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Published in final edited form as: Curr Opin Cell Biol. 2004 Apr;16(2):182–188. doi: 10.1016/j.ceb.2004.02.002

Mechanics and regulation of cytokinesis

Douglas N Robinson 1, James A Spudich 2
PMCID: PMC7336204  NIHMSID: NIHMS46274  PMID: 15196562

Abstract

Recent advances are revealing quantitative aspects of cytokinesis. Further, genetic analyses and cell imaging are providing insights into the molecular dynamics of cleavage furrow ingression as well as further refining our knowledge of the zones of the mitotic spindle that regulate the contractile properties of the overlying cortex. Ultimately, however, cortical mechanics are the result of signals that emanate from the mitotic spindle. A genuine quantitative understanding of cytokinesis must include a thorough analysis of the mechanical properties of the cortex and how signals modify these properties to dictate a well-controlled, error-free cytokinesis.

Introduction

Cytokinesis is the mechanical process that cleaves the mother cell into two daughter cells at the end of the cell cycle. During cytokinesis, the cell undergoes a series of stereotypical shape changes (Figure 1). The cell first rounds up into a nearly spherical mother cell and then elongates forming a cylindrical shape. A furrow begins to ingress but maintains continuous curvature with the global cortex. A discrete bridge forms that appears as a cylinder connecting the two daughter cells; the curvature of the bridge is discontinuous with the curvature of the two daughter cells. The bridge thins, lengthens and is ultimately severed, producing two daughter cells.

Figure 1.

Figure 1

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Diagram of the morphological changes of cytokinesis. The highly regimented nature of the shapes make cytokinesis a powerful model of cell shape change that is amenable to physical analyses. (a) The cell rounds up into a nearly spherical mother cell. (b) The cell elongates forming a cylindrical shape. (c) A furrow begins to ingress but maintains continuous curvature with the global cortex. (d) A discrete bridge forms that appears as a cylinder connecting the two daughter cells; the curvature of the bridge is discontinuous with the curvature of the two daughter cells. The bridge thins and lengthens. (e) The bridge is ultimately severed, producing two daughter cells. These shapes are highly stereotypical, at least for Dictyostelium. The cortical stretch modulus, Sc, is the viscoelasticity in the plane of the cortex. It is the energy cost for deforming the cell.

These basic steps are nearly ubiquitous among cell divisions of metazoan and ameboid organisms. Because cytokinesis is so highly regimented geometrically, it is an ideal model cell shape change for studies of cell mechanics and morphogenesis and naturally highlights the function of several cytoskeletal systems. The microtubule network and its associated proteins coordinate the separation of cytoplasmic and genetic material and serve as key regulators of the overlying cortical actin cytoskeleton, which controls the cell shape changes that lead to cell separation. The mechanical and regulatory control of this series of shape changes is the topic of this review, in which we synthesize our thinking on the mechanics of cytokinesis with recent discoveries on microtubule-dependent regulation.

Mechanics of cytokinesis

Because the cell is actively re-shaped during cytokinesis, work must be performed. This requires force production and the myosin-II mechanoenzyme plays a major but not exclusive role in this force production [1–3,4•]. These forces act in the mechanical context provided by the viscoelastic cortex. Thus, we have previously proposed a ‘balance-of-forces’ hypothesis in which the amount of force (F) required to be generated by the contractile ring is counter-balanced by the cortical stretch modulus (Sc), which is the viscoelasticity of the cell’s cortex parallel to the plane of the membrane [5•]. The cortical stretch modulus is the energy cost for deforming the cell away from a shape where the surface-area-to-volume ratio is minimized. In this force-balance hypothesis, the initial mother cell may be considered to be at an equilibrium state where the surface-area-to-volume ratio is minimized. As the mother cell passes through the intermediate shapes, the cell moves away from equilibrium. Production of the two nearly spherical daughter cells with minimal surface-area-to-volume ratios represents a return to an equilibrium state. During this process, there is a transition state (energy barrier) where a maximum amount of force is required. As the cortical stretch modulus is the energy cost for deforming the cell, it has a dual role in cytokinesis; prior to the transition state, it acts as a resistor that antagonizes the contractile ring, whereas after the transition state it facilitates furrow thinning as the cell strives to minimize the surface-area-to-volume ratio. Thus, the amount of force that needs to be produced by the contractile ring is proportional to the cortical stretch modulus and the stage of furrow ingression. Yoneda and Dan presented a simple relationship (F=2RfSccosΘ) where Rf is the radius of the furrow and cosΘ is a geometric parameter reflecting the geometry of the cell [6].

