This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Bockstaele, L.
Right arrow Articles by Roger, P. P.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bockstaele, L.
Right arrow Articles by Roger, P. P.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2009, p. 4188-4200, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01823-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Differential Regulation of Cyclin-Dependent Kinase 4 (CDK4) and CDK6, Evidence that CDK4 Might Not Be Activated by CDK7, and Design of a CDK6 Activating Mutation{triangledown}

Laurence Bockstaele,{dagger} Xavier Bisteau,{dagger} Sabine Paternot, and Pierre P. Roger*

Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles, Campus Erasme, B-1070 Brussels, Belgium

Received 1 December 2008/ Returned for modification 13 January 2009/ Accepted 21 May 2009

The homologous cyclin-dependent kinases (CDK) CDK4 and CDK6 integrate mitogenic and oncogenic signaling cascades with the cell cycle. Their activation requires binding to a D-type cyclin and then T-loop phosphorylation at T172 and T177 (respectively) by the only CDK-activating kinase identified in animal cells, cyclin H-CDK7. At odds with the existing data showing the constitutive activity of CDK7, we have recently identified the T172 phosphorylation of cyclin D-bound CDK4 as a crucial cell cycle regulatory target. Here we show that T172 phosphorylation of CDK4 is conditioned by its unique proline 173 residue. In contrast to CDK4, CDK6 does not contain such a proline and, unexpectedly, remained poorly phosphorylated and active in a variety of cells. Mutations of proline 173 did not adversely affect CDK4 activation by CDK7, but in cells they abolished CDK4 T172 phosphorylation and activity. Conversely, substituting a proline for the corresponding residue of CDK6 enforced its complete, apparently cyclin-independent T177 phosphorylation and dramatically increased its activity. These results lead us to propose that CDK4 might not be phosphorylated by CDK7 in intact cells but is more likely phosphorylated by another, presumably proline-directed kinase(s). Moreover, they provide a new model of a potentially oncogenic activating mutation of a CDK.

* Corresponding author. Mailing address: Institute of Interdisciplinary Research, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, B-1070 Brussels, Belgium. Phone: 32 2 555 41 53. Fax: 32 2 555 46 55. E-mail: proger{at}ulb.ac.be

{triangledown} Published ahead of print on 1 June 2009.

{dagger} L.B. and X.B. contributed equally to the study.

Molecular and Cellular Biology, August 2009, p. 4188-4200, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01823-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»