Moving the Greatwall

Wang et al. reveal how a mitotic kinase moves in and out of the nucleus to promote cell cycle progression.

Cyclin B and the cyclin-dependent kinase Cdk1 push cells into mitosis by phosphorylating numerous substrates in the nucleus and cytoplasm. The Greatwall (Gwl) kinase aids mitotic entry by inhibiting the phosphatase PP2A-B55, which would otherwise dephosphorylate cyclin B–Cdk1’s targets. Cdk1 activates Gwl at the start of mitosis, but Wang et al. discovered that Gwl’s localization is also regulated to ensure cells enter mitosis on time.

Gwl localizes to the nucleus of interphase cells, but Wang et al. noticed that the kinase exits the nucleus a few minutes before the nuclear envelope breaks down in prophase. The researchers identified two nuclear localization signals in Gwl’s central domain. Cdk1 and the mitotic kinase Polo phosphorylated this region of Gwl to promote the protein’s exclusion from the nucleus. Polo phosphorylation prompted the scaffold protein 14-3-3ɛ to bind and retain Gwl in the cytoplasm, possibly by masking the protein’s nuclear localization signals.

Gwl mutants lacking the nuclear localization signals permanently resided in the cytoplasm. These mutants failed to rescue the mitotic defects of flies lacking Gwl, suggesting that Gwl needs to localize to the nucleus during interphase, perhaps so that it can be activated by cyclin B–Cdk1. However, Gwl mutants that remained in the nucleus throughout prophase also delayed mitosis, indicating that Gwl’s early exit from the nucleus is required for mitotic progression. Senior author Vincent Archambault now wants to investigate how Gwl’s activity and localization are reversed at the end of mitosis and to determine which Cdk1 substrates Gwl is required to protect.