Using the Yoneda and Dan relationship, the amounts of myosin-II recruited to the cleavage furrow cortex were accurately predicted for Dictyostelium discoideum cytokinesis (Figure 2). First, force requirements were calculated by considering the cortical stretch modulus (1.5 nN/μm), as measured using microcapillary aspiration and the geometry of the dividing cell [7,8]. The myosin-II amounts required in the contractile ring were predicted by converting the force requirements into myosin-II molecules. This conversion was accomplished by considering the amount of force produced per head of myosin-II and the duty ratio (fraction of time spent in a force-generating state per ATPase cycle time). The amounts of myosin-II that are actually recruited to the cleavage furrow cortex were determined empirically using ratio imaging fluorescence microscopy and were found to correspond closely to the predicted values. For example, at the transition state, around 105 myosin-II hexameric monomers, representing about 10% of the total cellular myosin-II, were recruited to the cleavage furrow cortex, which is sufficient to produce up to 5 nN of force — extraordinarily close to the 7 nN predicted to be required.

Figure 2.

Figure 2

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Amounts of wild-type myosin-II recruited to the cleavage furrow cortex follow predicted trends. Actual amounts of Dictyostelium myosin-II were measured using fluorescence ratio imaging microscopy. The predicted amounts were determined by considering the minimal force required to maintain cell shape and the biophysical properties and cellular concentration of Dictyostelium myosin-II. In contrast, 3xAla myosin-II continues to accumulate in the cleavage furrow cortex, probably because it is not subject to regulated disassemblyby myosin heavy chain kinase C.

As the cortical stretch modulus is such a potent predictor of the amount of myosin-II that gets recruited to the cleavage furrow cortex, understanding its molecular basis becomes key to understanding the mechanics of cytokinesis. In principle, the cortical stretch modulus is dependent on the cortical viscoelasticity parallel to the plane of the cortex. The cortical viscoelasticity is a material property that reflects the kinetics of actin cross-linking proteins.

Genetic and biophysical studies in Dictyostelium have identified proteins involved in cytokinesis that control the cortical stretch modulus and viscoelasticity. Dynacortin and cortexillin are two actin-cross-linking proteins that modulate cortical viscoelasticity and how the cell shape changes with time during cytokinesis [9–11]; Girard et al., unpublished; Zhang and Robinson, unpublished). Dynacortin was identified in a genetic suppression experiment designed to detect suppressors of a cortexillin-I mutant [12]. The results of these studies indicate that global actin cross-linking through dynacortin, which is regulated by globally distributed RacE, acts antagonistically to the cleavage furrow cortical mechanics controlled by cortexillin-I and myosin-II.

Actin and myosin-II reorganization during cytokinesis

Actin and myosin-II have long been known to be key players in cytokinesis [1,13,14]. These are highly dynamic cytoskeletal elements, and their dynamics play a critical role in controlling the rates of furrow ingression. The first suggestion that actin dynamics are critical for cytokinesis came from Drosophila, in which twinstar mutants devoid of cofilin failed at cytokinesis, presumably because they over-accumulated filamentous actin in the cleavage furrow cortex [15]. Subsequently, actin dynamics have been confirmed to play a diverse and complex role in cytokinesis. In Dictyostelium, new actin is generated at the poles where Arp2/3 accumulates [16,17]. Rhodamine-labeled actin becomes incorporated into filamentous actin at the poles before flowing towards the cleavage furrow cortex. In mammalian cells, introduction of the barbed-end actinfilament-capping drug, cytochalasin D, into the poles of cells inhibits cytokinesis [18]. When cytochalasin D was introduced into the cleavage furrow region, furrow ingression accelerated. To reconcile these pieces of data, it has been proposed that new actin filaments assemble in the poles, travel to the furrow cortex and are disassembled as the cleavage furrow cortex constricts. As viscosity can be thought of as the energy cost for bulk flow, it is reasonable that removal of actin from the cleavage furrow region would reduce viscosity and cause an acceleration of cleavage furrow ingression [3]. Furthermore, as the contractile ring volume decreases towards the end of cytokinesis, it is expected that the contractile ring has to be disassembled and ultimately removed in order that the intercellular bridge may be severed. In Schizosaccaromyces pombe, actin dynamics have been shown to be a critical component regulating the rate of contractile ring constriction [19•,20•]. The assembly and dynamics of the cortical actin in this system depends on Arp2/3, formin, profilin and Wasp. Arp2/3- and formin-mediated nucleation mechanisms represent genetically independent pathways that lead to assembly of the cytokinetic ring inS. pombe. Further, both pathways are controlled by cdc15p, a PCH (pombe Cdc15 homology) protein [21•]. PCH proteins are known to regulate actin and contractile ring function in organisms ranging from yeasts to mammals [1]. It appears that new actin polymerization, combined with disassembly, regulates furrow ingression constriction [19•]. Interestingly, in C. elegans, Arp2/3 is not required for cytokinesis, whereas formin and profilin are, suggesting that formin-mediated nucleation drives actin assembly in this system [22•,23].

