agWn,Qn in n hamoZhang* Chuanmao and with Jiang Qing cycle Wang, spindle Gang mitotic the the coupling of in assembly kinases the mitotic of role The COMMENTARY ß Ato o orsodne([email protected]) correspondence China. for 100871, *Author Beijing Biotechnology, University, Membrane Peking and Differentiation Sciences, Bio-membrane and Life of Proliferation of Laboratory Cell College Key of State Laboratory The Key and Education duplicated of Ministry the The cell- and Mennella with phase, discrete 2012; coordinated S al., during is a occurring et duplication of progression, Centrosome Lawo cycle distribution 2012). 2012; al., Glover, toroidal et and around concentric (Fu domains a diameter spatial adopting separable PCM by occupy the components which the that structure, hierarchical super-resolution of recently ordered highly found using a mass actually have is amorphous However, groups an several granules. as microscopy, described electron-dense is of 2007). PCM Glover, the and (Bettencourt-Dias Conventionally, conserved ‘cartwheel’ symmetric organized are are a that in centrioles triplets (PCM); nine comprising material organelles pericentriolar surrounded the or centrioles the two cilium by of and primary consists circumstances, movement centrosome the transduction, A of signal certain development. for body center crucial basal is Under the which microtubule-organizing flagellum, as cells. acts main also animal centrosome the in is (MTOC) centrosome The Introduction assembly Spindle kinase, Mitotic , material, cycle, Pericentriolar , Cell WORDS: KEY abnormalities centrosomal ensuring between defects. thus spindle relationship help and cycle, will the process cell delineate this the Understanding to recent fidelity. with spindle the mitotic cycle to bipolar review coordinated centrosome are we the kinases mitotic couple Commentary, these cell how this on during progress and research In assembly separation spindle progression. mitotic duplication, cycle subsequent Aurora centrosome and and regulating maturation (Plks) kinases in cyclin- Polo-like kinases, (Neks), (CDKs), kinases role kinases NIMA-related spindle the dependent including dissect possibly to multipolar kinases, and begun mitotic have or instability of studies of monopolar number A in to tumorigenesis. results occur lead which abnormalities mitotic often formation, centrosome bipolar and However, the frequently stability. maintenance of the genomic and assembly separation of the chromosome accurate monitor for spindle and define to poles separate cell spindle the duplicated When the manner. , regulated cell undergoes spatiotemporally per mitotic highly once a only and duplicates in It cycle interphase cells. vertebrate in in center assembly maintenance microtubule-organizing spindle cytoskeleton major for the as (MTOC) acts centrosome The ABSTRACT 04 ulse yTeCmayo ilgssLd|Junlo elSine(04 2,41–12doi:10.1242/jcs.151753 4111–4122 127, (2014) Science Cell of Journal | Ltd Biologists of Company The by Published 2014. nalcnrsm-otiigcls wn otecuillinks crucial the to is Owing cycle, cells. centrosome division centrosome-containing cell the during all to separation in chromosome coupled faithful is for required that process 1). regulated (Fig. kinases Aurora and (Plks) (CDKs), kinases kinases Polo-like including cyclin-dependent kinases, (Neks), mitotic kinases multiple NIMA-related of activity depends orchestrated PCM maturation, the and, centrosome on the termed and size mitosis, process, nucleation in This microtubule of anchoring. for mitotic increases capacity when onset the for dramatically acquires the phase poles remarkably, centrioles At spindle G2 the 1). opposite surrounding (Fig. late the assembly until define spindle to together separate linked they are centrosomes bomlcnrsm ucin nueufihu spindle unfaithful induce aneuploidy. functions possibly, and, how formation understanding centrosome for framework abnormal spindle a mitotic providing bipolar before and cycle assembly, orchestrating and centrosome in the kinases of recent Tanenbaum mitotic regulation on of the focus role 2012; maturation we the Commentary, illustrate Schiebel, this that advances In and 1). and (Fig. 2010) Mardin Medema, and segregation 2007; Bettencourt-Dias centriole 2013; and Glover, centrosome Gopalakrishnan, biogenesis, formation and (Avidor-Reiss and procentriole centriole have disengagement, elongation, functions including and and dynamics engagement identified, centrosome in Using been involved important. processes are biological extremely different that is analysis, proteomics centrosome of and the regulation genomics the of in functions participate al., that the factors et Therefore, key 2009). (Basto the Cleveland, formation, characterizing and tumorigenesis Holland spindle 2007; even Fukasawa, mitotic 2008; and the abnormal of instability to functions chromosome lead and dynamics often structural centrosome the in cell and defects assembly division, spindle mitotic functions, centrosomal between a enpsuae htachsnrn ope ly an plays complex ring and a It mother 2006). that Stearns, the postulated and from (Tsou been mitosis daughter of has the end the of until maintained duplication established the is centrioles paired during the of disengagement arrangement centriole orthogonal in The kinases mitotic of Functions 1). general Table the kinases (see mitotic summarize process how this and of discuss duplication aspects mainly centrosome we in here, function 2014), al., et Go published Jana 2013; been Gopalakrishnan, have and number the biogenesis (Avidor-Reiss a centriole of recently As will on formation. orchestration reviews spindle biogenesis excellent the mitotic of of centriole of and understanding cycle into centrosome our insights enhance to New order greatly mitotic in fidelity. ensuring cycle thereby cell number, spindle centriole per uncontrolled once an only avoid biogenesis duplicates centriole in centrosome kinases The mitotic of role The ioi pnl seby opiae u precisely but complicated a assembly, spindle Mitotic nz,2012; ¨nczy, 4111

