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First published online March 19, 2008
doi: 10.1242/10.1242/jcs.009530

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Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis

Subbareddy Maddika^1,2,*, Sudharsana Rao Ande¹, Emilia Wiechec^1,3,4, Lise Lotte Hansen⁴, Sebastian Wesselborg^5, and Marek Los^1,2,,,¶

¹ Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada
² Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, R3E 0V9, Canada
³ Department of Human Genetics, University of Aarhus, DK-8000 C Aarhus, Denmark
⁴ Department of Experimental and Clinical Radiobiology, Oncology Center, Maria Sklodowka-Curie Memorial Institute, Wybrzeze Armii Krajowej 15, PL-44100 Gliwice, Poland
⁵ Department of Internal Medicine I, University of Tübingen, Tübingen, Germany

^¶ Author for correspondence (e-mail: mjelos{at}gmail.com)

Accepted 6 January 2008

Here, we show that CDK2, an S-phase cyclin-dependent kinase, is a novel target for Akt during cell cycle progression and apoptosis. Akt phosphorylates CDK2 at threonine 39 residue both in vitro and in vivo. Although CDK2 threonine 39 phosphorylation mediated by Akt enhances cyclin-A binding, it is dispensable for its basal binding and the kinase activity. In addition, for the first time, we report a transient nucleo-cytoplasmic shuttling of Akt during specific stages of the cell cycle, in particular during the late S and G2 phases. The Akt that is re-localized to the nucleus phosphorylates CDK2 and causes the temporary cytoplasmic localization of the CDK2–cyclin-A complex. The CDK2 cytoplasmic redistribution is required for cell progression from S to G2-M phase, because the CDK2 T39A mutant, which lacks the phosphorylation site and is defective in cytoplasmic localization, severely affects cell cycle progression at the transition from S to G2-M. Interestingly, we also show that the Akt/CDK2 pathway is constitutively activated by some anticancer drugs, such as methotrexate and docetaxel, and under these conditions it promotes, rather than represses, cell death. Thus, the constitutive activation of the Akt/CDK2 pathway and changed subcellular localization promotes apoptosis. By contrast, the transient, physiological Akt/CDK2 activation is necessary for cell cycle progression.

Key words: Akt, Apoptosis, Anti-cancer drugs, Cdk2, Cell cycle

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