.
Date: Jan. 31, 2005
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