The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling.

Activation of tyrosine kinases by numerous growth factor and cytokine receptors leads to tyrosine phosphorylation of the insulin receptor substrate (IRS)-proteins. Tyrosine-phosphorylated motifs on the IRS proteins bind to the SH2 domains in proteins that mediate downstream signals, including phosphatidylinositol 3'-kinase, GRB-2, and SHP-2. We investigated the function of the ...
two SHP-2 binding COOH-terminal tyrosines of IRS-1 by replacing them with phenylalanine (IRS-1(FCT)). IRS-1(FCT) failed to bind SHP-2 or mediate its tyrosine phosphorylation during insulin stimulation. Although several reports suggest a critical role for SHP-2 in insulin stimulated mitogen-activated protein kinase activation and cell proliferation, IRS-1(FCT) mediated these effects normally in 32D cells. Indeed, IRS-1(FCT) exhibited increased tyrosine phosphorylation, phosphatidylinositol 3'-kinase binding and activation of protein synthesis in response to insulin. These results suggest that SHP-2 attentuates the phosphorylation and downstream signal transmission of IRS-1 and that the interaction of IRS-1 and SHP-2 is an important regulatory event which attenuates insulin metabolic responses.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Animals, CHO Cells, Calcium-Calmodulin-Dependent Protein Kinases, Cell Division, Cricetinae, Enzyme Activation, Humans, Insulin, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Phosphoproteins, Phosphorylation, Protein Binding, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases, Rats, Signal Transduction, Tyrosine
J. Biol. Chem.
Date: Oct. 09, 1998
Download Curated Data For This Publication
4501
Switch View:
  • Interactions 1