title: CK1δ kinase activity is modulated by Chk1-mediated phosphorylation.
abstract: CK1δ, 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 CK1δ. Cellular kinases phosphorylating CK1δ within its C-terminal domain have been identified but still more information regarding the role of site-specific phosphorylation in modulating the activity of CK1δ is required. Here we show that Chk1 phosphorylates rat CK1δ at serine residues 328, 331, 370, and threonine residue 397 as well as the human CK1δ transcription variants 1 and 2. CK1δ mutant proteins bearing one, two or three mutations at these identified phosphorylation sites exhibited significant differences in their kinetic properties compared to wild-type CK1δ. Additionally, CK1δ co-precipitates with Chk1 from HT1080 cell extracts and activation of cellular Chk1 resulted in a significant decrease in cellular CK1δ kinase activity. Taken together, these data point towards a possible regulatory relationship between Chk1 and CK1δ.
authors.affiliation: Department of General and Visceral Surgery, Ulm University Hospital, Ulm, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Bischof
authors.forename: Sven-Jannis
authors.initials: SJ
authors.lastname: Randoll
authors.forename: Nadine
authors.initials: N
authors.lastname: Süßner
authors.forename: Doris
authors.initials: D
authors.lastname: Henne-Bruns
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Pinna
authors.forename: Uwe
authors.initials: U
authors.lastname: Knippschild
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D048148:Casein Kinase Idelta / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013912:Threonine / Q000235:genetics / Q000378:metabolism
chemical_list: D011993:Recombinant Fusion Proteins; D013912:Threonine; D012694:Serine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D048148:Casein Kinase Idelta; D000071877:Checkpoint Kinase 1; C000605871:Chek1 protein, rat