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  • The EMBO Journal (2008) 27, 679 - 691
  • doi:10.1038/emboj.2008.6

Published online: 31 January 2008

Phosphorylation of Skp2 regulated by CDK2 and Cdc14B protects it from degradation by APCCdh1 in G1 phase

Geneviève Rodier1,45, Philippe Coulombe1,2,46, Pierre-Luc Tanguay1,2, Christel Boutonnet1 and Sylvain Meloche1,2,3

  1. Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montreal, Quebec, Canada
  2. Department of Molecular Biology, Université de Montréal, Montreal, Quebec, Canada
  3. Department of Pharmacology, Université de Montréal, Montreal, Quebec, Canada

Correspondence to:

Sylvain Meloche, Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, 2950 chemin de Polytechnique, Marcelle-Coutu Pavilion, Montreal, Quebec, Canada H3C 3J7. Tel.: +1 514 343 6966; Fax: +1 514 343 5839; E-mail: sylvain.meloche@umontreal.ca

4These authors contributed equally to this work

5Present address: Institut de Génétique Moléculaire, CNRS-UMII, 34293 Montpellier, France

6Present address: Institut de Génétique Humaine, CNRS, 34396 Montpellier, France

Received 19 September 2007; Accepted 8 January 2008

The p27Kip1 ubiquitin ligase receptor Skp2 is often overexpressed in human tumours and displays oncogenic properties. The activity of SCFSkp2 is regulated by the APCCdh1, which targets Skp2 for degradation. Here we show that Skp2 phosphorylation on Ser64/Ser72 positively regulates its function in vivo. Phosphorylation of Ser64, and to a lesser extent Ser72, stabilizes Skp2 by interfering with its association with Cdh1, without affecting intrinsic ligase activity. Cyclin-dependent kinase (CDK)2-mediated phosphorylation of Skp2 on Ser64 allows its expression in mid-G1 phase, even in the presence of active APCCdh1. Reciprocally, dephosphorylation of Skp2 by the mitotic phosphatase Cdc14B at the M right arrow G1 transition promotes its degradation by APCCdh1. Importantly, lowering the levels of Cdc14B accelerates cell cycle progression from mitosis to S phase in an Skp2-dependent manner, demonstrating epistatic relationship of Cdc14B and Skp2 in the regulation of G1 length. Thus, our results reveal that reversible phosphorylation plays a key role in the timing of Skp2 expression in the cell cycle.

  • Keywords:

    • APC,
    • cell cycle,
    • p27Kip1,
    • protein phosphorylation,
    • ubiquitin–proteasome pathway