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Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
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Phosphorylation of Skp2 regulated by CDK2 and Cdc14B protects it from degradation by APC(Cdh1) in G1 phase

Geneviève Rodier1, Philippe Coulombe, Pierre-Luc Tanguay

  • 1Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montreal, Quebec, Canada.

The EMBO Journal
|February 2, 2008
PubMed

Insights

Skp2 phosphorylation by CDK2 stabilizes the protein by blocking degradation, allowing its expression. Cdc14B dephosphorylation promotes Skp2 degradation, controlling cell cycle progression.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Skp2 is an oncogenic ubiquitin ligase receptor frequently overexpressed in human tumors.
  • APC(Cdh1) regulates SCF(Skp2) activity by targeting Skp2 for degradation.

Purpose of the Study:

  • To investigate the role of Skp2 phosphorylation in regulating its stability and cell cycle function.
  • To elucidate the interplay between Skp2 phosphorylation, APC(Cdh1), CDK2, and Cdc14B in cell cycle control.

Main Methods:

  • In vivo studies of Skp2 phosphorylation.
  • Analysis of Skp2 association with Cdh1.
  • Investigation of CDK2 and Cdc14B roles in Skp2 regulation.
  • Assessment of cell cycle progression upon modulation of Cdc14B levels.

Main Results:

  • Skp2 phosphorylation at Ser64/Ser72 positively regulates its function and stabilizes the protein by inhibiting Cdh1 binding.
  • CDK2-mediated phosphorylation of Skp2 at Ser64 permits its expression during mid-G1 phase despite active APC(Cdh1).
  • Cdc14B dephosphorylation of Skp2 at the M to G1 transition promotes its degradation by APC(Cdh1).
  • Reduced Cdc14B levels accelerate cell cycle progression from mitosis to S phase in an Skp2-dependent manner.

Conclusions:

  • Reversible phosphorylation of Skp2 by CDK2 and Cdc14B is crucial for precise timing of Skp2 expression during the cell cycle.
  • This phosphorylation-dependent regulation of Skp2 stability by APC(Cdh1) and Cdc14B is critical for controlling G1 phase length and cell cycle progression.

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