Functional Relevance of PP2A-B55 Phosphatases in the Mammalian Cell Cycle

Resumo

Reversible protein phosphorylation is an essential mechanism of cell cycle regulation. Whereas the role of mitotic kinases has been deeply characterized, the identity and specific functions of mitotic phosphatases in mammalian cells has not been fully resolved yet. Protein phosphatase 2A (PP2A) is a major serine/threonine phosphatase in eukaryotic cells and there is evidence that PP2A complexes containing the B55 family of regulatory subunits play a key role in dephosphorylating CDK substrates during mitosis in different organisms. This fact makes these phosphatase complexes might be important for mitosis in mammals. To address the functional relevance of those PP2A-B55 complexes in mammalian cell cycle, we have generated loss-of-function mouse models for Ppp2r2a (B55α) and Ppp2r2d (B55δ), which encode the ubiquitous and cell cycle-related isoforms out of the four existing ones in mammals (B55α, β, γ, δ). Using these models we have found that B55α, but not B55δ, is required during late embryonic development and therefore essential for mouse survival. Moreover, at the cellular level, both isoforms have specific and overlapping roles in cell cycle regulation. PP2A-B55-null cells display defects in timing and chromosome segregation during mitosis resulting in impaired proliferation. Interestingly, analysis of cell cycle progression in B55-null cells has also revealed a new role for PP2A/B55 complexes in chromosome clustering during mitosis, which is mediated through the perichromosomal protein Ki-67. Treatment of B55 deficient cells with microtubule depolymerizing drugs leads to massive chromosome scattering in mitosis, excessive Ki67 accumulation and eventually mitotic cell death. These data highlight the importance of these phosphatase complexes in regulating mammalian mitosis and the response to microtubule poisons, a common chemotherapeutic reagent used for cancer treatment