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Molecular and Cellular Biology, February 2002, p. 1016-1026, Vol. 22, No. 4
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.4.1016-1026.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Molecular Mechanism of Insulin-Induced Degradation of Insulin Receptor Substrate 1

Rachel Zhande, John J. Mitchell, Jiong Wu, and Xiao Jian Sun*

Endocrinology Division, University of Vermont College of Medicine, Burlington, Vermont 05405

Received 16 August 2001/ Returned for modification 7 October 2001/ Accepted 13 November 2001

Insulin receptor substrate 1 (IRS-1) plays an important role in the insulin signaling cascade. In vitro and in vivo studies from many investigators have suggested that lowering of IRS-1 cellular levels may be a mechanism of disordered insulin action (so-called insulin resistance). We previously reported that the protein levels of IRS-1 were selectively regulated by a proteasome degradation pathway in CHO/IR/IRS-1 cells and 3T3-L1 adipocytes during prolonged insulin exposure, whereas IRS-2 was unaffected. We have now studied the signaling events that are involved in activation of the IRS-1 proteasome degradation pathway. Additionally, we have addressed structural elements in IRS-1 versus IRS-2 that are required for its specific proteasome degradation. Using ts20 cells, which express a temperature-sensitive mutant of ubiquitin-activating enzyme E1, ubiquitination of IRS-1 was shown to be a prerequisite for insulin-induced IRS-1 proteasome degradation. Using IRS-1/IRS-2 chimeric proteins, the N-terminal region of IRS-1 including the PH and PTB domains was identified as essential for targeting IRS-1 to the ubiquitin-proteasome degradation pathway. Activation of phosphatidylinositol 3-kinase is necessary but not sufficient for activating and sustaining the IRS-1 ubiquitin-proteasome degradation pathway. In contrast, activation of mTOR is not required for IRS-1 degradation in CHO/IR cells. Thus, our data provide insight into the molecular mechanism of insulin-induced activation of the IRS-1 ubiquitin-proteasome degradation pathway.

* Corresponding author. Mailing address: Given Building C-350, UVM College of Medicine, Burlington, VT 05405. Phone: (802) 6556-2683. Fax: (802) 656-8031. E-mail: xsun{at}zoo.uvm.edu.

Molecular and Cellular Biology, February 2002, p. 1016-1026, Vol. 22, No. 4
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.4.1016-1026.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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