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Molecular and Cellular Biology, July 2006, p. 5070-5085, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02006-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulated Activating Thr172 Phosphorylation of Cyclin-Dependent Kinase 4(CDK4): Its Relationship with Cyclins and CDK "Inhibitors"

Laurence Bockstaele,1 Hugues Kooken,1 Frederick Libert,1 Sabine Paternot,1 Jacques E. Dumont,1 Yvan de Launoit,2 Pierre P. Roger,1* and Katia Coulonval1,3

Institute of Interdisciplinary Research,1 Department of Molecular Virology,2 Protein Chemistry Department, Faculté de Médecine, Université Libre de Bruxelles, Campus Erasme, B-1070 Brussels, Belgium3

Received 14 October 2005/ Returned for modification 11 November 2005/ Accepted 7 April 2006

Cyclin-dependent kinase 4 (CDK4) is a master integrator of mitogenic and antimitogenic extracellular signals. It is also crucial for many oncogenic transformation processes. Various molecular features of CDK4 activation remain poorly known or debated, including the regulation of its association with D-type cyclins, its activating Thr172 phosphorylation, and the roles of Cip/Kip CDK "inhibitors" in these processes. Thr172 phosphorylation of CDK4 was reinvestigated using two-dimensional gel electrophoresis in various experimental systems, including human fibroblasts, canine thyroid epithelial cells stimulated by thyrotropin, and transfected mammalian and insect cells. Thr172 phosphorylation of CDK4 depended on prior D-type cyclin binding, but Thr172 phosphorylation was also found in p16-bound CDK4. Opposite effects of p27 on cyclin D3-CDK4 activity observed in different systems depended on its stoichiometry in this complex. Thr172-phosphorylated CDK4 was enriched in complexes containing p21 or p27, even at inhibitory levels of p27 that precluded CDK4 activity. Deletion of the p27 nuclear localization signal sequence relocalized cyclin D3-CDK4 in the cytoplasm but did not affect CDK4 phosphorylation. Within cyclin D3 complexes, T-loop phosphorylation of CDK4, but not of CDK6, was directly regulated, identifying it as a determining target for cell cycle control by extracellular factors. Collectively, these unexpected observations indicate that CDK4-activating kinase(s) should be reconsidered.

* Corresponding author. Mailing address: IRIBHM, ULB, Campus Erasme, Building C, 808 Route de Lennik, B-1070 Brussels, Belgium. Phone: 322 555 4153. Fax: 322 555 4655. E-mail: proger{at}ulb.ac.be.

Molecular and Cellular Biology, July 2006, p. 5070-5085, Vol. 26, No. 13
0270-7306/06/$08.00+0     doi:10.1128/MCB.02006-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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