Human Cdc14a Becomes a Cell Cycle Gene in Controlling Cdk1 Activity at the G2/M Transition

Human Cdc14A becomes a cell cycle gene in controlling Cdk1 activity at the G2/M transition

María P. Sacristán,* Sara Ovejero and Avelino Bueno Centro de Investigación del Cáncer; Departamento de Microbiología y Genética; Universidad de Salamanca/CSIC; Salamanca, Spain

dc14 belongs to a dual-specificity mitotic entry and progression through Cphosphatase family highly con- the early events of mitosis until all chro- served through evolution that preferen- mosomes have aligned at the metaphase tially reverses CDK (Cyclin dependent plate. Following this, entry into anaphase kinases)-dependent phosphorylation and progression through late mitotic events. In the yeast Saccharomyces cere- stages requires the inactivation of Cdk1 visiae, Cdc14 is an essential regulator of and the dephosphorylation of most of its late mitotic stages and exit from mitosis substrates.1,2 Cdk1-Cyclin B1 complexes by counteracting CDK activity at the end activity is, therefore, strictly controlled. of mitosis. However, many studies have The activation of Cdk1-Cyclin B1 at the shown that Cdc14 is dispensable for exit- entry into mitosis depends on both phos- ©2011 Landes Bioscience. Landes ©2011 ing mitosis in all other model systems phorylation and dephosphorylation pro- analyzed. In fission yeast, the Cdc14 cesses. Thus, for full activity Cdk1 needs Do not distribute. not homologDo Flp1/Clp1 regulates the stabil- to be phosphorylated by Cdk-activating ity of the mitotic inducer Cdc25 at the kinase on its T loop.3 In addition, inhibi- end of mitosis to ensure Cdk1 inactiva- tory phosphorylations at the ATP-binding tion before cytokinesis. We have recently site (T14 and Y15) carried out by Wee1 4 reported that human Cdc14A, the Cdc14 and Myt1 kinases at G2 have to be elimi-

isoform located at the centrosomes dur- nated. This occurs at the G2/M transition, ing interphase, downregulates Cdc25 when the activity of Cdc25 phosphatases,

activity at the G2/M transition to prevent Cdc25A, Cdc25B and Cdc25C, exceeds premature activation of Cdk1-Cyclin B1 that of the opposing kinases Wee1 and complexes and untimely entry into mito- Myt1.4 Active Cdk1-Cyclin B1 complexes sis. Here we speculate about new molecu- then stimulate their own activation by lar mechanisms for Cdc14A and discuss directly activating Cdc25 phosphatases the current evidence suggesting that and inhibiting Wee1 and Myt1 kinases. Cdc14 phosphatase plays a role in cell Moreover, a remarkably complex network cycle control in higher eukaryotes. of different kinases and phosphatases Key words: cell cycle, mitosis, phospha- also controls these positive and negative tases, CDK, Cdc25, Cdc14 Many cellular processes in eukaryotes Cdk1 regulators. The result is the timely Abbreviations: APC, anaphase promot- are controlled by reversible protein phos- and spatially accurate activation of the ing complex; CDK, cyclin dependent phorylation. This post-translational Cdk1-Cyclin B1 complexes, responsible kinases; FEAR, cdc fourteen early ana- modification is controlled by kinase and for the entry into mitosis and progression phase release network; MEN, mitotic exit phosphatase activities. Cell cycle progres- through the early mitotic stages.5-8 In con- network; rDNA, ribosomal DNA sion is one such process, in which multiple trast, Cdk1 has to be inactivated at the Submitted: 12/21/10 independent regulatory steps, controlled metaphase-anaphase transition to allow by the action of kinases and phosphatases progression through late mitotic phases. Accepted: 12/25/10 on key substrates, are involved. Among Moreover, the ordered dephosphoryla- DOI: 10.4161/cc.10.3.14643 the kinases, the cyclin-dependent protein tion of Cdk1-Cyclin B1 substrates and *Correspondence to: María P. Sacristán; kinase 1 (Cdk1) associated with B type APC (Anaphase Promoting Complex)- Email: [email protected] cyclins plays a crucial role, since it drives mediated proteolysis of mitotic regulators

