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CDK1-PP2A-B55 interplay ensures cell cycle oscillation via Apc1-loop300

Kim Hou Chia1, Hiroko Takaki1, Kazuyuki Fujimitsu1

  • 1Cell Cycle Control Group, University College London (UCL) Cancer Institute, London WC1E 6DD, UK.

Cell Reports
|April 28, 2024
PubMed

Insights

Researchers identified the anaphase-promoting complex/cyclosome (APC/C) as a key regulator of cell cycle oscillations. Phosphorylation of its Apc1-loop300 domain by CDK1 and PP2A-B55 is crucial for proper cell division timing.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cell cycle progression depends on precise regulation of protein phosphorylation and dephosphorylation.
  • The anaphase-promoting complex/cyclosome (APC/C) is a critical E3 ubiquitin ligase complex that controls cell cycle transitions.
  • Identifying the key substrates and regulatory mechanisms governing APC/C activity is essential for understanding cell cycle control.

Purpose of the Study:

  • To investigate the role of phospho-regulation in controlling the activity of the anaphase-promoting complex/cyclosome (APC/C).
  • To identify the specific regulatory elements and enzymes involved in APC/C phospho-regulation during mitosis.
  • To elucidate how APC/C regulation impacts key cell cycle events like Cyclin B degradation.

Main Methods:

  • Utilized biochemical assays to study the phosphorylation status of APC/C components.
  • Employed genetic manipulation, including kinase depletion and domain deletion, to assess functional consequences.
  • Investigated protein-protein interactions using co-immunoprecipitation and analyzed protein degradation dynamics.

Main Results:

  • The Apc1-loop300 domain (Apc1-300L) of the APC/C was identified as a critical substrate for CDK1 and PP2A-B55.
  • Dephosphorylation of Apc1-300L by PP2A-B55, particularly upon premature activation, stalls APC/C activity and delays Cyclin B degradation.
  • This delay can be rescued by inhibiting PP2A-B55 or mutating the Apc1-300L phosphorylation site, and it specifically impairs further Cdc20 recruitment to the APC/C.

Conclusions:

  • The phospho-regulation of the Apc1-loop300 domain is a pivotal mechanism controlling APC/C activity and cell cycle progression.
  • The interplay between CDK1 and PP2A-B55 on APC/C is a primary determinant of cell cycle oscillation.
  • APC/C acts as a central substrate regulated by the CDK-phosphatase partnership, highlighting its role in cell cycle timing.
Keywords:
APC/CCDKCP: Cell biologyCP: Molecular biologyCdc20Cell cyclePP2A-B55intrinsically disordered regionsmitosisphosphatasephosphorylationubiquitin ligase

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