Abstract
The kinase Wee1 has been recognized for a quarter century as a key inhibitor of Cyclin dependent kinase 1 (Cdk1) and mitotic entry in eukaryotes. Nonetheless, Wee1 regulation is not well understood and its large amino-terminal regulatory domain (NRD) has remained largely uncharted. Evidence has accumulated that cyclin B/Cdk1 complexes reciprocally inhibit Wee1 activity through NRD phosphorylation. Recent studies have identified the first functional NRD elements and suggested that vertebrate cyclin A/Cdk2 complexes also phosphorylate the NRD. A short NRD peptide, termed the Wee box, augments the activity of the Wee1 kinase domain. Cdk1/2-mediated phosphorylation of the Wee box (on T239) antagonizes kinase activity. A nearby region harbors a conserved RxL motif (RxL1) that promotes cyclin A/Cdk2 binding and T239 phosphorylation. Mutation of either T239 or RxL1 bolsters the ability of Wee1 to block mitotic entry, consistent with negative regulation of Wee1 through these sites. The region in human somatic Wee1 that encompasses RxL1 also binds Crm1, directing Wee1 export from the nucleus. These studies have illuminated important aspects of Wee1 regulation and defined a specific molecular pathway through which cyclin A/Cdk2 complexes foster mitotic entry. The complexity, speed, and importance of regulation of mitotic entry suggest that there is more to be learned.
Highlights
Wee1 is a Cyclin dependent kinase 1 (Cdk1) kinase Mitotic entry is the paradigmatic cell cycle transition and example of Cdk regulation
Wee1 is regulated at multiple levels, including transcription [4], translation [5], and protein stability [6,7,8,9,10], but we focus here on recent progress made in understanding the effects of Cdk1/2 phosphorylation on Wee1 activity and localization
Transient transfection of RxL1 and T239A mutants was each associated with an increased fraction of cells in G2 phase. These observations suggest that cyclin A/Cdk2 complexes inhibit Wee1 activity via binding to RxL1 and phosphorylation of T239 and define a molecular pathway through which cyclin A/ Cdk2 complexes drive mitotic entry. Consistent with these in vivo data, studies in human somatic cell extracts showed that recombinant cyclin A can direct the phosphorylation and inactivation of Wee1 more efficiently than cyclin B, and combined addition of cyclins A and B induced nuclear envelope breakdown more efficiently than addition of either cyclin alone [26]
Summary
Wee is a Cdk kinase Mitotic entry is the paradigmatic cell cycle transition and example of Cdk regulation. These observations suggest that cyclin A/Cdk complexes inhibit Wee activity via binding to RxL1 and phosphorylation of T239 and define a molecular pathway through which cyclin A/ Cdk complexes drive mitotic entry Consistent with these in vivo data, studies in human somatic cell extracts showed that recombinant cyclin A can direct the phosphorylation and inactivation of Wee more efficiently than cyclin B, and combined addition of cyclins A and B induced nuclear envelope breakdown more efficiently than addition of either cyclin alone [26]. These results provide evidence for a bifunctional region encompassing RxL1 and the NES that mediates binding of cyclin A/Cdk complexes and Crm, respectively These interactions result in Wee box phosphorylation, inhibition of kinase activity, and nuclear export of somatic Wee (Fig 3)
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