Association of Insulin Receptor Substrate Proteins with Bcl-2 and Their Effects on Its Phosphorylation and Antiapoptotic Function
- 1 February 2000
- journal article
- Published by American Society for Cell Biology (ASCB) in Molecular Biology of the Cell
- Vol. 11 (2), 735-746
- https://doi.org/10.1091/mbc.11.2.735
Abstract
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.Keywords
This publication has 52 references indexed in Scilit:
- Interleukin-3-Induced Phosphorylation of BAD Through the Protein Kinase AktScience, 1997
- Programmed Cell Death in Animal DevelopmentCell, 1997
- Mutant of Insulin Receptor Substrate-1 Incapable of Activating Phosphatidylinositol 3-Kinase Did Not Mediate Insulin-stimulated Maturation of Xenopus laevis OocytesPublished by Elsevier BV ,1996
- Growth and Survival Signals transmitted via Two Distinct NPXY Motifs within Leukocyte Tyrosine Kinase, an Insulin Receptor-related Tyrosine KinasePublished by Elsevier BV ,1996
- Structure of the IRS-1 PTB Domain Bound to the Juxtamembrane Region of the Insulin ReceptorCell, 1996
- A Grb2-associated docking protein in EGF- and insulin-receptor signallingNature, 1996
- An Epidermal Growth Factor Receptor-Leukocyte Tyrosine Kinase Chimeric Receptor Generates Ligand-dependent Growth Signals through the Ras Signaling PathwayPublished by Elsevier BV ,1995
- Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell deathCell, 1993
- bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell deathCell, 1993
- Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocationCell, 1986