Inhibition of Phosphatidylinositol 3-Kinase by c-Abl in the Genotoxic Stress Response*
- Zhi-Min Yuan,
- Taiju Utsugisawa,
- Yinyin Huang,
- Takatoshi Ishiko,
- Shuji Nakada,
- Surender Kharbanda,
- Ralph Weichselbaum‡ and
- Donald Kufe
- From the Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 and the‡Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois 60637
Abstract
Activation of phosphatidylinositol (PI) 3-kinase by growth factors results in phosphorylation of phosphatidylinositol lipids at the D3 position. Although PI 3-kinase is essential to cell survival, little is known about mechanisms that negatively regulate this activity. Here we show that the c-Abl tyrosine kinase interacts directly with the p85 subunit of PI 3-kinase. Activation of c-Abl by ionizing radiation exposure is associated with c-Abl-dependent phosphorylation of PI 3-kinase. We also show that phosphorylation of p85 by c-Abl inhibits PI 3-kinase activityin vitro and in irradiated cells. These findings indicate that c-Abl negatively regulates PI 3-kinase in the stress response to DNA damage.
Footnotes
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↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are: IR, ionizing radiation; PI, phosphatidylinositol; DNA-PK, DNA-dependent protein kinase; ATM, ataxia telangiectasia mutated; Gy, gray; GST, glutathione S-transferase; HI, heat-inactivated.
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- Received June 19, 1997.
- Revision received July 21, 1997.