Journal of Cell Science COMMENTARY nw sSO1 n rmtsislclzto nthe on localization its promotes 4112 also and is which SGOL1) SGO1, of as variant splice known (a sSgo1 phosphorylates Plk1 both duplication centrosome suppresses of and (Scho dramatically disengagement interference activity centriole RNA precocious by kinase or Scho artificially the inhibitor 2005; an requires (Lonc during al., interphase overduplication et prolonged probably centriole (Hauf Plk1 cleavage Consistently, its process, separase enhances this which by Scc1, During phosphorylating (Scho 2006). by separase functions Stearns, of help and the Tsou with removed 2013; and Nasmyth, and Oliveira 2009). 2013; al., al., CDK1 et et Plk1, Tsou (Cabral for by PCM prerequisite regulated the a tightly and is is and 1). centrioles al., Table duplication, paired et 1; centrosome the (Fig. (Matsuo of 2007) al., disengagement respectively et Thein The 2009; Scc1), al., by et of Nakamura protease and 2012; cysteine cleavage centrosome a promotes the separin; ring as to that known preventing Rad21) as cohesin (also as separase the known in known inactivating recruiting (also (also function by Scc1 astrin subunit splitting respectively) and centrosome SPAG5, Aki1 premature architecture, and Furthermore, orthogonal 2009). CC2D1A (Scho this al., controversial still et maintaining is this in although role important SCF by asse (mediated the degradation for its responsible basi induces is structural Plk4 hPOC5 the of whereas form Autophosphorylation length, CPAP centriole. procentriole and centros the STIL determine the of the SAS6, antagonistically stabilizes for portion CPAP Cep135, Centrobin responsible distal and Then, elongation. CP110 are the Procentriole circle). elongation. con (iii) Cep192 of dotted Plk4. mainly procentriole and the and linker, promote Cep152 SCF-FBXW5 within proteinaceous en to APC/C, duplication. a shown the by TuSC centriole disengagement, (as from regulated centriole of tightly duplication occurs After is Initiation centriole centrosome, astrin. which (ii) initiate the cartwheel, and established. to separase from is Plk4 PCM, ring LRRC45, CDK1, of cohesin Plk1, and recruitment the by Cep68 of regulated , displacement is C-Nap1, and the of phase by cycle. G1 accompanied cell early is the to disengagement and mitosis Centriole cycle disengagement. centrosome Centriole the (i) between Interplay 1. Fig. v ioa pnl seby h eaae etooe c srbs TC oasml h ioa ioi pnl.Teinrcrl hw h diffe the shows circle inner The spindle. mitotic red. Ne bipolar in and the shown CDK1 Plk1, assemble are AurA, to kinases by MTOCs mitotic Both regulated robust and appendages. tightly as is cycle subdistal process act cell and This centrosomes the distal centrosomes. separated of assembles mature The phases two centriole assembly. form mother to spindle formed separate Bipolar newly and (v) the (orange) PCM duplication, additional centriole recruit After centrosomes separation. and Maturation (iv) pnmttcei,tecnrsmlchsnrn sboe down broken is ring cohesin centrosomal the exit, mitotic Upon ce ta. 01 sue l,20) tews,Plk1 Otherwise, 2009). al., et Tsou 2011; al., et ¨ckel ae ta. 00,adihbto fPk ihachemical a with Plk1 of inhibition and 2010), al., et ˇarek (iv) Centrosome andseparation maturation Nek2A AurA CDK1 Plk1

