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Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation

Markus Welcker1, Jeffrey Singer, Keith R Loeb

  • 1Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Molecular Cell
|October 11, 2003
PubMed

Insights

Cyclin E degradation is more complex than previously thought. Multiple phosphorylation sites and Cdk2 activity are crucial for regulating cyclin E protein levels, not just autophosphorylation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The regulation of cyclin E protein abundance is critical for cell cycle progression.
  • A proposed model suggested autophosphorylation-triggered ubiquitination via SCFFbw7 mediated cyclin E degradation.

Purpose of the Study:

  • To investigate the in vivo regulation of cyclin E degradation.
  • To determine the adequacy of the autophosphorylation-triggered ubiquitination model for cyclin E turnover.

Main Methods:

  • In vivo studies to examine cyclin E degradation pathways.
  • Analysis of cyclin E phosphorylation sites and their role in turnover.
  • Investigation of Cdk2 activity and its involvement in cyclin E regulation.

Main Results:

  • Cyclin E-Cdk2 complex assembly is necessary for Fbw7 pathway-mediated turnover.
  • Cdk2 activity, through S384 phosphorylation, is required for cyclin E turnover.
  • T380 phosphorylation is Cdk2-independent and primarily mediated by GSK3.
  • Phosphorylation at T62 and S372 sites is also essential for cyclin E turnover.

Conclusions:

  • The regulation of cyclin E turnover is controlled by multiple biological inputs.
  • The previously proposed model of autophosphorylation-triggered ubiquitination is an inadequate explanation for cyclin E degradation.

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