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Published on: June 6, 2017
The Greatwall-PP2A axis in cell cycle control
Peng Wang1, Marcos Malumbres, Vincent Archambault
1Department of Biochemistry, Institut de recherche en immunologie et en cancérologie, Université de Montréal, Édouard-Montpetit Blvd., Montréal, QC, Canada, H3T 1J4.
Abstract:
Cell cycle progression is largely controlled by reversible protein phosphorylation mediated by cyclically activated kinases and phosphatases. It has long been known that cyclin B-Cdk1 activation triggers mitotic entry, and the enzymatic network controlling its activation and inactivation has been well characterized. Much more recently protein phosphatase 2A (PP2A) together with its B55 regulatory subunit has been recognized as the major activity dephosphorylating Cdk1 targets. Moreover, PP2A-B55 activity is high in late M phase and interphase, but low at mitotic entry. A series of discoveries in the fly and frog model systems have uncovered the molecular mechanism mediating this regulation. The Greatwall (Gwl) kinase activates endosulfines, which become specific inhibitors of PP2A-B55. Cdk1-dependent activation of Gwl at mitotic entry leads to PP2A-B55 downregulation, which synergizes with Cdk1 activation to promote the phosphorylated states of several mitotic substrates. Much less is known on the mechanisms inactivating Gwl and endosulfines at mitotic exit. Recent reports show the importance of spatiotemporal regulation of Gwl, endosulfines, and PP2A-B55 for cell cycle progression. The various systems and cell types differ in their dependence on the Gwl-PP2A axis for cell cycle progression. Moreover, this pathway also regulates gene expression in yeast, and this function could be conserved in metazoans.
Insights
The Greatwall (Gwl) kinase pathway regulates cell cycle progression by controlling protein phosphatase 2A (PP2A)-B55 activity. This pathway
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cell cycle progression relies on reversible protein phosphorylation by kinases and phosphatases.
- Cyclin B-Cdk1 activation initiates mitosis, with its enzymatic network well-understood.
- Protein phosphatase 2A (PP2A) with its B55 subunit is a key phosphatase for Cdk1 targets, but its activity varies across the cell cycle.
Purpose of the Study:
- To elucidate the molecular mechanisms regulating PP2A-B55 activity during the cell cycle.
- To investigate the role of the Greatwall (Gwl) kinase and endosulfines in controlling PP2A-B55.
- To understand the spatiotemporal regulation of the Gwl-endosulfine-PP2A axis.
Main Methods:
- Studies were conducted in model systems including fly and frog.
- Investigated the activation of endosulfines by Gwl kinase.
- Analyzed the Cdk1-dependent regulation of Gwl and its impact on PP2A-B55 activity.
Main Results:
- Gwl kinase activates endosulfines, which inhibit PP2A-B55.
- Cdk1-dependent Gwl activation at mitotic entry reduces PP2A-B55 activity.
- This downregulation of PP2A-B55 complements Cdk1 activation to promote mitotic substrate phosphorylation.
Conclusions:
- The Gwl-endosulfine-PP2A axis is crucial for cell cycle progression, particularly mitotic entry.
- Spatiotemporal regulation of this pathway is vital, with variations across cell types and organisms.
- The pathway's role in gene expression suggests conserved functions beyond cell cycle control.
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