Genomes and Genes
cdc2 protein kinase
Summary: Phosphoprotein with protein kinase activity that functions in the G2/M phase transition of the CELL CYCLE. It is the catalytic subunit of the MATURATION-PROMOTING FACTOR and complexes with both CYCLIN A and CYCLIN B in mammalian cells. The maximal activity of cyclin-dependent kinase 1 is achieved when it is fully dephosphorylated.
- Dehé P, Coulon S, Scaglione S, Shanahan P, Takedachi A, Wohlschlegel J, et al. Regulation of Mus81-Eme1 Holliday junction resolvase in response to DNA damage. Nat Struct Mol Biol. 2013;20:598-603 pubmed publisher..We propose that linking Mus81-Eme1 DNA damage-induced activation to cell-cycle progression ensures efficient resolution of Holliday junctions that escape dissolution by Rqh1-TopIII while preventing unnecessary DNA cleavages. ..
- Zeng X, Chen S, Huang H. Phosphorylation of EZH2 by CDK1 and CDK2: a possible regulatory mechanism of transmission of the H3K27me3 epigenetic mark through cell divisions. Cell Cycle. 2011;10:579-83 pubmed..Together, CDK phosphorylation of EZH2 at T350 may represent a key regulatory mechanism of EZH2 function that is essential for the maintenance of H3K27me3 marks through cell divisions. ..
- Mochida S, Maslen S, Skehel M, Hunt T. Greatwall phosphorylates an inhibitor of protein phosphatase 2A that is essential for mitosis. Science. 2010;330:1670-3 pubmed publisher..This converts Ensa into a potent and specific inhibitor of PP2A-B55?. This pathway represents a previously unknown element in the control of mitosis. ..
- Juanes M, Khoueiry R, Kupka T, Castro A, Mudrak I, Ogris E, et al. Budding yeast greatwall and endosulfines control activity and spatial regulation of PP2A(Cdc55) for timely mitotic progression. PLoS Genet. 2013;9:e1003575 pubmed publisher..However, this conserved module is adapted to account for differences in the regulation of mitotic entry in different organisms. ..
- Trunnell N, Poon A, Kim S, Ferrell J. Ultrasensitivity in the Regulation of Cdc25C by Cdk1. Mol Cell. 2011;41:263-74 pubmed publisher..The model shows how the continuously variable regulators of mitosis work collectively to generate a switch-like, hysteretic response. ..
- Yang Q, Ferrell J. The Cdk1-APC/C cell cycle oscillator circuit functions as a time-delayed, ultrasensitive switch. Nat Cell Biol. 2013;15:519-25 pubmed publisher..Principles uncovered here may also apply to other activator-repressor oscillators and help in designing robust synthetic clocks. ..
- Sacristán M, Ovejero S, Bueno A. Human Cdc14A becomes a cell cycle gene in controlling Cdk1 activity at the G?/M transition. Cell Cycle. 2011;10:387-91 pubmed..Here we speculate about new molecular mechanisms for Cdc14A and discuss the current evidence suggesting that Cdc14 phosphatase plays a role in cell cycle control in higher eukaryotes. ..
- Kaneko S, Li G, Son J, Xu C, Margueron R, Neubert T, et al. Phosphorylation of the PRC2 component Ezh2 is cell cycle-regulated and up-regulates its binding to ncRNA. Genes Dev. 2010;24:2615-20 pubmed publisher..A phospho-mimic at residue 345 increased HOTAIR ncRNA binding to Ezh2, while the phospho-mimic at residue 487 was ineffectual. An Ezh2 domain comprising T345 was found to be important for binding to HOTAIR and the 5' end of Xist. ..
- Glover D. The overlooked greatwall: a new perspective on mitotic control. Open Biol. 2012;2:120023 pubmed publisher..I discuss how these alternating states of preferential PP2A-B55 or Cdk1-CycB activity can have an impact upon the regulation of Polo kinase and its ability to bind different partner proteins as mitosis progresses. ..
