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Molecular and Cellular Biology, June 2001, p. 3947-3958, Vol. 21, No. 12
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.
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


*
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.
Present address: Tularik, Genomics, Greenlawn, NY 11740.
Present address: Amgen Inc., Thousand Oaks, CA 91320-1799.
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