Myosin-II dynamics are also specifically regulated during cytokinesis of Dictyostelium. Comparison of the amounts of wild-type myosin-II with those of a mutant myosin-II, 3xAla, that is constitutively assembled into thick filaments indicates that regulation of myosin-II filament assembly/disassembly by heavy chain phosphorylation controls the flux of myosin-II that is sent to the cleavage furrow cortex (see Figure 2). Furthermore, cortical myosin-II turnover dynamics are specifically controlled by myosin-II heavy chain phosphorylation and the entire equatorial myosin-II pool appears to turn over with a half-life of just 7s [24]. Three isoforms of myosin-II heavy chain kinase (MHCK) are found in Dictyostelium and one isoform (MHCK C) is recruited to the cleavage furrow cortex late in cytokinesis, presumably to facilitate disassembly of the myosin-II thick filaments for final remodeling of the cortex before daughter cell separation [25•]. Using a novel fluorescence resonance energy transfer (FRET)-based sensor, Chisholm and colleagues show that myosin light chain kinase (MLCK) is globally distributed but that its activity increases in the cleavage furrow of mammalian cells [26•]. Regulatory light chain phosphorylation by MLCK stimulates increased myosin-II activity, although this does not appear to be essential for successful cytokinesis, at least in Dictyostelium [27]. The increased MLCK activity in the cleavage furrow cortex may signify a positive feedback mechanism that ensures strong myosin-II contractile activity in the contractile ring.

It is not well understood how myosin-II is targeted to the cleavage furrow cortex of any cell type. In S. pombe, a myosin-II progenitor remains stably associated in a punctate spot throughout interphase and the cytokinetic myosin-II ring appears to grow out from this spot [20•,28]. Furthermore, maintenance of the myosin-II spot depends on an UCS (UNC-45/CRO1/SHE4) domain protein, Ring3p. UCS-domain containing proteins facilitate the function of different myosins partly by providing a chaperone function for the motor domain [29•,30].

Regulation from the mitotic spindle during cytokinesis

A pivotal aspect of cytokinesis is the temporal and spatial control of the cortical distribution of actin, myosin and other cortical elements during mitosis and cytokinesis. In the past few years, several elegant studies have further defined how the spindle directs the assembly and contraction of the contractile ring. Several studies over the past decades have implicated either the central spindle or the astral microtubules in guiding the formation of a single central furrow [13]. As different microtubule populations have been implicated in different systems, researchers have suggested that the differences may be due to organism differences. However, in a recent study in C. elegans, both astral and central spindle microtubules contribute to defining the contractile zone and the precise geometry of the spindle appears to determine which set of microtubules contributes. Further, it has been suggested that the contractile ring is assembled where the density of microtubules is at a local minimum [31]. This idea is consistent with another recent study in mammalian cells, which suggested that the bipolar spindle is really a combination of two monopolar spindles [32•]. The microtubules that radiate past the chromosomes become stably associated with the cortex and are proposed to determine the site of contractile ring formation. Perhaps these stable microtubules help stabilize focal-adhesion-like complexes to facilitate the formation of contractile ring actin [1]. By contrast, astral microtubules were observed to be highly dynamic. Highly dynamic microtubules have been proposed to be generated by the microtubule destabilizer katanin. Mutants of katanin in C. elegans assemble overly long microtubules, while Nedd8, a ubiquitin-like degradation system, appears to keep katanin activity in check (Figure 3) [33•]. Mutants of Nedd8 fail to inactivate katanin, resulting in short astral microtubules. Intriguingly, Nedd8 mutants display ectopic furrow formation (extra furrows in addition to the normal equatorial cleavage furrow) during cytokinesis, suggesting that the astral microtubules normally keep the local polar cortex quiescent so that the equatorial cortex can contract. Mutations in one of the katanin subunits, encoded by Mei-I, suppresses the Nedd8 mutant ectopic furrowing activity. The ectopic furrowing activity is reminiscent of the phenotype observed when mammalian cells were treated with Rho inhibitors [34].

