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  • The EMBO Journal (2006) 25, 5159 - 5170
  • doi:10.1038/sj.emboj.7601388

Published online: 19 October 2006

C-terminal phosphorylation controls the stability and function of p27kip1

Uta Kossatz1,a, Jörg Vervoorts1,2,a, Irina Nickeleit1,a, Holly A Sundberg1, J Simon C Arthur3, Michael P Manns4 and Nisar P Malek1,4

  1. Institute for Molecular Biology, Hannover Medical School, Hannover, Germany
  2. Institute for Biochemistry, Klinikum der RWTH, Aachen, Germany
  3. MRC Protein Phosphorylation Unit, University of Dundee, Dundee, Scotland
  4. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

Correspondence to:

Nisar P Malek, Institute for Molecular Biology, Hannover Medical School, Carl Neuberg Strasse 1, Lower Saxony, 30625 Hannover, Germany. Tel.: +49 511 532 4585; Fax: +49 511 532 4283; E-mail: Malek.Nisar@MH-Hannover.de

aThese authors contributed equally to this work

Received 5 April 2006; Accepted 21 September 2006

Entry of cells into the cell division cycle requires the coordinated activation of cyclin-dependent kinases (cdks) and the deactivation of cyclin kinase inhibitors. Degradation of p27kip1 is known to be a central component of this process as it allows controlled activation of cdk2-associated kinase activity. Turnover of p27 at the G1/S transition is regulated through phosphorylation at T187 and subsequent SCFskp2-dependent ubiquitylation. However, detailed analysis of this process revealed the existence of additional pathways that regulate the abundance of the protein in early G1 and as cells exit quiescence. Here, we report on a molecular mechanism that regulates p27 stability by phosphorylation at T198. Phosphorylation of p27 at T198 prevents ubiquitin-dependent degradation of free p27. T198 phosphorylation also controls progression through the G1 phase of the cell cycle by regulating the association of p27 with cyclin–cdk complexes. Our results unveil the molecular composition of a pathway, which regulates the abundance and activity of p27kip1 during early G1. They also explain how the T187- and the T198-dependent turnover systems synergize to allow cell cycle progression in G1.

  • Keywords:

    • cell cycle,
    • p27,
    • phosphorylation,
    • turnover,
    • ubiquitin