Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216.
Human Cdc25C is a dual-specificity protein phosphatase that controls entry into mitosis by dephosphorylating the protein kinase Cdc2. Throughout interphase, but not in mitosis, Cdc25C was phosphorylated on serine-216 and bound to members of the highly conserved and ubiquitously expressed family of 14-3-3 proteins. A mutation preventing phosphorylation of serine-216 abrogated 14-3-3 binding. Conditional overexpression of this mutant perturbed mitotic timing and allowed cells to escape the G2 checkpoint arrest induced by either unreplicated DNA or radiation-induced damage. Chk1, a fission yeast kinase involved in the DNA damage checkpoint response, phosphorylated Cdc25C in vitro on serine-216. These results indicate that serine-216 phosphorylation and 14-3-3 binding negatively regulate Cdc25C and identify Cdc25C as a potential target of checkpoint control in human cells.
Peng
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Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Graves
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Thoma
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Wu
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Shaw
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Piwnica-Worms
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D048948:14-3-3 Proteins; D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000378:metabolism*; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004261:DNA Replication; D016195:G2 Phase; D005720:Gamma Rays; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008938:Mitosis; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016196:S Phase; D014446:Tyrosine 3-Monooxygenase; D020687:cdc25 Phosphatases
D048948:14-3-3 Proteins; D018797:Cell Cycle Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D010768:Phosphoserine; D014446:Tyrosine 3-Monooxygenase; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C517009:CDC25C protein, human; D020687:cdc25 Phosphatases