Figure 3.

Figure 3

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The mitotic spindle provides spatio-temporal control of wild type cytokinesis. (a) Schematic relating spindle morphology and furrowing activity of wild type and Nedd-8 mutants. Red arrows indicate contractile activity. Black arrows represent positive signals that stimulate furrowing. Black inhibition bars indicate inhibitory signals that block ectopic furrow activity. (b) Summary of pathway of Nedd-8 control of ectopic furrowing through modulation of katanin and astral microtubules [33•]. Rho also inhibits ectopic furrowing in mammalian cells [34].

Several studies indicate that Rho activation in the region of the cleavage furrow is an essential component of the regulation of new actin polymerization and the timing of cytokinesis. Regulators of Rho including the ECT2/pebble Rho guanine nucleotide exchange factor and the RhoGAP (encoded by Drosophila RacGap50C, C. elegans cyk-4, and mammalian MgcRacGAP) [35–37] associate with the central spindle. C. elegans cyk-4 forms a complex in vitro and in vivo with the mitotic kinesin-like protein 1 (MKLP1) family member zen-4 (the cyk-4/zen-4 complex is referred to as centralspindlin) (Figure 4) [36]. The RacGAP activity is converted into RhoGAP activity via phosphorylation by Aurora B serine/threonine kinase. The timing of cytokinesis depends on the activity of the anaphase-promoting complex, which controls multiple targets [38]. Some of this regulation is undoubtedly mediated by cyclin B and cyclin B3 isoforms, which appear to directly or indirectly regulate Rho activity [39].

Figure 4.

Figure 4

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Mitotic kinesin-like proteins localize to central spindle or midbody microtubules at different stages of cytokinesis. Three protein–protein interactions have been indicated to date. MKLP1 forms complexes with RhoGAPs, Cyk-4 and MgcRacGap. The CHO1 splice variant of MKLP1 includes an extra exon (exon 18), which encodes an actin binding domain. CHO1 can bind filamentous actin. MKLP1s also have a nucleotide-independent microtubule-binding site in their tail domain (not indicated). MKLP2 is phosphorylated by polo-like kinase 1 on multiple sites including a site in the neck linker. Phosphorylation of MKLP2’s neck linker site is required for polo-like kinase 1 to localize to the central spindle. The authors propose that polo-like kinase 1 binds the MKLP2 neck linker through its polo box domain for central spindle localization [42•].

MKLP1-family proteins appear to function at several levels during cytokinesis in addition to the role described above for MKLP1 and zen-4. Drosophila MKLP1-family protein, pavarotti (Pav-KLP), associates with polo kinase in co-immunoprecipitation experiments [40,41]. In mammalian cells, polo-like kinase 1 (plk1) phosphorylates a second MKLP-like protein, MKLP2 (also named rabkinesin6/RAB6-KIFL), and this phosphorylation appears to create a binding site required for the maintenance of plk1 localization to the central spindle (Figure 4) [42•]. By itself, Plk1 weakly binds microtubules, which appear to enhance its activity towards MKLP2. Thus, synergy between MKLP2, plk1 and microtubules helps restrict plk1 to the central spindle, where it presumably phosphorylates additional targets to regulate cytokinesis. CHO1, a splice variant of MKLP1, has an extra domain encoded by a single exon that binds actin (Figure 4). Antibody inhibition studies suggest that CHO1 function through this domain is required for the final severing of the intercellular bridge [43]. Thus, we are beginning to elucidate on a molecular level how the central spindle communicates with the cell cortex.

