CK1ε targets Cdc25A for ubiquitin-mediated proteolysis under normal conditions and in response to checkpoint activation.
Cdc25A phosphatase, which is essential in cell cycle progression, is degraded by the proteasome throughout interphase and in response to genotoxic stress. Phosphorylation of Cdc25A on Ser82 in the DSG motif is important in the recognition by β-TrCP, resulting in targeting of Cdc25A for ubiquitination. Chk1 is known to phosphorylate Cdc25A on Ser76, and NEK11 or CK1α relays phosphorylation of Cdc25A to Ser82 in a hierarchical manner. In this study, we found that CK1ε has unique enzymatic activity on the serine residue in the DSG motif using a β-catenin N-terminal region as a substrate. We then examined whether CK1ε has activity on the DSG motif of Cdc25A. We found CK1ε directly phosphorylated Ser82 without any prior phosphorylation of Cdc25A, and depletion of CK1ε stabilized the cellular Cdc25A in 293 cells. Moreover, we found that CK1ε also has activity as a relaying kinase like NEK11 or CK1α when the cell is exposed to DNA damage. Taken together, our results indicate that CK1ε regulates the cellular levels of Cdc25A in parallel with Chk1-dependent Cdc25A degradation, contributing to the precise control of cell division.
College of Pharmacy and Research Institute for Drug Developmen, Pusan National University, Busan, Republic of Korea.
Shunfu
S
Piao
Su-Jin
SJ
Lee
Yongbin
Y
Xu
Jungsug
J
Gwak
Sangtaek
S
Oh
Bum-Joon
BJ
Park
Nam-Chul
NC
Ha
D020816:Amino Acid Motifs; D001665:Binding Sites; D048149:Casein Kinase 1 epsilon / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D006801:Humans; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011494:Protein Kinases / Q000502:physiology; D054875:Ubiquitination; D020687:cdc25 Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D011494:Protein Kinases; C000605867:CHEK1 protein, human; D048149:Casein Kinase 1 epsilon; D000071877:Checkpoint Kinase 1; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D046988:Proteasome Endopeptidase Complex