The Greatwall–PP2A Axis in Cell Cycle Control

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.

The LIV-1-GRPEL1 axis adjusts cell fate during anti-mitotic agent-damaged mitosis

“…Despite a long history of research, the mechanism that regulates PP2A-B55 α activity during cell-cycle progression is still poorly understood. The only key regulator identified to date is Greatwall kinase (also known as MASTL) [44][45][46] . In the current study, GRPEL1 appears to constitute a novel mechanism for inhibiting PP2A-B55 α activity during damaged mitosis through direct protein-protein interactions.…”

The Chlamydomonas cell cycle

“…The results suggested that the model required revision to consider not just mitotic cyclin-Cdk levels, but the balance between Cdk and counteracting phosphatase (Cdc14 in budding yeast). Phosphatase PP2A-B55 may play a similar role in some animal systems (Wang et al, 2011). These phosphatases are regulated to be highly active only at the time of mitotic exit, providing an additional (but organism-specific) regulatory loop (not illustrated in Figure 1).…”

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…27,28 As such, the Greatwall-PP2A network has been proposed as a key signaling axis that promotes normal Cdk1-driven entry through mitosis. 29 PP2A also acts on other mitotic mediators, including the key mitosis-specific kinase, Polo-like kinase 1 (PLK1), which localizes to centrosomes during mitosis and when inactivated by PP2A is an important hallmark of G2/M arrest and activation of the DNA damage response. 30 PP2A also participates in a negative feedback loop, antagonizing Aurora B and Plk1 kinases, thus maintaining the spindle assembly checkpoint until microtubules are properly attached to chromosome kinetichores.…”