Format

Send to

Choose Destination
Nature. 2014 Apr 24;508(7497):541-5. doi: 10.1038/nature13079. Epub 2014 Mar 9.

Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus.

Author information

1
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
2
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
Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
5
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.
6
Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
7
Cell Signaling Technology, Danvers, Massachusetts 01923, USA.
8
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
9
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.).
10
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
11
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.).

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.

Comment in

PMID:
24670654
PMCID:
PMC4076493
DOI:
10.1038/nature13079
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center