Circumventing the Greatwall

Okumura et al. reveal how cyclin B–Cdk1 can activate itself at the start of M phase without the help of Greatwall kinase.

In order to push cells into M phase, cyclin B–Cdk1 must suppress the protein phosphatase PP2A-B55, which would otherwise oppose the cyclin-dependent kinase and prevent it from becoming fully active. Cyclin B–Cdk1 inhibits PP2A-B55 by activating a kinase called Greatwall. Greatwall, in turn, phosphorylates members of the Ensa/Arpp19 protein family, allowing them to bind and inhibit PP2A-B55. But some cell types, such as starfish oocytes, can fully activate cyclin B–Cdk1 and transition into M phase in the absence of Greatwall, suggesting that PP2A-B55 is inhibited by additional pathways.

Okumura et al. found that starfish oocytes lacking Greatwall still required Arpp19 for cyclin B–Cdk1 activation and meiotic M phase entry. Cyclin B–Cdk1 phosphorylated Arpp19 directly—on a different site to Greatwall—allowing it to partially inhibit PP2A-B55 even in Greatwall’s absence. This partial inhibition was sufficient for cyclin B–Cdk1 to become fully activated and for oocytes to transition into M phase. Phosphorylation by Greatwall further increased Arpp19’s ability to inhibit PP2A-B55, which could be important later in meiosis. Oocytes lacking Greatwall transitioned into M phase but failed to segregate their chromosomes, a defect rescued by injecting Arpp19 protein phosphorylated by Greatwall.

Senior author Takeo Kishimoto now wants to determine whether Greatwall kinase promotes M phase progression by phosphorylating additional substrates besides Arpp19.