Casein Kinase 1δ-dependent Wee1 Protein Degradation

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 delta-dependent Wee1 degradation. Small-molecule CK1 delta inhibitors specifically disrupted Wee1 destruction and arrested HeLa cell proliferation. Pharmacological inhibition, siRNA knockdown, or conditional deletion of CK1 delta also reduced Wee1 turnover. Thus, these studies define a previously unappreciated role for CK1 delta in controlling the cell cycle.