title: A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.
abstract: Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.
authors.affiliation: Division of Integrated Cancer Genomics, Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, Arizona 85004, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Faber
authors.forename: Candice
authors.initials: C
authors.lastname: Horn
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Donoho
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Briggs
authors.forename: Christiane M
authors.initials: CM
authors.lastname: Robbins
authors.forename: Galen
authors.initials: G
authors.lastname: Hostetter
authors.forename: Sophie
authors.initials: S
authors.lastname: Boguslawski
authors.forename: Tracy Y
authors.initials: TY
authors.lastname: Moses
authors.forename: Stephanie
authors.initials: S
authors.lastname: Savage
authors.forename: Mark
authors.initials: M
authors.lastname: Uhlik
authors.forename: Aimin
authors.initials: A
authors.lastname: Lin
authors.forename: Jian
authors.initials: J
authors.lastname: Du
authors.forename: Yue-Wei
authors.initials: YW
authors.lastname: Qian
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Zeckner
authors.forename: Greg
authors.initials: G
authors.lastname: Tucker-Kellogg
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Touchman
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.forename: Spyro
authors.initials: S
authors.lastname: Mousses
authors.forename: Michael
authors.initials: M
authors.lastname: Bittner
authors.forename: Richard
authors.initials: R
authors.lastname: Schevitz
authors.forename: Mei-Huei T
authors.initials: MH
authors.lastname: Lai
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Blanchard
authors.forename: James E
authors.initials: JE
authors.lastname: Thomas
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000737:chemistry*; D001943:Breast Neoplasms / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics; D004252:DNA Mutational Analysis; D004789:Enzyme Activation / Q000235:genetics; D005260:Female; D006801:Humans; D007938:Leukemia / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics; D010750:Phosphoproteins / Q000737:chemistry*; D017434:Protein Structure, Tertiary / Q000235:genetics; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D001798:Blood Proteins; D010750:Phosphoproteins; C039077:platelet protein P47; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt