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...

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Veröffentlicht in:Molecular biology of the cell 2000-02, Vol.11 (2), p.735-746
Hauptverfasser: Ueno, H, Kondo, E, Yamamoto-Honda, R, Tobe, K, Nakamoto, T, Sasaki, K, Mitani, K, Furusaka, A, Tanaka, T, Tsujimoto, Y, Kadowaki, T, Hirai, H
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container_issue 2
container_start_page 735
container_title Molecular biology of the cell
container_volume 11
creator Ueno, H
Kondo, E
Yamamoto-Honda, R
Tobe, K
Nakamoto, T
Sasaki, K
Mitani, K
Furusaka, A
Tanaka, T
Tsujimoto, Y
Kadowaki, T
Hirai, H
description 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.
doi_str_mv 10.1091/mbc.11.2.735
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subjects Animals
Apoptosis - drug effects
Apoptosis Regulatory Proteins
bcl-2-Associated X Protein
bcl-X Protein
Binding Sites
Cell Line
Humans
Insulin - pharmacology
Insulin Receptor Substrate Proteins
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Models, Biological
Molecular Weight
Phosphatidylinositol 3-Kinases - metabolism
Phosphoproteins - antagonists & inhibitors
Phosphoproteins - chemistry
Phosphoproteins - genetics
Phosphoproteins - metabolism
Phosphorylation - drug effects
Phosphotyrosine - metabolism
Protein Binding
Protein Structure, Tertiary
Proteins - genetics
Proteins - metabolism
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 - chemistry
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Signal Transduction - drug effects
Transfection
title Association of insulin receptor substrate proteins with Bcl-2 and their effects on its phosphorylation and antiapoptotic function
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