- Johnson N, Li Y, Walton Z, Cheng K, Li D, Rodig S, et al. Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition. Nat Med. 2011;17:875-82 pubmed publisher..Because reduced Cdk1 activity impaired BRCA1 function and consequently, repair by homologous recombination, inhibition of Cdk1 represents a plausible strategy for expanding the utility of PARP inhibitors to BRCA-proficient cancers. ..
- Holt J, Lane S, Jennings P, Garcia Higuera I, Moreno S, Jones K. APC(FZR1) prevents nondisjunction in mouse oocytes by controlling meiotic spindle assembly timing. Mol Biol Cell. 2012;23:3970-81 pubmed publisher..This study implicates FZR1 as a major regulator of prometaphase whose activity helps to prevent chromosome nondisjunction...
- Wurzenberger C, Gerlich D. Phosphatases: providing safe passage through mitotic exit. Nat Rev Mol Cell Biol. 2011;12:469-82 pubmed publisher..By contrast, in animal cells, it is now emerging that mitotic exit relies on distinct regulatory networks, including the protein phosphatases PP1 and PP2A. ..
- Kang Q, Pomerening J. Punctuated cyclin synthesis drives early embryonic cell cycle oscillations. Mol Biol Cell. 2012;23:284-96 pubmed publisher..Taken together, the results of this study underscore that attenuating cyclin synthesis late in interphase improves both the efficiency and robustness of the CDK1-APC oscillator. ..
- Domingo Sananes M, Kapuy O, Hunt T, Novak B. Switches and latches: a biochemical tug-of-war between the kinases and phosphatases that control mitosis. Philos Trans R Soc Lond B Biol Sci. 2011;366:3584-94 pubmed publisher..The bistable character of the switch implies the existence of a CycB threshold for entry into mitosis. The end of G2 phase is determined by the point where CycB level crosses the CycB threshold for Cdk1 activation. ..
- McCusker D, Royou A, Velours C, Kellogg D. Cdk1-dependent control of membrane-trafficking dynamics. Mol Biol Cell. 2012;23:3336-47 pubmed publisher..Cdk1 thus modulates membrane-trafficking dynamics, which is likely to play an important role in coordinating cell surface growth with cell cycle progression. ..
- Hara M, Abe Y, Tanaka T, Yamamoto T, Okumura E, Kishimoto T. Greatwall kinase and cyclin B-Cdk1 are both critical constituents of M-phase-promoting factor. Nat Commun. 2012;3:1059 pubmed publisher..M-phase-promoting factor is thus a system consisting of one kinase (cyclin B-Cdk1) that directs mitotic entry and a second kinase (Greatwall kinase) that suppresses the protein phosphatase 2A-B55 which opposes cyclin B-Cdk1...
- Maia A, García Z, Kabeche L, Barisic M, Maffini S, Macedo Ribeiro S, et al. Cdk1 and Plk1 mediate a CLASP2 phospho-switch that stabilizes kinetochore-microtubule attachments. J Cell Biol. 2012;199:285-301 pubmed publisher..We propose that Cdk1 and Plk1 mediate a fine CLASP2 "phospho-switch" that temporally regulates KT-MT attachment stability. ..
- Kõivomägi M, Valk E, Venta R, Iofik A, Lepiku M, Morgan D, et al. Dynamics of Cdk1 substrate specificity during the cell cycle. Mol Cell. 2011;42:610-23 pubmed publisher..Finally, we identified several Cln2-, Clb3-, and Clb2-specific Cdk1 targets. We propose that robust timing and ordering of cell cycle events depend on gradual changes in the substrate specificity of Cdk1. ..
- Kruse T, Zhang G, Larsen M, Lischetti T, Streicher W, Kragh Nielsen T, et al. Direct binding between BubR1 and B56-PP2A phosphatase complexes regulate mitotic progression. J Cell Sci. 2013;126:1086-92 pubmed publisher..Our data suggest that BubR1 counteracts Aurora B kinase activity at improperly attached kinetochores by recruiting B56-PP2A phosphatase complexes. ..
