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Molecular and Cellular Biology, June 2001, p. 3947-3958, Vol. 21, No. 12
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.12.3947-3958.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

PTEN Expression Causes Feedback Upregulation of Insulin Receptor Substrate 2

Laura Simpson,1 Jing Li,1,dagger Danny Liaw,1 Ian Hennessy,1 Jonathan Oliner,2,Dagger Fred Christians,2 and Ramon Parsons1,*

Institute of Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York 10032,1 and Affymetrix, Santa Clara, California 950512

Received 15 September 2000/Returned for modification 5 December 2000/Accepted 16 March 2001

PTEN is a tumor suppressor that antagonizes phosphatidylinositol-3 kinase (PI3K) by dephosphorylating the D3 position of phosphatidylinositol (3,4,5)-triphosphate (PtdIns-3,4,5-P3). Given the importance of PTEN in regulating PtdIns-3,4,5-P3 levels, we used Affymetrix GeneChip arrays to identify genes regulated by PTEN. PTEN expression rapidly reduced the activity of Akt, which was followed by a G1 arrest and eventually apoptosis. The gene encoding insulin receptor substrate 2 (IRS-2), a mediator of insulin signaling, was found to be the most induced gene at all time points. A PI3K-specific inhibitor, LY294002, also upregulated IRS-2, providing evidence that it was the suppression of the PI3K pathway that was responsible for the message upregulation. In addition, PTEN, LY294002, and rapamycin, an inhibitor of mammalian target of rapamycin, caused a reduction in the molecular weight of IRS-2 and an increase in the association of IRS-2 with PI3K. Apparently, PTEN inhibits a negative regulator of IRS-2 to upregulate the IRS-2-PI3K interaction. These studies suggest that PtdIns-3,4,5-P3 levels regulate the specific activity and amount of IRS-2 available for insulin signaling.

* Corresponding author. Mailing address: Institute of Cancer Genetics, College of Physicians & Surgeons, Columbia University, 1150 St. Nicholas Ave., Russ Berrie Pavilion, Rm. 302, New York, NY 10032. Phone: (212) 304-7385. Fax: (212) 304-5511. E-mail: rep15{at}columbia.edu.

dagger Present address: Tularik, Genomics, Greenlawn, NY 11740.

Dagger Present address: Amgen Inc., Thousand Oaks, CA 91320-1799.

Molecular and Cellular Biology, June 2001, p. 3947-3958, Vol. 21, No. 12
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.12.3947-3958.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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