Letter abstract
Nature Cell Biology 5, 545 - 551 (2003)
Published online: 27 May 2003 | doi:10.1038/ncb994
Dual phosphorylation controls Cdc25 phosphatases and mitotic entry
Dmitry V. Bulavin1, Yuichiro Higashimoto2, Zoya N. Demidenko3, Sarah Meek4,5, Paul Graves4,6, Crissy Phillips1, Hui Zhao4, Sally A. Moody3, Ettore Appella2, Helen Piwnica-Worms4,5 & Albert J. Fornace, Jr1
Negative regulation of the Cdc25C protein phosphatase by phosphorylation on Ser 216, the 14-3-3-binding site, is an important regulatory mechanism used by cells to block mitotic entry under normal conditions and after DNA damage. During mitosis, Cdc25C is not phosphorylated on Ser 216 and ionizing radiation (IR) does not induce either phosphorylation of Ser 216, or binding to 14-3-3. Here, we show that Cdc25C is phosphorylated on Ser 214 during mitosis, which in turn prevents phosphorylation of Ser 216. Mutation of Ser 214 to Ala reconstitutes Ser 216 phosphorylation and 14-3-3 binding during mitosis. Introduction of exogenous Cdc25CS214A into HeLa cells depleted of endogenous Cdc25C results in a substantial delay to mitotic entry. This effect was fully reversed in a S214A/S216A double-mutant, implying that the inhibitory effect of S214A mutant was entirely dependent on Ser 216 phosphorylation. A similar regulatory mechanism may also apply to another mitotic phosphatase, Cdc25B, as well as mitotic phosphatases of other species, including Xenopus laevis. We propose that this pathway ensures that Cdc2 remains active once mitosis is initiated and is a key control mechanism for maintaining the proper order of cell-cycle transitions.
- Gene Response Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
- Department of Anatomy and Cell Biology, The George Washington University Medical Center, Washington, DC 20037, USA.
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
- Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
- Current address, Department of Pharmacology and Cancer Biology, Duke University Medical School C115 LSRC, Research Drive, Box 3818 Durham, NC 27710.
Correspondence to: Dmitry V. Bulavin1 e-mail: bulavin@nih.gov
Correspondence to: Albert J. Fornace, Jr1 e-mail: fornace@nih.gov
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