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Molecular and Cellular Biology, March 2000, p. 1489-1496, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Insulin-Like Growth Factor I-Induced Degradation of Insulin Receptor Substrate 1 Is Mediated by the 26S Proteasome and Blocked by Phosphatidylinositol 3'-Kinase Inhibition

Adrian V. Lee,* Jennifer L. Gooch,dagger Steffi Oesterreich,Dagger Rebecca L. Guler, and Douglas Yee§

Division of Medical Oncology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas 78284-7884

Received 6 May 1999/Returned for modification 11 July 1999/Accepted 24 November 1999

Insulin receptor substrate 1 (IRS-1) is a critical adapter protein involved in both insulin and insulin-like growth factor (IGF) signaling. Due to the fact that alteration of IRS-1 levels can affect the sensitivity and response to both insulin and IGF-I, we examined the ability of each of these ligands to affect IRS-1 expression. IGF-I (10 nM) stimulation of MCF-7 breast cancer cells caused a transient tyrosine phosphorylation of IRS-1 that was maximal at 15 min and decreased thereafter. The decrease in tyrosine phosphorylation of IRS-1 was paralleled by an apparent decrease in IRS-1 levels. The IGF-mediated decrease in IRS-1 expression was posttranscriptional and due to a decrease in the half-life of the IRS-1 protein. Insulin (10 nM) caused tyrosine phosphorylation of IRS-1 but not degradation, whereas high concentrations of insulin (10 µM) resulted in degradation of IRS-1. IGF-I (10 nM) stimulation resulted in transient IRS-1 phosphorylation and extracellular signal-related kinase (ERK) activation. In contrast, insulin (10 nM) caused sustained IRS-1 phosphorylation and ERK activation. Inhibition of 26S proteasome activity by the use of lactacystin or MG132 completely blocked IGF-mediated degradation of IRS-1. Furthermore, coimmunoprecipitation experiments showed an association between ubiquitin and IRS-1 that was increased by treatment of cells with IGF-I. Finally, IGF-mediated degradation of IRS-1 was blocked by inhibition of phosphatidylinositol 3'-kinase activity but was not affected by inhibition of ERK, suggesting that this may represent a direct negative-feedback mechanism resulting from downstream IRS-1 signaling. We conclude that IGF-I can cause ligand-mediated degradation of IRS-1 via the ubiquitin-mediated 26S proteasome and a phosphatidylinositol 3'-kinase-dependent mechanism and that control of degradation may have profound effects on downstream activation of signaling pathways.

* Corresponding author. Present address: Baylor College of Medicine, One Baylor Plaza MS:600, Houston, TX 77030. Phone: (713) 798-1624. Fax: (713) 798-1642. E-mail: avlee{at}bcm.tmc.edu.

dagger Present address: Division of Nephrology, Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78284-7884.

Dagger Present address: Baylor College of Medicine, Houston, TX 77030.

§ Present address: University of Minnesota Cancer Center, Minneapolis, MN 55455.

Molecular and Cellular Biology, March 2000, p. 1489-1496, Vol. 20, No. 5
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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