Conclusions

As well as being a fascinating dynamic cell process in itself, cytokinesis offers a significant repertoire of potential drug target candidates for the treatment of cancer. The pathophysiology of other diseases may also be due at least in part to defects in cytokinesis. For example, brains of patients with the neurological disease globoid cell leukodystrophy develop multinucleated globoid cells, probably as a result of the accumulation of a lipid metabolite, psychosine [44]. A recent study also showed that a cytokinesis defect in mouse cardiac myocytes caused by mutations in nonmuscle myosin-IIB correlates with a novel form of cardiac hypertrophy [45•]. Thus, the development of drugs targeting cytokinesis factors is of considerable medical interest [46,47•].

Cytokinesis is an elegant cell shape change that requires the integrated function of many cytoskeletal systems. The spindle provides spatio-temporal control over the mechanical events of the cell cortex. However, how these signals translate into cortical mechanisms is still not understood. The amount of force generated by the contractile ring must be sufficient to overcome the cortical viscoelasticity of the global cell cortex. It is probable that the ultimate readout from the spindle involves changes in cortical actin cross-linking and myosin-II mechanochemistry, thereby specifying the force-balance that governs the shape changes of cytokinesis. By studying the biochemical and feedback control of the mechanics of cytokinesis, it may be possible to understand how cells complete cytokinesis with such high fidelity in a wide variety of mechanical environments such as in a tissue or blood stream.

Acknowledgements

We thank the members of the Robinson laboratory for helpful comments on the manuscript and the Burroughs-Wellcome Fund (DNR) and the NIH (R01#GM066817 to DNR and R01#GM46551 to JAS) for support.