- Laurell E, Beck K, Krupina K, Theerthagiri G, Bodenmiller B, Horvath P, et al. Phosphorylation of Nup98 by multiple kinases is crucial for NPC disassembly during mitotic entry. Cell. 2011;144:539-50 pubmed publisher..Together, our data provide evidence for a phosphorylation-dependent mechanism underlying disintegration of NPCs during prophase. Moreover, we identify mitotic phosphorylation of Nup98 as a rate-limiting step in mitotic NPC disassembly. ..
- Wei Y, Chen Y, Li L, Lang J, Yeh S, Shi B, et al. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells. Nat Cell Biol. 2011;13:87-94 pubmed publisher..These findings define a signalling link between CDK1 and EZH2 that may have an important role in diverse biological processes, including cancer-cell invasion and osteogenic differentiation of mesenchymal stem cells. ..
- Shindo N, Kumada K, Hirota T. Separase sensor reveals dual roles for separase coordinating cohesin cleavage and cdk1 inhibition. Dev Cell. 2012;23:112-23 pubmed publisher..Therefore, by consecutively acting as a protease and a cdk1 inhibitor, separase coordinates two key processes to achieve simultaneous and abrupt separation of sister chromatids. ..
- Hu C, Ozlu N, Coughlin M, Steen J, Mitchison T. Plk1 negatively regulates PRC1 to prevent premature midzone formation before cytokinesis. Mol Biol Cell. 2012;23:2702-11 pubmed publisher..We suggest that PRC1 is regulated by Plk1, rather than Cdk1 as previously proposed, because its activity must be spatiotemporally regulated both preanaphase and postanaphase, and Cdk1 activity is too binary for this purpose. ..
- Su K, Takaki T, Petronczki M. Targeting of the RhoGEF Ect2 to the equatorial membrane controls cleavage furrow formation during cytokinesis. Dev Cell. 2011;21:1104-15 pubmed publisher..We propose that targeting of Ect2 to the equatorial membrane represents a key step in the delivery of the cytokinetic signal to the cortex. ..
- Cundell M, Bastos R, Zhang T, Holder J, Gruneberg U, Novak B, et al. The BEG (PP2A-B55/ENSA/Greatwall) pathway ensures cytokinesis follows chromosome separation. Mol Cell. 2013;52:393-405 pubmed publisher..Therefore, temporal order during mitotic exit is promoted by the metazoan BEG pathway. ..
- Potapova T, Sivakumar S, Flynn J, Li R, Gorbsky G. Mitotic progression becomes irreversible in prometaphase and collapses when Wee1 and Cdc25 are inhibited. Mol Biol Cell. 2011;22:1191-206 pubmed publisher..These findings suggest that the positive feedback in Cdk activation serves to overcome the activity of Cdk-opposing phosphatases and thus sustains forward progression in mitosis. ..
- Abe S, Nagasaka K, Hirayama Y, Kozuka Hata H, Oyama M, Aoyagi Y, et al. The initial phase of chromosome condensation requires Cdk1-mediated phosphorylation of the CAP-D3 subunit of condensin II. Genes Dev. 2011;25:863-74 pubmed publisher..These observations provide an explanation for how Cdk1 induces chromosome assembly in cells entering mitosis, and underscore the significance of the cooperative action of Plk1 with Cdk1. ..
- Lyons N, Morgan D. Cdk1-dependent destruction of Eco1 prevents cohesion establishment after S phase. Mol Cell. 2011;42:378-89 pubmed publisher..We also show that deregulation of Eco1 results in chromosome separation defects in anaphase. We conclude that this regulatory mechanism helps optimize the level of sister chromatid cohesion, ensuring a robust and efficient anaphase. ..