www.landesbioscience.com Cell Cycle 387 govern the final mitotic stages and allow the mitotic spindle, the spindle pole bod- Moreover, the results of a recent study exit from mitosis.2 In the budding yeast ies and the medial ring.25,26 During early using cell lines in which Cdc14A or Saccharomyces cerevisiae, many key mitotic mitosis, Flp1/Clp1 is inhibited by Cdk1 Cdc14B genes were deleted by gene tar- substrates of Cdk1 are dephosphorylated phosphorylation until the end of mitosis, geting suggest that both phosphatases by Cdc14, a dual-specificity phosphatase when it becomes activated by self-cata- are required for efficient DNA repair.46 that constitutes an essential regulator of lyzed dephosphorylation.27 Flp1/ Clp1 is Surprisingly, however, these knockout late mitosis in this organism. Extensive not required for mitotic exit, but it does cells did not display any other phenotype genetic and biochemical studies have con- contribute to Cdk1 inhibition in late corresponding to the above mentioned tributed to characterizing its numerous mitosis by dephosphorylation, and hence Cdc14 functions, which were elucidated roles at the end of mitosis as well as its degradation of the Cdk1 activating pro- by RNA interference (RNAi)-mediated strict regulation in both space and time.9-11 tein Cdc25. Consequently, Flp1/Clp1 silencing experiments.46 Different reasons Cdc14 remains sequestered in the nucleo- coordinates cytokinesis with cell cycle could explain these discrepancies, among 28-30 lus from G1 until metaphase. In anaphase, progression. Additional functions of others the total versus partial depletion Cdc14 is released by the consecutive action Flp1/Clp1 are its contribution to chromo- of the protein, the functional redundancy of two regulatory cascades—the Cdc some segregation, the regulation of spindle between Cdc14 isoforms or with other Fourteen Early Anaphase Release (FEAR) midzone functions, and full activation of phosphatases, the genetic background of network and the Mitotic Exit Network the checkpoint response to replicative the cell type used, as well as the phase of (MEN),9—to reach a number of nuclear stress.31-33 the cell cycle when the protein depletion and cytoplasmic substrates. In this organ- The mammal genomes encode two comes into effect. New studies are needed ism, Cdc14 triggers Cdk1 inactivation at Cdc14 isoforms, Cdc14A and Cdc14B, to shed light on the probably numer- the end of mitosis through the dephos- and in hominids, a third isoform, ous roles of Cdc14 in higher eukaryotes. phorylation of both the Cdk1 inhibitor Cdc14Bretro/Cdc14C, which is very Furthermore, several targets of Cdc14A Sic1 and its transcription factor Swi5, similar to Cdc14B, is originated from a and/or Cdc14B, some of them validated resulting in Sic1 accumulation and activa- retrogene.34 Given the important roles both in vivo and in vitro, have also been tion, and also through dephosphorylation of Cdc14 phosphatase in yeast, human identified, suggesting their potential con- of the APC activator Cdh1, responsible for Cdc14 homologs have been addressed in tribution to a number of different molecu- ©2011 Landes Bioscience. mitotic cyclin degradation.Landes 12 Moreover,©2011 many functional studies aimed at shed- lar functions.47-53 In view of this extensive multiple events during anaphase such as ding light on their molecular functions. number of findings, sometimes even con- the localization of chromosomaldistribute. passengernot HumanDo Cdc14A complements the lack troversial (reviewed in ref. 54), human proteins to the spindle midzone, the regu- of Cdc14 in S. cerevisiae.35 Moreover, Cdc14 phosphatases could be involved in lation of spindle dynamics, the inhibition both human Cdc14A and Cdc14B iso- many cellular processes; some specific to of ribosomal DNA (rDNA) transcription forms are able, although through different Cdc14A or Cdc14B isoforms, and other and the contribution to the accurate segre- molecular mechanisms, to rescue Flp1/ ones to both of them. The different local- gation of rDNA and telomeric regions,13-23 Clp1-deficient fission yeast cells,36 indicat- ization of each isoform, centrosomal ver- as well as cytokinesis,24 are also regulated ing that some functional homology exits sus nucleolar/nuclear, suggests that they by Cdc14. All these functions make this among human and yeast Cdc14 proteins. likely have different functions in the cell. phosphatase essential for regulation of late Human Cdc14A, which is preferen- However, at the time of mitosis both of mitotic events and the exit from mitosis in tially centrosomal in interphase, has been them leave their corresponding subcellular budding yeast. implicated in the regulation of centrosome localization and diffuse throughout the Cdc14 is highly conserved through replication, and consequently in chromo- cell, gaining the opportunity to reach the evolution and Cdc14 homologs have been some segregation and cytokinesis.37,38 same substrates, and to share some com- identified in a wide range of organisms Human Cdc14B, whose localization is mon functions, unless this possibility is ranging from yeast to mammals. However, mainly nucleolar during interphase, has limited by specific regulatory mechanisms the control of mitotic exit by Cdc14 seems been implicated in several specific func- for each isoform. to be exclusive to budding yeast. In the tions, including mitotic exit,39 nuclear We have recently demonstrated that fission yeastSchizosaccharomyces pombe, organization,40 mitotic-spindle assembly,41 human Cdc14A modulates the timing the Cdc14 homolog Flp1/Clp1 is a non- centriole duplication,42 regulation of the of mitosis by inhibiting Cdk1-Cyclin 43 55 essential protein. However, cells lacking G1 phase length, and also in the G2 DNA B1 activity at the G2/M transition. flp1/clp1 gene are advanced in mitosis and damage checkpoint efficiency.44 Moreover, Consistent with this cell cycle regula- divide at reduced size as a consequence of certain other functions have been sug- tory role, we found that cells depleted a cell cycle defect.25,26 As in S. cerevisiae, gested for both Cdc14A and Cdc14B for Cdc14A accelerate their entry into Flp1/Clp1 localizes predominantly to the isoforms. Thus, the two human Cdc14 mitosis. Based on the hypothesis that nucleolus during interphase, but it also phosphatases are able to regulate PR-Set7 human Cdc14 homologs might down- resides at the spindle pole body. As cells histone methyltransferase degradation regulate Cdc25 phosphatases, as their enter mitosis, Flp1/Clp1 is released from at the end of mitosis, which seems to be fission yeast counterpart does,28,29 we the nucleolus and localizes to the nucleus, necessary for proper mitotic progression.45 found that Cdc14A interacts with and