Abbreviations

Arp2/3

actin-related protein 2/3

F

Force

FRET

fluorescence resonance energy transfer

MHCK

myosin-II heavy chain kinase

MKLP

mitotic kinesin-like protein

MLCK

myosin-II light chain kinase

PCH

pombe Cdc15 homology

PLK1

Polo-like kinase 1

Rf

furrow radius

Sc

cortical stretch modulus

UCS

UNC-45/CRO1/SHE4

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

  • 1.Robinson DN, Spudich JA: Towards a molecular understanding of cytokinesis. Trends Cell Biol 2000, 10:228–237. [DOI] [PubMed] [Google Scholar]
  • 2.Uyeda TQP, Kitayama C, Yumura S: Myosin II-independent cytokinesis in dictyostelium: its mechanism and implications. Cell Struct Funct 2000, 25:1–10. [DOI] [PubMed] [Google Scholar]
  • 3.Robinson DN: Cell division: biochemically controlled mechanics. Curr Biol 2001, 11:R737–R740. [DOI] [PubMed] [Google Scholar]
  • 4.•.Nagasaki A, de Hostos EL, Uyeda TQP: Genetic and morphological evidence for two parallel pathways of cell-cycle-coupled cytokinesis in Dictyostelium. J Cell Sci 2002, 115:2241–2251. [DOI] [PubMed] [Google Scholar]; The authors provide evidence that myosin-II and coronin contribute to successful cytokinesis. They suggest that both proteins function in independent force-generating pathways.
  • 5.•.Robinson DN, Cavet G, Warrick HM, Spudich JA: Quantitation of the distribution and flux of myosin-II during cytokinesis. BMC Cell Biol 2002, 3:4. [DOI] [PMC free article] [PubMed] [Google Scholar]; The authors show that the amounts of myosin-II sent to the cleavage furrow cortex correspond to the predicted amounts and trends determined by considering the minimal force requirements.
  • 6.Yoneda M, Dan K: Tension at the surface of the dividing sea-urchin egg. J Exp Biol 1972, 57:575–587. [DOI] [PubMed] [Google Scholar]
  • 7.Gerald N, Dai J, Ting-Beall HP, DeLozanne A: A role for Dictyostelium RacE in cortical tension and cleavage furrow progression. J Cell Biol 1998, 141:483–492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Dai J, Ting-Beall HP, Hockmuth RM, Sheetz MP, Titus MA: Myosin I contributes to the generation of resting cortical tension. Biophys J 1999, 77:1168–1176. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Robinson DN, Ocon SS, Rock RS, Spudich JA: Dynacortin is a novel actin bundling protein that localizes to dynamic actin structures. J Biol Chem 2002, 277:9088–9095. [DOI] [PubMed] [Google Scholar]
  • 10.Weber I, Gerisch G, Heizer C, Murphy J, Badelt K, Stock A, Schwartz J-M, Faix J: Cytokinesis mediated through the recruitment of cortexillins into the cleavage furrow. EMBO J 1999, 18:586–594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Simson R, Wallraff E, Faix J, Niewöhner J, Gerisch G, Sackmann E: Membrane bending modulus and adhesion energy of wild-type and mutant cells of Dictyostelium lacking talin or cortexillins. Biophys J 1998, 74:514–522. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Robinson DN, Spudich JA: Dynacortin, a genetic link between equatorial contractility and global shape control discovered by library complementation of a Dictyostelium discoideum cytokinesis mutant. J Cell Biol 2000, 150:823–838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Rappaport R: Cytokinesis in Animal Cells. Edited by Barlow PW, Bard JBL, Green PB, Kirk DL. Cambridge: Cambridge University Press; 1996. [Google Scholar]
  • 14.Glotzer M: Animal cell cytokinesis. Annu Rev Cell Dev Biol 2001, 17:351–386. [DOI] [PubMed] [Google Scholar]
  • 15.Gunsalus KC, Bonaccorsi S, Williams E, Verni F, Gatti M, Goldberg ML: Mutations in twinstar, a Drosophila gene encoding a cofilin/ADF homologue, results in defects in centrosome migration and cytokinesis. J Cell Biol 1995, 131:1243–1259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Neujahr R, Heizer C, Albrecht R, Ecke M, Schwartz J-M, Weber I, Gerisch G: Three-dimensional patterns and redistribution of myosin II and actin in mitotic Dictyostelium cells. J Cell Biol 1997, 139:1793–1804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Insall R, Mueller-Tautenberger A, Machesky L, Koehler J, Simmeth E, Atkinson SJ, Weber I, Gerisch G: Dynamics of the Dictyostelium Arp2/3 complex in endocytosis, cytokinesis, and chemotaxis. Cell Motil Cytoskeleton 2001, 50:115–128. [DOI] [PubMed] [Google Scholar]
  • 18.O’Connell CB, Warner AK, Wang Y-l: Distinct roles of the equatorial and polar cortices in the cleavage of adherent cells. Curr Biol 2001, 11:702–707. [DOI] [PubMed] [Google Scholar]
