Abstract
Cdc14 enzymes compose a family of highly conserved phosphatases that are present in a wide range of organisms, including yeast and humans, and that preferentially reverse the phosphorylation of Cyclin-Dependent Kinase (Cdk) substrates. The budding yeast Cdc14 orthologue has essential functions in the control of late mitosis and cytokinesis. In mammals, however, the two Cdc14 homologues, Cdc14A and Cdc14B, do not play a prominent role in controlling late mitotic events, suggesting that some Cdc14 functions are not conserved across species. Moreover, in yeast, Cdc14 is regulated by changes in its subcellular location and by phosphorylation events. In contrast, little is known about the regulation of human Cdc14 phosphatases. Here, we have studied how the human Cdc14A orthologue is regulated during the cell cycle. We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages. Interestingly, in vivo and in vitro experiments revealed that, unlike in yeast, Cdk1-mediated phosphorylation of human Cdc14A did not control its catalytic activity but likely modulated its interaction with other proteins in early mitosis. These findings point to differences in Cdk1-mediated mechanisms of regulation between human and yeast Cdc14 orthologues.
Highlights
Cdc[14] family members are dual-specificity phosphatases that preferentially reverse CyclinDependent Kinase (Cdk)-dependent phosphorylations[1]
Based on the banding pattern obtained by immunodetection, it has been suggested that human Cdc14A phosphatase could be a phosphoprotein[29]
We routinely noticed that electrophoretic mobility of the inactive form of Cdc14A, phosphatase dead or Cdc14A(PD), appeared slightly decreased when compared with the wild-type protein (Supplementary Figure S1), suggesting that Cdc14A is phosphorylated in the cell and that it is able to modify its own phosphorylation state
Summary
Cdc[14] family members are dual-specificity phosphatases that preferentially reverse Cdk-dependent phosphorylations[1]. The interphase nucleolar Flp[1] is released from the nucleolus early in mitosis to concentrate on the kinetochores and contractile ring and to disperse throughout the nucleus and cytoplasm[9,10,37] In this case, there is an additional mechanism to control its catalytic activity, it differs from the S. cerevisiae one. Cdc14A has been involved in late mitotic processes, such as chromosome segregation, and later on, cytokinesis[18,38,39] These observations suggest that Cdc14A phosphatase participates in the dynamic control of protein phosphorylation during mitosis, and that it should be subjected to strict spatiotemporal regulation. Cdk1-mediated Cdc14A phosphorylation in early mitosis may modulate its protein interaction pattern These results suggest a clear divergence between yeast and human Cdc[14] phosphatases, regarding to the mechanisms of their regulation through the cell cycle
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