title: Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.
abstract: Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Pengda
authors.initials: P
authors.lastname: Liu
authors.affiliation: 1] Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Begley
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michowski
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Ginzberg
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Daming
authors.initials: D
authors.lastname: Gao
authors.affiliation: 1] Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Peiling
authors.initials: P
authors.lastname: Tsou
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Wenjian
authors.initials: W
authors.lastname: Gan
authors.affiliation: 1] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [3] Cancer Genetics Program and Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Antonella
authors.initials: A
authors.lastname: Papa
authors.affiliation: Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Byeong Mo
authors.initials: BM
authors.lastname: Kim
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Lixin
authors.initials: L
authors.lastname: Wan
authors.affiliation: Cell Signaling Technology, Danvers, Massachusetts 01923, USA.
authors.forename: Amrik
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhai
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yuan
authors.affiliation: 1] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, China (Z.W.); Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital, New York, New York 10065, USA (L.C.).
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Tae Ho
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Kun-Ping
authors.initials: KP
authors.lastname: Lu
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
authors.affiliation: 1] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [3] Cancer Genetics Program and Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Marc W
authors.initials: MW
authors.lastname: Kirschner
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.affiliation: 1] Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, China (Z.W.); Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital, New York, New York 10065, USA (L.C.).
authors.forename: Lewis
authors.initials: L
authors.lastname: Cantley
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Wei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D056751:Cyclin A2 / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D009830:Olfactory Bulb / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D010769:Phosphothreonine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000737:chemistry* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D056751:Cyclin A2; D046912:Multiprotein Complexes; D010769:Phosphothreonine; D010768:Phosphoserine; D000076225:Mechanistic Target of Rapamycin Complex 2; D051058:Oncogene Protein v-akt; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051357:Cyclin-Dependent Kinase 2