Casein Kinase 1δ-dependent Wee1 Protein Degradation (original) (raw)

Background: Wee1 is an essential gene in mammals that encodes the cell cycle and cancer associated protein Wee1 kinase. Results: Inhibition of CK1␦ kinase increases the levels of Wee1 protein kinase. Conclusion: Casein kinase 1␦ is required for Wee1 degradation in HeLa cells and mouse embryonic fibroblasts. Significance: This is a previously unappreciated role for CK1␦ in controlling Wee1 degradation and cell cycle progression. Eukaryotic mitotic entry is controlled by Cdk1, which is activated by the Cdc25 phosphatase and inhibited by Wee1 tyrosine kinase, a target of the ubiquitin proteasome pathway. Here we use a reporter of Wee1 degradation, K328M-Wee1-luciferase, to screen a kinase-directed chemical library. Hit profiling identified CK1␦-dependent Wee1 degradation. Small-molecule CK1␦ inhibitors specifically disrupted Wee1 destruction and arrested HeLa cell proliferation. Pharmacological inhibition, siRNA knockdown, or conditional deletion of CK1␦ also reduced Wee1 turnover. Thus, these studies define a previously unappreciated role for CK1␦ in controlling the cell cycle.