Publication Date:
2014-03-29
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076493/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076493/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Pengda -- Begley, Michael -- Michowski, Wojciech -- Inuzuka, Hiroyuki -- Ginzberg, Miriam -- Gao, Daming -- Tsou, Peiling -- Gan, Wenjian -- Papa, Antonella -- Kim, Byeong Mo -- Wan, Lixin -- Singh, Amrik -- Zhai, Bo -- Yuan, Min -- Wang, Zhiwei -- Gygi, Steven P -- Lee, Tae Ho -- Lu, Kun-Ping -- Toker, Alex -- Pandolfi, Pier Paolo -- Asara, John M -- Kirschner, Marc W -- Sicinski, Piotr -- Cantley, Lewis -- Wei, Wenyi -- 2P01CA120964/CA/NCI NIH HHS/ -- 5T32HL007893/HL/NHLBI NIH HHS/ -- CA177910/CA/NCI NIH HHS/ -- GM089763/GM/NIGMS NIH HHS/ -- GM094777/GM/NIGMS NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- R01 CA132740/CA/NCI NIH HHS/ -- R01 CA167677/CA/NCI NIH HHS/ -- R01 CA177910/CA/NCI NIH HHS/ -- R01 GM041890/GM/NIGMS NIH HHS/ -- R01 GM089763/GM/NIGMS NIH HHS/ -- R01 GM094777/GM/NIGMS NIH HHS/ -- R01 HL111430/HL/NHLBI NIH HHS/ -- R01CA132740/CA/NCI NIH HHS/ -- S10 OD010612/OD/NIH HHS/ -- T32 HL007893/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Apr 24;508(7497):541-5. doi: 10.1038/nature13079. Epub 2014 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; 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. ; Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 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. ; Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. ; Cell Signaling Technology, Danvers, Massachusetts 01923, USA. ; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. ; 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.). ; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 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.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670654" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apoptosis/genetics
;
Cell Cycle/*physiology
;
Cell Proliferation
;
Cyclin A2/metabolism
;
Cyclin-Dependent Kinase 2/metabolism
;
Embryonic Stem Cells/cytology/metabolism
;
Enzyme Activation
;
Male
;
Mice
;
Multiprotein Complexes/metabolism
;
Neoplasms/enzymology/pathology
;
Olfactory Bulb/cytology/enzymology/metabolism
;
Oncogene Protein v-akt/chemistry/metabolism
;
Phosphorylation
;
Phosphoserine/metabolism
;
Phosphothreonine/metabolism
;
Proto-Oncogene Proteins c-akt/*chemistry/*metabolism
;
TOR Serine-Threonine Kinases/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
