Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function.

Insulin receptor substrate (IRS) proteins are docking proteins that couple growth factor receptors to various effector molecules, including phosphoinositide-3 kinase, Grb-2, Syp, and Nck. Here we show that IRS-1 associates with the loop domain of Bcl-2 and synergistically up-regulates antiapoptotic function of Bcl-2. IRS-2 but not IRS-3 binds to Bcl-2, ...
and IRS-1 associates with Bcl-XL but not with Bax or Bik. Overexpression of IRS-1 suppresses phosphorylation of Bcl-2 induced by stimulation with insulin, and the hypophosphorylation may lead to its enhanced antiapoptotic activity. The binding site for Bcl-2 is located on the carboxyl half-domain of IRS-1. IRS-3, which lacks the corresponding region, dominant-negatively abrogates the survival effects of IRS-1 and Bcl-2. For the antiapoptotic activity of IRS-1, binding to Bcl-2 is more critical than activating phosphoinositide-3 kinase. Our results indicate that IRS proteins transmit signals from the insulin receptor to Bcl-2, thus regulating cell survival probably through regulating phosphorylation of Bcl-2.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, Animals, Apoptosis, Apoptosis Regulatory Proteins, Binding Sites, Cell Line, Humans, Insulin, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Models, Biological, Molecular Weight, Phosphoproteins, Phosphorylation, Phosphotyrosine, Protein Binding, Protein Structure, Tertiary, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Signal Transduction, Transfection, bcl-2-Associated X Protein, bcl-X Protein
Mol. Biol. Cell
Date: Feb. 01, 2000
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