Abstract
Budding and fission yeast Cdc14 homologues, a conserved family of serine-threonine phosphatases, play a role in the inactivation of mitotic cyclin-dependent kinases (CDKs) by molecularly distinct mechanisms. Saccharomyces cerevisiae Cdc14 protein phosphatase inactivates CDKs by promoting mitotic cyclin degradation and the accumulation of a CDK inhibitor to allow budding yeast cells to exit from mitosis. Schizosaccharomyces pombe Flp1 phosphatase down-regulates CDK/cyclin activity, controlling the degradation of the Cdc25 tyrosine phosphatase for fission yeast cells to undergo cytokinesis. In the present work, we show that human Cdc14 homologues (hCdc14A and hCdc14B) rescued flp1-deficient fission yeast strains, indicating functional homology. We also show that hCdc14A and B interacted in vivo with S. pombe Cdc25 and that hCdc14A dephosphorylated this mitotic inducer both in vitro and in vivo. Our results support a Cdc14 conserved inhibitory mechanism acting on S. pombe Cdc25 protein and suggest that human cells may regulate Cdc25 in a similar manner to inactivate Cdk1-mitotic cyclin complexes.
Highlights
Entry into mitosis is regulated by the activation of cyclin-dependent kinases (CDKs)1; in contrast, mitotic exit depends on the inhibition of CDK activity and a reversal of CDK phosphorylation events [1, 2]
The Cdc14 family of phosphatases is conserved in most if not all eukaryotes and is considered a major player in controlling the mitotic exit and cytokinesis antagonizing the action of mitotic CDKs [4, 5, 16, 17, 22, 23, 36, 37]
The molecular mechanisms by which Cdc14 regulates CDK inactivation at the end of mitosis are best understood in S. cerevisiae, in which additional roles of Cdc14 during late mitotic stages have been found (6 –9)
Summary
Entry into mitosis is regulated by the activation of cyclin-dependent kinases (CDKs); in contrast, mitotic exit depends on the inhibition of CDK activity and a reversal of CDK phosphorylation events [1, 2]. In the budding yeast Saccharomyces cerevisiae, the phosphatase Cdc is essential for antagonizing this mitotic CDK activity, allowing cells to exit from mitosis and to coordinate cytokinesis events [3, 4]. Flp does not dephosphorylate the Rum and Ste9/Srw proteins, homologues of Sic and Hct of S. cerevisiae, respectively Instead, it antagonizes mitotic CDK activity by promoting the phosphorylation of the conserved tyrosine residue Tyr in Cdc, in part by downregulating the Cdc phosphatase, which dephosphorylates Tyr15 [16, 17]. Once Cdc has been dephosphorylated by Flp, it rapidly becomes unstable as S. pombe cells exit from mitosis This Flp1-driven indirect down-regulation of CDK activity is required for cytokinesis to proceed in a timely fashion [16]. We propose that hCdc14A would act like the S. pombe homologue Flp by dephosphorylating the mitotic inducer Cdc
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