388 Cell Cycle Volume 10 Issue 3 dephosphorylates Cdc25B, inhibiting its activity. Moreover, Cdc14A also exerts an inhibitory effect on the catalytic activity of Cdc25A, even though this appears to be an indirect effect exerted by a still unknown protein55 (Fig. 1). All Cdc25 isoforms appear hyperphosphorylated at the onset of mitosis (reviewed in ref. 56). The phosphorylation of Cdc25B by several kinases, including Cdk1-Cyclin B1, results in hyperactivation of its phosphatase activity. Cdc14A reverses Cdk1-Cyclin B1-dependent Cdc25B modification, preventing its full activation. In the case of Cdc25A, its phosphorylation is associated with the stabilization of this mitotic inducer by preventing its recognition by the ubiquitination machinery.57 However the deregulation of Cdc14A affects the

activity of Cdc25A at the G2/M transition, suggesting a new mechanism of Cdc25A regulation based on changes in its catalytic activity indirectly modulated by Cdc14A. Our work adds one more piece to the complex network that regulates ©2011 Landes Bioscience. Cdk1 ‑Cyclin B1 activityLandes at the time©2011 of entry into mitosis.8 It has been reported previously that human distribute. Cdc14A, butnot not Do Figure 1. Working hypothesis of human Cdc14A phosphatase inhibiting Cdk1 activity at the G2/M Cdc14B, is able to regulate S. pombe Cdk1 transition. Cdc14A is preferentially localized to the centrosome during interphase (1), and at the activity through the dephosphorylation onset of mitosis it is released from the centrosome and diffuses throughtout the cell (2). Cdc14A and downregulation of SpCdc25 pro- reverses Cdk1-dependent Cdc25B phosphorylation and inhibits its catalytic activity. Moreover, Cdc14A also inhibits Cdc25A activity through an unknown mechanism. Consequently, Cdc14A tein in cells lacking the flp1/clp1+ gene.36 interferes with the full activation of Cdk1-Cyclin B1 complexes at the G2/M transition. We speculate Moreover, Xenopus Cdc14A can also that Cdc14A could also inhibit Cdk1-Cyclin B1 complexes activity through the Cdk1 inhibitory dephosphorylate Cdc25, which might be kinases Wee1 and/or Myt1. Moreover, a Cdk1-dependent inhibitory effect on Cdc14A could then allow full activation of Cdk1-Cyclin B1 complexes to enter into mitosis. its target in preventing the G2/M transition in this organism.58 These data suggest that regulation of the Cdc25s cell The finding of Cdc25 regulation by the regulation of Cdc25A and Cdc25B

cycle phosphatases by Cdc14 could be an Cdc14A at the G2/M transition raises could be performed by the pool of Cdc14A

evolutionary conserved mechanism, and important questions about the mecha- released from the centrosome at the G2/M that the role of Cdc14 in CDK inhibition nisms regulating human Cdc14 phospha- transition. The two possibilities are not also exists in higher eukaryotes, although tases, which in turn may provide novel mutually exclusive. to control different cell cycle transitions. insights for understanding their physiolog- An even more interesting issue is Supporting the latter notion, the C. ele- ical functions in mammals. An interesting whether Cdc14A could act on additional gans Cdc14 ortholog has been shown to issue is whether or not Cdc14A already targets to regulate Cdk1 activity. The participate in the maintenance of the G1 controls Cdk1 activity on centrosomes, direct inhibitors of Cdk1, Wee1 and Myt1 cell cycle arrest of specific precursor cells where Cdc14A and Cdc25B co-localize kinases are potential candidates. At the by promoting the stabilization of the and where Cdc25B initiates the activation entry into mitosis, Wee1 and Myt1 are Cdk inhibitor CKI1.59 Moreover, human of Cdk1-Cyclin B1 complexes.61-63 Upon directly regulated by Cdk1. Thus, the Cdc14A can efficiently dephoshorylate analyzing Cdc25B in purified centro- phosphorylation of Wee1 and Myt1 by Cdh1 and activate APC in vitro48 and in somal extracts, we found that it is dephos- Cdk1-Cyclin B1 complexes promotes the vivo to regulate the ordered degradation phorylated in cells overexpressing Cdc14A degradation of Wee1 and the inhibition of mitotic regulators at the end of mito- (our own unpublished result), suggesting of Myt1 kinase activity, thereby further sis.60 All this evidence supports a role for that Cdc14A is already acting at the cen- amplifying Cdk1 activation.64,65 Cdc14A Cdc14 in cell cycle control in multicellular trosome to prevent the initial activation of could prevent the full activation of Cdk1

organisms. Cdk1. However, another possibility is that at the G2/M transition by also reversing

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