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RESEARCH PRODUCT
AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.
Rosalia RabinovskyLucia E. RamehJesse S. BoehmPiyush GuptaPeter SandyAnna C. SchinzelAnna C. SchinzelDavid A. BarbieDavid A. BarbieTyler JacksKrishna Murthi VasudevanBhaskar DuttaGordon B. MillsJessica J. KimAysegul A. SahinBryan T. HennessyPanisa PochanardLevi A. GarrawayMichael A. DaviesDavid E. RootAna M. Gonzalez-anguloKatherine Stemke-haleYiling LuHsiuyi TsengSerena J. SilverEric S. LanderSo Young KimSo Young KimAna LluchCorwin JoyWilliam R. SellersWilliam R. SellersWilliam C. HahnJan H. ReilingChontelle J. McnearIan F. DunnQing ShengSebastian Hoerschsubject
Cancer Researchanimal structuresCell SurvivalClass I Phosphatidylinositol 3-KinasesAKT1AKT2Breast NeoplasmsCELLCYCLEBiologyProtein Serine-Threonine Kinasesmedicine.disease_causeArticle03 medical and health sciencesPhosphatidylinositol 3-Kinases0302 clinical medicineCell Line TumorNeoplasmsmedicinePTENHumansProtein kinase BneoplasmsPI3K/AKT/mTOR pathway030304 developmental biology0303 health sciencesGene Expression ProfilingPTEN PhosphohydrolasePyruvate Dehydrogenase Acetyl-Transferring KinaseCell Biology3. Good healthEnzyme ActivationOncology030220 oncology & carcinogenesisCancer cellMutationCancer researchbiology.proteinFemaleSignal transductionCarcinogenesisProto-Oncogene Proteins c-aktSignal Transductiondescription
SummaryDysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2009-07-01 | Cancer cell |