Microtubule (iii) Procentriole elongation ce ta. 01 Tsou 2011; al., et ¨ckel C-Nap1 ce ta. 2011). al., et ¨ckel Daughter centriole ce ta. 2011; al., et ¨ckel Cohesin ring PCM Plk4 P Mother centriole SCF (v) Bipolarspindleassembly β -TrCP G2 h etooeccecnit fsvrlsesta r ikdt h elcycle. cell the to linked are that steps several of consists cycle centrosome The hPOC5 CP110 M S α Centrobin γ / ope/ylsm ACC a 3uiutnlgs)would ligase) ubiquitin -promoting E3 by (an mediated (APC/C) is that complex/cyclosome onset, degradation anaphase protease At B1 2000). the Osada, cyclin disrupts and formation (Simizu separase complex of cyclin stable activity its this through – separase subunit phosphorylated centriole B1 to phosphorylate from binds to induces PCM and functions the separase CDK1 indirectly of Alternatively, dissociation centrosome. perhaps the the promoting activity by reduced is disengagement below), kinase CDK1 (discussed As maturation 2012). CDK1 centrosome al., for et efficiently (Matsuo required component) separation PCM centriole (a agreement pericentrin induces In of anaphase. cleavage in this, apart with PCM centrioles with the coupled ‘tear’ forces the disassembly pulling by microtubule together cortical held until are PCM centrioles Nasmyth, paired and the Oliveira Accordingly, 2013; 2013). al., et (Cabral respectively embryos, ciiy u o oei laae ssfiin o centriole for sufficient is kinase CDK1 cleavage, in cohesin reduction in disengagement not a or but forces activity, to cytoskeleton with order PCM in disengagement centriole duplication. to centrosome poles, license contribute exit spindle mitotic also upon and activity dominant-negative phosphorylated kinase centrioles might Plk1 be of of sSgo1 shutdown separation cannot that suggesting the that of induces mutant Plk1, a Overexpression by of (Wang especially 2008). cleavage mutants, premature al., from cohesin et protect to centrosome -TuSC β CPAP - oee,ohrrprshv rudta oprto fthe of cooperation that argued have reports other However, Chromosome

Separase ora fCl cec 21)17 1142 doi:10.1242/jcs.151753 4111–4122 127, (2014) Science Cell of Journal G1 Astrin C-Nap1 anradtselegans Caenorhabditis Cep192 Cep152 Plk4 CDK1 PCM Plk1 CPAP Cep135 SAS6 STIL b disengagement -TrCP Cartwheel duplication Rootletin, Cep68,LRRC45 Distal appendage opeetcnroereduplication. centriole prevent to ) Subdistal appendage (ii) Centriole (i) Centriole initiation SCF-FBXW5 a APC/C / b Plk4 tblndmr htncet at nucleate that dimers -tubulin ioi or mitosis Drosophila omal sofa sisting mbly rent k2A. dof c -

Journal of Cell Science COMMENTARY

Table 1. Factors involved in centriole biogenesis Steps of centriole biogenesis Factors Properties References

Maintaining orthogonal arrangement of paired Cohesin complex Maintains the orthogonal architecture of paired Kitajima et al., 2004; Scho¨ckel et al., 2011; Wang et al., 2008 centrioles; preventing premature centriole splitting centrioles sSgo1 Protects the cohesin ring from untimely dissociation Kitajima et al., 2004; Wang et al., 2008 Astrin Negatively regulates separase activity Thein et al., 2007 Aki1 Responsible for centrosomal recruitment of Scc1 Nakamura et al., 2009 Pericentrin Substrate of separase that maintains centriole Matsuo et al., 2012 engagement Promoting centriole disengagement before centrosome CDK1 Multiple roles; see the main text Oliveira and Nasmyth, 2013; Simizu and Osada, 2000 duplication Plk1 Multiple roles; see the main text Mardin and Schiebel, 2012; Scho¨ckel et al., 2011; Tsou et al., 2009; Wang et al., 2008 Separase Cleaves the cohesin ring and pericentrin Lee and Rhee, 2012; Nakamura et al., 2009; Tsou et al., 2009; Zhang et al., 2008 PCM and Cooperatively promote separation of paired centrioles Cabral et al., 2013 cytoskeleton Establishing the cartwheel structure; initiating SAS6 Basis of the ninefold symmetry of the cartwheel Gudi et al., 2011; Kitagawa et al., 2011b; van Breugel et al., procentriole formation structure 2011 Cep152 Recruits Plk4 and SAS6 for the initiation of centriole Cizmecioglu et al., 2010; Hatch et al., 2010; Kim et al., 2013 duplication Cep192 Cooperates with Cep152 to recruit Plk4 to the Kim et al., 2013; Sonnen et al., 2013 centrosome Plk4 Multiple roles; see the main text Bettencourt-Dias et al., 2005; Habedanck et al., 2005;

