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Vol. 11, Issue 2, 735-746, February 2000

Association of Insulin Receptor Substrate Proteins with Bcl-2 and Their Effects on Its Phosphorylation and Antiapoptotic Function

Hiroo Ueno,* Eisaku Kondo,dagger Ritsuko Yamamoto-Honda,Dagger Kazuyuki Tobe,Dagger Tetsuya Nakamoto,* Ko Sasaki,* Kinuko Mitani,* Akihiro Furusaka,§ Teruji Tanaka,§ Yoshihide Tsujimoto,|| Takashi Kadowaki,Dagger and Hisamaru Hirai*

Departments of  *Hematology and Oncology and  Dagger Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113, Japan;  dagger Department of Pathology, Okayama University, School of Medicine, Okayama 700, Japan;  §Department of Internal Medicine I, Daisan Hospital, Jikei University School of Medicine, Tokyo 201, Japan; and  ||Department of Medical Genetics, Biomedical Research Center, Osaka University Medical School, Osaka 565, Japan

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.

Corresponding author. E-mail address: hhirai-tky{at}umin.ac.jp.

Molecular Biology of the Cell
Vol. 11, 735-746, February 2000
Copyright © 2000 by The American Society for Cell Biology


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