How a phosphatase knows where to be and what to control

One enzyme complex oversees several key steps in cell division; but where it ends up in the cell and what exact processes it controls are dictated by its regulatory subunit.
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Artistic impression of dividing cells. Image credit: Vallardi et al. (CC BY 4.0)

The cells in our body are a hive of activity, but that activity must be kept under control. This is never more critical than when a cell divides, because unchecked cell division can lead to cancer. Fortunately, enzymes called kinases and phosphatases exist to control the countless proteins in a cell; these enzymes help ensure that each step of cell division is complete before moving on to the next.

Kinases control other proteins by adding bulky phosphate groups to them, while phosphatases remove those groups. For a long time, phosphatases were assumed to be less specific than their kinase counterparts. Yet it has now become clear that phosphatases achieve specificity by interacting with a range of regulatory subunits.

A phosphatase called PP2A oversees a number of key steps in cell division by working together with its regulatory B56 subunit. In human cells, there are five separate genes that encode B56 subunits, and all of these B56 ‘isoforms’ were thought to exert the same influence on the PP2A phosphatase. The fact, however, that different isoforms are found at different locations within the cell suggested otherwise.

To investigate this, Vallardi et al. focused on a particular stage of cell division when the activity of the PP2A-B56 complex is essential. Before a cell divides it duplicates its genetic material and the two copies of each chromosome are held together until the cell is ready to pull them apart. The experiments compared two representative B56 isoforms: one that concentrates at the centromere, the region where the copied chromosomes are held together; and another found at the kinetochore, a nearby structure that is involved in pulling the two chromosomes apart. By eliminating all but one isoform and measuring the ensuing activity of the PP2A-B56 complex, Vallardi et al. could differentiate between the main regulatory roles of each isoform. These experiments showed that B56 isoforms control separate processes during cell division, which mirrors their different locations within the cell.

Next, Vallardi et al. looked at the receptor proteins that recruit each isoform to its position. Removing or relocating different receptors showed how they anchor select B56 isoforms in different positions while the associated PP2A enzymes get to work on different processes. Further experiments using ‘hybrid’ subunits made from parts of two different B56 isoforms then helped to reveal the site on the B56 subunits that determines which receptors they bind to. Together these findings show that slight differences between each B56 isoform ultimately dictate where they localise and what processes they control when cells divide.