Kleylein-Sohn et al., 2007; Puklowski et al., 2011; doi:10.1242/jcs.151753 4111–4122 127, (2014) Science Cell of Journal Rogers et al., 2009; Swallow et al., 2005 Cep135 Stabilizes the cartwheel structure by interacting with Cottee et al., 2013; Hatzopoulos et al., 2013; Lin et al., 2013a; SAS6 and CPAP Roque et al., 2012 STIL Establishes the linkage between centriolar scaffold and Arquint and Nigg, 2014; Kitagawa et al., 2011a; Lin et al., 2013b Promoting procentriole elongation and determining c-TuSC Provides the template for Kollman et al., 2010 centriole length CPAP Connects the cartwheel with microtubules and Cottee et al., 2013; Hatzopoulos et al., 2013; Lin et al., 2013b; promotes procentriole elongation Schmidt et al., 2009; Tang et al., 2009 Cep120 Promotes procentriole elongation Comartin et al., 2013; Lin et al., 2013b Centrobin Stabilizes centriolar microtubules Gudi et al., 2011 CP110 Determines the length of newly formed centrioles Chen et al., 2002; Li et al., 2013; Schmidt et al., 2009 hPOC5 Ensures centriolar integrity Azimzadeh et al., 2009 Ensuring centriole duplication initiation and preventing APC/C Degradation of FBXW5 and STIL Arquint and Nigg, 2014; Puklowski et al., 2011 centriole re-duplication SCF Degradation of SAS6 and Plk4 D’Angiolella et al., 2010; Holland et al., 2010; Puklowski et al., 2011; Rogers et al., 2009

