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Two Bistable Switches Govern M Phase Entry.

Satoru Mochida1, Scott Rata2, Hirotsugu Hino3

  • 1Priority Organization for Innovation and Excellence, Kumamoto University, Kyoyoto-honjo 1, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Institute for Medical Embryology and Genetics, Kumamoto University, Kyoyoto-honjo 1, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; International Research Center for Medical Science, Kumamoto University, Kyoyoto-honjo 1, 2-2-1 Honjo, Chuo-ku, Kumamoto 860-0811, Japan; Precursory Research for Embryonic Science and Technology (PRESTO) Program, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.

Current Biology : CB
|November 28, 2016
PubMed
Summary
This summary is machine-generated.

Mitotic entry relies on switch-like protein phosphorylation. We discovered a second mechanism involving the Greatwall (Gwl)-endosulfine (ENSA) pathway that ensures irreversible cell cycle progression, independent of Cdk1 auto-activation.

Keywords:
Greatwall kinasePP2Acyclin-dependent kinasehysteresismitosisrobustnessthreshold

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The transition from interphase to M phase is crucial for cell division, requiring precise regulation of protein phosphorylation.
  • Cyclin-dependent kinase 1 (Cdk1):cyclin B (CycB) complex drives this transition, historically thought to rely on Cdk1 auto-activation via Tyr15 dephosphorylation.
  • This auto-activation creates a bistable switch, ensuring irreversible commitment to mitosis.

Purpose of the Study:

  • To investigate the mechanisms underlying switch-like and irreversible mitotic entry.
  • To determine if Cdk1 auto-activation is essential for this process.
  • To elucidate the role of the Greatwall (Gwl)-endosulfine (ENSA) pathway in regulating mitotic entry.

Main Methods:

  • Biochemical reconstitution using purified components.
  • Mathematical modeling of pathway dynamics.
  • Analysis of Cdk1 phosphorylation thresholds in a luminescent substrate assay.

Main Results:

  • Cdk1 auto-activation is dispensable for irreversible, switch-like mitotic entry.
  • The Gwl-ENSA pathway, which inhibits the phosphatase PP2A:B55, is necessary and sufficient for switch-like mitotic phosphorylations.
  • A reconstituted Gwl-ENSA system demonstrated a distinct Cdk1 threshold for initiating, but not maintaining, mitotic phosphorylation, indicating bistability.

Conclusions:

  • Two interlinked bistable mechanisms ensure robust and irreversible mitotic entry.
  • The Gwl-ENSA pathway provides a critical, previously unrecognized, bistable switch for mitotic commitment.
  • This finding redefines our understanding of cell cycle regulation and mitotic commitment.