  • 19.•.Pelham RJ, Chang F: Actin dynamics in the contractile ring during cytokinesis in fission yeast. Nature 2002, 419:82–86. [DOI] [PubMed] [Google Scholar]; The authors suggest that actin dynamics control the rates and success of cytokinesis in fission yeast.
  • 20.•.Wu J-Q, Kuhn JR, Kovar DR, Pollard TD: Spatial and temporal pathway for assembly and constriction of the contractile ring in fission yeast cytokinesis. Dev Cell 2003, 5:723–734. [DOI] [PubMed] [Google Scholar]; The authors carefully quantify the events of cytokinesis in S. pombe, including the precise timing of recruitment of 12 contractile ring proteins. The paper represents an essential step towards developing a mechanistic framework for contractile ring assembly and constriction in fission yeast.
  • 21.•.Carnahan RH, Gould KL: The PCH family protein, cdc15p, recruits two F-actin nucleation pathways to coordinate cytokinetic actin ring formation in Schizosaccharomyces pombe. J Cell Biol 2003, 162:851–862. [DOI] [PMC free article] [PubMed] [Google Scholar]; This very interesting protein, cdc15, appears to control two independent actin-nucleating mechanisms that lead to assembly of the cytokinetic actin ring in fission yeast.
  • 22.•.Severson AF, Baille DL, Bowerman B: A formin homology protein and a profilin are required for cytokinesis and Arp2/3-independent assembly of cortical microfilaments in C. elegans. Curr Biol 2002, 12:2066–2075. [DOI] [PubMed] [Google Scholar]; Here, the authors demonstrate that formin and profilin are used for actin assembly in cytokinesis; Arp2/3 does not appear to be required.
  • 23.Pruyne D, Evangelista M, Yang C, Bi E, Zigmond S, Bretscher A, Boone C: Role of formins in actin assembly: nucleation and barbed-end association. Science 2002, 297:612–615. [DOI] [PubMed] [Google Scholar]
  • 24.Yumura S: Myosin II dynamics and cortical flow during contractile ring formation in Dictyostelium cells. J Cell Biol 2001, 154:137–145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.•.Liang W, Licate LS, Warrick HM, Spudich JA, Egelhoff TT: Differential localization in cells of myosin II heavy chain kinases during cytokinesis and polarized migration. BMC Cell Biol 2002, 3:19. [DOI] [PMC free article] [PubMed] [Google Scholar]; One specific isoform of myosin heavy chain kinase, MHCK C, localizes to the cleavage furrow cortex late in cytokinesis, presumably to promote disassembly of the myosin-II thick filaments to allow completion of cytokinesis.
  • 26.•.Chew T-L, Wolf WA, Gallagher PJ, Matsumura F, Chisholm RL: A fluorescent resonant energy transfer-based biosensor reveals transient and regional myosin light chain kinase activation in lamella and cleavage furrows. J Cell Biol 2002, 156:543–553. [DOI] [PMC free article] [PubMed] [Google Scholar]; In this paper, the authors use a very elegant FRET-based sensor to identify populations of cellular myosin-II that are phosphorylated on their light chains. It suggests in which locations myosin-II is active.
  • 27.Ostrow BD, Chen P, Chisholm RL: Expression of a myosin regulatory light chain phosphorylation site mutant complements the cytokinesis and developmental defects of Dictyostelium RMLC null cells. J Cell Biol 1994, 127:1945–1955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Wong KCY, D’souza VM, Naqvi NI, Motegi F, Mabuchi I, Balasubramanian MK: Importance of a myosin II-containing progenitor for actomyosin ring assembly in fission yeast. Curr Biol 2002, 12:724–729. [DOI] [PubMed] [Google Scholar]
  • 29.•.Barral JM, Hutagalung AH, Brinker A, Hartl FU, Epstein HF: Role of myosin assembly protein UNC-45 as a molecular chaperone for myosin. Science 2002, 295:669–671. [DOI] [PubMed] [Google Scholar]; In this interesting paper, the authors show that UNC-45 serves as a molecular chaperone for myosin-II motor domain.
  • 30.Wesche S, Arnold M, Jansen R-P: The UCS domain protein She4p binds to myosin motor domains and is essential for class I and class V myosin function. Curr Biol 2003, 13:715–724. [DOI] [PubMed] [Google Scholar]
  • 31.Dechant R, Glotzer M: Centrosome separation and central spindle assembly act in redundant pathways that regulate microtubule density and trigger cleavage furrow formation. Dev Cell 2003, 4:333–344. [DOI] [PubMed] [Google Scholar]
  • 32.•.Canman JC, Cameron LA, Maddox PS, Straight A, Tirnauer JS, Mitchison TJ, Fang G, Kapoor TM, Salmon ED: Determining the position of the cell division plane. Nature 2003, 424:1074–1078. [DOI] [PubMed] [Google Scholar]; Using pharmacological trickery, the authors are able to generate monopolar spindles and then bypass the mitotic checkpoint so that cytokinesis can progress. Surprisingly, monopolar spindles are sufficient to specify the division plane at sites where stable microtubules appear to associate with the cortex.