- Kishimoto T. A primer on meiotic resumption in starfish oocytes: the proposed signaling pathway triggered by maturation-inducing hormone. Mol Reprod Dev. 2011;78:704-7 pubmed publisher..Mitotic kinases including Aurora, Plk1 and Greatwall are activated downstream of cyclin B-Cdc2. The starfish oocyte thus provides a simple model system for the study of meiotic resumption...
- Liang H, Lim H, Venkitaraman A, Surana U. Cdk1 promotes kinetochore bi-orientation and regulates Cdc20 expression during recovery from spindle checkpoint arrest. EMBO J. 2012;31:403-16 pubmed publisher..Our findings provide fresh insights into the regulation of mitosis and have implications for the therapeutic efficacy of anti-mitotic drugs. ..
- Dreier M, Bekier M, Taylor W. Regulation of sororin by Cdk1-mediated phosphorylation. J Cell Sci. 2011;124:2976-87 pubmed publisher..This mitotic block is abolished by ZM447439, an Aurora kinase inhibitor, suggesting that prematurely separated sister chromatids activate the spindle assembly checkpoint through an Aurora kinase-dependent pathway. ..
- Farrell J, Shermoen A, Yuan K, O Farrell P. Embryonic onset of late replication requires Cdc25 down-regulation. Genes Dev. 2012;26:714-25 pubmed publisher..These findings suggest that high Cdc25 and Cdk1 contribute to the speed of the rapid, pre-MBT S phases and that down-regulation of these activities plays a broader role in MBT-associated changes than was previously suspected. ..
- Chow J, Poon R, Ma H. Inhibitory phosphorylation of cyclin-dependent kinase 1 as a compensatory mechanism for mitosis exit. Mol Cell Biol. 2011;31:1478-91 pubmed publisher..These findings indicate that, in the absence of sufficient APC/C activity, an alternative mechanism that utilized the classic inhibitory phosphorylation of CDK1 could mediate mitotic exit. ..
- Domínguez Kelly R, Martin Y, Koundrioukoff S, Tanenbaum M, Smits V, Medema R, et al. Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease. J Cell Biol. 2011;194:567-79 pubmed publisher..Importantly, Wee1 and Mus81 interact in vivo, suggesting direct regulation. Altogether, these results demonstrate a novel role of Wee1 in controlling Mus81 and DNA replication in human cells. ..
- Harvey S, Enciso G, Dephoure N, Gygi S, Gunawardena J, Kellogg D. A phosphatase threshold sets the level of Cdk1 activity in early mitosis in budding yeast. Mol Biol Cell. 2011;22:3595-608 pubmed publisher..These results define a new role for PP2A(Cdc55) and reveal a systems-level mechanism by which dynamically opposed kinase and phosphatase activities can modulate signal strength. ..
- Keck J, Jones M, Wong C, Binkley J, Chen D, Jaspersen S, et al. A cell cycle phosphoproteome of the yeast centrosome. Science. 2011;332:1557-61 pubmed publisher..Our work establishes the extent and complexity of this prominent posttranslational modification in centrosome biology and provides specific examples of phosphorylation control in centrosome function. ..
- Krasinska L, Domingo Sananes M, Kapuy O, Parisis N, Harker B, Moorhead G, et al. Protein phosphatase 2A controls the order and dynamics of cell-cycle transitions. Mol Cell. 2011;44:437-50 pubmed publisher..Therefore, by counteracting both Cdk1 activation and activity of mitotic kinases, PP2A ensures robust separation of S phase and mitosis and dynamic transitions between the two states...
- Manchado E, Guillamot M, de Carcer G, Eguren M, Trickey M, Garcia Higuera I, et al. Targeting mitotic exit leads to tumor regression in vivo: Modulation by Cdk1, Mastl, and the PP2A/B55?,? phosphatase. Cancer Cell. 2010;18:641-54 pubmed publisher..These data illustrate the relevance of critical players of mitotic exit in mammals and their implications in the balance between cell death and mitotic exit in tumor cells. ..
