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Molecular and Cellular Biology, July 2005, p. 5725-5737, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5725-5737.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Akt/Protein Kinase B-Dependent Phosphorylation and Inactivation of WEE1Hu Promote Cell Cycle Progression at G2/M Transition

Kazuhiro Katayama,1 Naoya Fujita,1 and Takashi Tsuruo1,2*

Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032,1 Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan2

Received 4 November 2004/ Returned for modification 20 December 2004/ Accepted 1 April 2005

The serine/threonine kinase Akt is known to promote cell growth by regulating the cell cycle in G1 phase through activation of cyclin/Cdk kinases and inactivation of Cdk inhibitors. However, how the G2/M phase is regulated by Akt remains unclear. Here, we show that Akt counteracts the function of WEE1Hu. Inactivation of Akt by chemotherapeutic drugs or the phosphatidylinositide-3-OH kinase inhibitor LY294002 induced G2/M arrest together with the inhibitory phosphorylation of Cdc2. Because the increased Cdc2 phosphorylation was completely suppressed by wee1hu gene silencing, WEE1Hu was associated with G2/M arrest induced by Akt inactivation. Further analyses revealed that Akt directly bound to and phosphorylated WEE1Hu during the S to G2 phase. Serine-642 was identified as an Akt-dependent phosphorylation site. WEE1Hu kinase activity was not affected by serine-642 phosphorylation. We revealed that serine-642 phosphorylation promoted cytoplasmic localization of WEE1Hu. The nuclear-to-cytoplasmic translocation was mediated by phosphorylation-dependent WEE1Hu binding to 14-3-3{theta} but not 14-3-3ß or -{sigma}. These results indicate that Akt promotes G2/M cell cycle progression by inducing phosphorylation-dependent 14-3-3{theta} binding and cytoplasmic localization of WEE1Hu.

* Corresponding author. Mailing address: Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-0032, Japan. Phone: 81-3-5841-7861. Fax: 81-3-5841-8487. E-mail: ttsuruo{at}iam.u-tokyo.ac.jp.

Molecular and Cellular Biology, July 2005, p. 5725-5737, Vol. 25, No. 13
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.13.5725-5737.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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