title: A kinase-independent function of AKT promotes cancer cell survival.
abstract: The serine-threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. In this study, we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function alterations in MET, HER2, or Phosphatidyl-Inositol-3-Kinase (PI3K), catalytically inactive AKT (K179M) protected from drug induced cell death in a PH-domain dependent manner. An AKT kinase domain mutant found in human melanoma (G161V) lacked enzymatic activity in vitro and in AKT1/AKT2 double knockout cells, but promoted growth factor independent survival of primary human melanocytes. ATP-competitive AKT inhibitors failed to block the kinase-independent function of AKT, a liability that limits their effectiveness compared to allosteric AKT inhibitors. Our results broaden the current view of AKT function and have important implications for the development of AKT inhibitors for cancer.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States.
authors.forename: Igor
authors.initials: I
authors.lastname: Vivanco
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States.
authors.forename: Zhi C
authors.initials: ZC
authors.lastname: Chen
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, United States.
authors.forename: Barbara
authors.initials: B
authors.lastname: Tanos
authors.affiliation: Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: Barbara
authors.initials: B
authors.lastname: Oldrini
authors.affiliation: Department of Pharmacology, Weill-Cornell Graduate School of Biomedical Sciences, New York, United States.
authors.forename: Wan-Ying
authors.initials: WY
authors.lastname: Hsieh
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Yannuzzi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States.
authors.forename: Carl
authors.initials: C
authors.lastname: Campos
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States.
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*
chemical_list: D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; PI3K; cell biology; cell survival; human; human biology; kinase inhibitor; kinase-independent; medicine; mouse; oncogenic