  • 33.•.Kurz T, Pintard L, Willis JH, Hamill DR, Gönczy P, Peter M, Bowerman B: Cytoskeletal regulation by the Nedd8 ubiquitin-like protein modification pathway. Science 2002, 295:1294–1298. [DOI] [PubMed] [Google Scholar]; Here, the authors show that neddylation appears to control levels of katanin and therefore its activity. Without Nedd8, katanin destroys astral microtubules, leading to ectopic furrow induction. Mutations in katanin subunits can suppress Nedd8 mutants, providing further genetic evidence for Nedd-8 regulation of katanin.
  • 34.O’Connell CB, Wheatley SP, Ahmed S, Wang Y-l: The small GTP-binding protein Rho regulates cortical activities in cultured cells during division. J Cell Biol 1999, 144:305–313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Somers WG, Saint R: A RhoGEF and Rho family GTPase-activating protein complex links the contractile ring to cortical microtubules at the onset of cytokinesis. Dev Cell 2003, 4:29–39. [DOI] [PubMed] [Google Scholar]
  • 36.Mishima M, Kaitna S, Glotzer M: Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity. Dev Cell 2002, 2:41–54. [DOI] [PubMed] [Google Scholar]
  • 37.Minoshima Y, Kawashima T, Hirose K, Tonozuka Y, Kawajiri A, Bao YC, Deng X, Tatsuka M, Narumiya S, May WS et al. : Phosphorylation by aurora B converts MgcRacGAP to a RhoGAP during cytokinesis. Dev Cell 2003, 4:549–560. [DOI] [PubMed] [Google Scholar]
  • 38.Shuster CB, Burgess DR: Transitions regulating the timing of cytokinesis in embryonic cells. Curr Biol 2002, 12:854–858. [DOI] [PubMed] [Google Scholar]
  • 39.Echard A, O’Farrell PH: The degradation of two mitotic cyclins contributes to the timing of cytokinesis. Curr Biol 2003, 13:373–383. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Adams RR, Tavares AAM, Salzburg A, Bellen HJ, Glover DM: Pavarotti encodes a kinesin-like protein required to organize the central spindle and contractile ring for cytokinesis. Genes Dev 1998, 12:1483–1494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Lee KS, Yuan YO, Kuriyama R, Erikson R: Plk is an M-phase specific protein kinase and interacts with a kinesin-like protein, CHO1/MKLP-1. Mol Cell Biol 1995, 15:7143–7151. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.•.Neef R, Preisinger C, Sutcliffe J, Kopajtich R, Nigg EA, Mayer TU, Barr FA: Phosphorylation of mitotic kinesin-like protein 2 by polo-kinase 1 is required for cytokinesis. J Cell Biol 2003, 162:863–875. [DOI] [PMC free article] [PubMed] [Google Scholar]; The authors show how polo-like kinase 1 creates its own binding site at the central spindle by phosphorylating MKLP2. Plk1 then binds MKLP2 through its polo box. Plk1 weakly binds microtubules alone and microtubules stimulate its ability to phosphorylate MKLP2. Thus, microtubules, MKLP2 and plk1 synergistically enhance plk1’s recruitment to the central spindle.
  • 43.Kuriyama R, Gustus C, Terada Y, Uetake Y, Matuliene J: CHO1, a mammalian kinesin-like protein, interacts with F-actin and is involved in the terminal phase of cytokinesis. J Cell Biol 2002, 156:783–790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Kanazawa T, Nakamura S, Momoi M, Yamaji T, Takematsu H, Yano H, Sabe H, Yamamoto A, Kawasaki T, Kozutsumi Y: Inhibition of cytokinesis by a lipid metabolite, psychosine. J Cell Biol 2000, 149:943–950. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.•.Takeda K, Kishi H, Ma X, Yu Z-X, Adelstein RS: Ablation and mutation of nonmuscle myosin heavy chain II-B results in a defect in cardiac myocyte cytokinesis. Circ Res 2003, 93:330–337. [DOI] [PubMed] [Google Scholar]; The authors demonstrate that non-muscle myosin-IIB is required for cytokinesis in mouse cardiac myocytes. Further, only 6% of the total cellular myosin-II is sufficient for cytokinesis. This agrees favorably with the results of [5•].
  • 46.Cheung A, Dantzig JA, Hollingworth S, Baylor SM, Goldman YE, Mitchison TJ, Straight AF: A small-molecule inhibitor of skeletal muscle myosin II. Nat Cell Biol 2002, 4:83–88. [DOI] [PubMed] [Google Scholar]
  • 47.•.Straight AF, Cheung A, Limouze J, Chen I, Westwood NJ, Sellers JR, Mitchison TJ: Dissecting temporal and spatial control of cytokinesis with a myosin II inhibitor. Science 2003, 299:1743–1747. [DOI] [PubMed] [Google Scholar]; Pharmacological inhibition of myosin-II using a new drug, blebbistatin, demonstrates that myosin-II is required for cytokinesis in mammalian cells. The authors demonstrate that cytokinesis can be dissected pharmacologically.

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