Phosphatase regulation in cell division: With emphasis on PP2A-B56

Protein phosphatase 2A-B56 (PP2A-B56) is a key regulator of mitosis, playing an essential role in maintaining chromosomal stability and ensuring the fidelity of cell division. As a component of the PP2A holoenzyme, the B56 regulatory subunit confers substrate specificity, primarily through interactions with the conserved LxxIxE motif on target proteins. This review highlights the molecular mechanisms by which PP2A-B56 regulates key processes in cell division, including chromosome cohesion and condensation, kinetochore-microtubule attachment, spindle assembly checkpoint silencing, and activation of the anaphase-promoting complex/cyclosome. In meiosis, PP2A-B56 safeguards centromeric cohesion and facilitates the transition between divisions, with recruitment strategies that differ across species. Recent studies also emphasize its role in protecting oocyte quality and fertility by maintaining chromosomal stability. Furthermore, the competition among multiple LxxIxE-containing substrates for PP2A-B56 binding introduces an additional layer of temporal and spatial regulation. Finally, we discuss how perturbations in PP2A-B56 activity contribute to chromosomal instability and tumorigenesis. Understanding of PP2A-B56's substrate recognition and regulatory dynamics provides a framework for therapeutic targeting in disorders involving defective cell division.