CK1δ Kinase Activity Is Modulated by Chk1-Mediated Phosphorylation

CK1 delta, a member of the casein kinase 1 family, is involved in the regulation of various cellular processes and has been associated with the pathophysiology of neurodegenerative diseases and cancer. Therefore recently, interest in generating highly specific inhibitors for personalized therapy has increased enormously. However, the efficacy of newly developed inhibitors is affected by the phosphorylation state of CK1 delta. Cellular kinases phosphorylating CK1 delta within its C-terminal domain have been identified but still more information regarding the role of site-specific phosphorylation in modulating the activity of CK1 delta is required. Here we show that Chk1 phosphorylates rat CK1d at serine residues 328, 331, 370, and threonine residue 397 as well as the human CK1 delta transcription variants 1 and 2. CK1 delta mutant proteins bearing one, two or three mutations at these identified phosphorylation sites exhibited significant differences in their kinetic properties compared to wild-type CK1 delta. Additionally, CK1 delta co-precipitates with Chk1 from HT1080 cell extracts and activation of cellular Chk1 resulted in a significant decrease in cellular CK1 delta kinase activity. Taken together, these data point towards a possible regulatory relationship between Chk1 and CK1 delta.