- Chen X, Niu H, Chung W, Zhu Z, Papusha A, Shim E, et al. Cell cycle regulation of DNA double-strand break end resection by Cdk1-dependent Dna2 phosphorylation. Nat Struct Mol Biol. 2011;18:1015-9 pubmed publisher..Poorly recruited dna2T4A S17A S237A and dna2?N248 mutant proteins promote resection only in the presence of Exo1, suggesting cross-talk between Dna2- and Exo1-dependent resection pathways. ..
- Santos S, Wollman R, Meyer T, Ferrell J. Spatial positive feedback at the onset of mitosis. Cell. 2012;149:1500-13 pubmed publisher..We propose that spatial positive feedback ensures a rapid, complete, robust, and irreversible transition from interphase to mitosis and suggest that bistable spatiotemporal switches may be widespread in biological regulation. ..
- Isoda M, Sako K, Suzuki K, Nishino K, Nakajo N, Ohe M, et al. Dynamic regulation of Emi2 by Emi2-bound Cdk1/Plk1/CK1 and PP2A-B56 in meiotic arrest of Xenopus eggs. Dev Cell. 2011;21:506-19 pubmed publisher..Thus, Emi2 stability and activity are dynamically regulated by Emi2-bound multiple kinases and PP2A phosphatase. Our data also suggest a general role for Cdk1 substrate phosphorylation motifs in M phase regulation. ..
- Morillo S, Abanto E, Román M, Frade J. Nerve growth factor-induced cell cycle reentry in newborn neurons is triggered by p38MAPK-dependent E2F4 phosphorylation. Mol Cell Biol. 2012;32:2722-37 pubmed publisher..These results indicate that NGF-induced cell cycle reentry in neurons depends on the activation of a novel, cdk4/6-independent pathway that may participate in neurodegeneration...
- Trovesi C, Falcettoni M, Lucchini G, Clerici M, Longhese M. Distinct Cdk1 requirements during single-strand annealing, noncrossover, and crossover recombination. PLoS Genet. 2011;7:e1002263 pubmed publisher..Thus, Cdk1 promotes DSB repair by single-strand annealing and noncrossover recombination by acting mostly at the resection level, whereas additional events require Cdk1-dependent regulation in order to generate crossover outcomes. ..
- Avunie Masala R, Movshovich N, Nissenkorn Y, Gerson Gurwitz A, Fridman V, Kõivomägi M, et al. Phospho-regulation of kinesin-5 during anaphase spindle elongation. J Cell Sci. 2011;124:873-8 pubmed publisher..In mid to late anaphase, phosphorylation of Cin8 causes its detachment from the spindles, which reduces the spindle elongation rate and aids in maintaining spindle morphology. ..
- Ohta M, Sato M, Yamamoto M. Spindle pole body components are reorganized during fission yeast meiosis. Mol Biol Cell. 2012;23:1799-811 pubmed publisher..Thus Plo1 and a centrin play central roles in the meiotic SPB remodeling, which is essential for generating the proper number of meiotic SPBs and, thereby provide unique characteristics to meiotic divisions. ..
- Davydenko O, Schultz R, Lampson M. Increased CDK1 activity determines the timing of kinetochore-microtubule attachments in meiosis I. J Cell Biol. 2013;202:221-9 pubmed publisher..These results indicate that the slow increase in CDK1 activity in meiosis I acts as a timing mechanism to allow stable K-MT attachments only after bipolar spindle formation, thus preventing attachment errors. ..
- Diani L, Colombelli C, Nachimuthu B, Donnianni R, Plevani P, Muzi Falconi M, et al. Saccharomyces CDK1 phosphorylates Rad53 kinase in metaphase, influencing cellular morphogenesis. J Biol Chem. 2009;284:32627-34 pubmed publisher..Moreover, the Ser-to-Asp mutation, mimicking a constitutive phosphorylation state at site 774, causes sensitivity to calcofluor, supporting a functional linkage between Rad53 and cellular morphogenesis. ..