title: Inhibition of phosphatidylinositol 3-kinase by c-Abl in the genotoxic stress response.
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 activity in vitro and in irradiated cells. These findings indicate that c-Abl negatively regulates PI 3-kinase in the stress response to DNA damage.
authors.affiliation: Division of Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Z M
authors.initials: ZM
authors.lastname: Yuan
authors.forename: T
authors.initials: T
authors.lastname: Utsugisawa
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: T
authors.initials: T
authors.lastname: Ishiko
authors.forename: S
authors.initials: S
authors.lastname: Nakada
authors.forename: S
authors.initials: S
authors.lastname: Kharbanda
authors.forename: R
authors.initials: R
authors.lastname: Weichselbaum
authors.forename: D
authors.initials: D
authors.lastname: Kufe
mesh_terms: D006801:Humans; D009153:Mutagens / Q000633:toxicity*; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D009153:Mutagens; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D016315:Proto-Oncogene Proteins c-abl