This table lists only the components discussed in the main text. 4113

Journal of Cell Science h ntaino etooedpiainadt prevent to and duplication centrosome 2011). of guarantee reduplication. al., to initiation biogenesis functions centriole et to of the ligases, stages ubiquitin different phase (Puklowski E3 regulating ensuring in with G1 together thereby duplication Plk4, targets and SAS6, Collectively, centrosome of mitosis APC/C degradation correct during premature Furthermore, the degradation SAS6. prevent for ubiquitylate to FBXW5 its However, to respectively suppresses 2011). which the FBXW5, al., STIL, ability phosphorylates et of Plk4 and Puklowski this, reduplication 2014; alleviate and SAS6 Nigg, the FBXW5) and ubiquitylating inhibiting (Arquint by F-box to the contribute centrosome (Cunha- employing can degradation case both APC/C Furthermore, for this 2002). Nigg, (in complex, and SCF Meraldi SCF 2013; al., the et Ferreira thus and Slimb), uohshrltsisaioai eiu e23 thereby the Plk4 with Ser293, interaction 2006). its residue protein promote substrates Nakayama, to F-box acid specific phosphodegron and a amino targeting generating its (Nakayama for F-box complex autophosphorylates variable responsible degradation SCF a as The is well for 2009). as that Rbx1, al., 2009; and et protein Cullin1 al., Rogers Skp1, of 2010; et consists al., (Cunha-Ferreira et amplification Holland centrosome limit l4i atrrgltro etooeduplication centrosome of regulator master a is duplication centrosome Plk4 initiating in functions Plk4 inducing by 1). CDK1, Table duplication 1; and centrosome (Fig. Plk1 disengagement licensing by centriole regulated for cohesin PCM, required of the cleavage are of both centrosomal dissociation that of the conceivable cleavage and is the it promote Overall, to cohesin. separase active release COMMENTARY eoemttcety h ulctdcnrsmssprt and separate 4114 centrosomes formation. duplicated spindle the to bipolar entry, DNA accurate mitotic on chromosomal Before depends replicated cells of daughter distribution accurate assembly The and spindle separation bipolar centrosome and in maturation kinases mitotic of Role the TUBGCP6; to as phosphorylates Plk4 known Plk4 here, (also 2013); 2010; al., recruit GCP6 et al., Sonnen Cep152, et 2013; to Dzhindzhev al., 2010; et 2007) Cep192 Kim al., et al., with (Cizmecioglu protein et centrosome centrosomal collaborates the Kleylein-Sohn disengagement, Cep152 centriole 2005; After 1). al., (Fig. et (Bettencourt-Dias rti ,acmoetof component a 6, protein n TL om h e athe eurdfrprocentriole for required cartwheel new CENPJ) as proximal the known formation. the forms (also CPAP towards STIL, Cep135, centrioles and with loaded pre-existing together is and, of cartwheel, ends SAS6, sides the Then, of the 2010). basis al., onto structural et biogenesis the Hatch centriole constitutes 2012; the which al., initiate et to (Bahtz order machinery in factors, unidentified eitdb h 3uiutnlgs ope SCF complex ligase ubiquitin E3 the newly by the to mediated of 1). sensor Table part 1; distal (Fig. a promotes the centriole ensures daughter assembling as hPOC5 mainly formed Moreover, by acts – length. integrity centriole centriolar Cep120 CP110 final the with whereas determine together elongation, – centriolar procentriole CPAP subunits. determine to tubulin length; CP110 their with antagonistically with acts interacting CPAP this directly centriolar formed of by newly elongation microtubules the for stabilizes microtubules centrobin and triplet procentriole, nine the of nucleation uigmtss h ciiyo l4i uoeuae and autoregulated is Plk4 of activity the mitosis, During c tblnsalcmlx( complex small -tubulin b TC tevrert ooo of homolog vertebrate (the -TrCP c TR) n osbyohrcurrently other possibly and -TuRC), c TS)iiitsthe initiates -TuSC) c tblncomplex -tubulin Slimb/ Drosophila b -TrCP to nldn es D1 l1adArr Ar) in (AurA), A and described Aurora as below. been have discussed well assembly, are and as spindle mitotic maturation, subsequent Plk1 and in kinases, separation mitotic CDK1, microtubule centrosome several orchestrating of enhancing Neks, roles The by including to anchoring. distal/sub-distal is centriole maturation and mother PCM the nucleation formed centrosome phase, and newly M the facilitate centrosomes, to on assemble G2 the the appendages (Yang from from into Simultaneously, separation C-Nap1 incorporated 2006). centrosome of al., induces dissociation et the ends efficiently and as proximal the centrioles, serves centrosome to binding C-Nap1 parental by factors components, complete 1 of other al., (Figs the linker 2013) for allow al., et the site et docking He Bahmanyar Among 2007; to al., 2). 2005; et Graser and al., removed 1998; al., centriole et et Fry be after 2008; (Bahe separation to together centrosome centrosomes needs duplicated disengagement, joins LRRC45, which Cep68, 1). rootletin, (Fig. CEP250), [consisting as poles b linker known spindle (also proteinaceous as C-Nap1 fibrous of the serve process, to this directions During opposite in move e2,tgte ihPk,CK n uA euae centrosome regulates AurA, and CDK1 separation Plk1, with together Nek2A, noacmlxwt e2 n h rti hshts gamma 1 phosphatase protein the the and assembles Nek2A In preferentially with complex 2011). Mst2 a into al., phosphorylation, functions Plk1 et of Plk1 (Mardin absence Mst2 Moreover, by phosphorylating pathway 2010). centrosome disjunction selectively centrosome Mst2–Nek2A al., stimulate the of to to et upstream centrosomal Nek2A rootletin (Mardin to its allows and disjunction Nek2A which mediate C-Nap1 recruitment, phosphorylates phosphorylate centrosomal and its Mst2 Nek2A and promote Mst2 Subsequently, with 2011). al., localization. et interact (Mardin have centrosome Nek2A hSav1 regulating studies of in as upstream participate Recent known Plk1 separation (also and regulated. [Mst2 hSav1] and components tightly STK3) pathway Hippo is that Nek2A revealed of activity disjunction centrosome 2014). the centrosomal al., subsequent which with the et and (Hardy C-Nap1, interaction triggering C-Nap1 thereby its of of dissociation Cep135, and domain protein oligomerization C-terminal centriolar its the both in phosphorylates disturbs Consistently, Nek2A sites 2). that (Fig. reported 2013) and multiple recently al., Faragher colleagues et He and 2008; 1998; Fry al., al., et Fry et 2003; Fry, premitotic (Bahmanyar promote to separation centrioles centrosome parental of inter-region the from and LRRC45 including rootletin, , a Nek2A linker C-Nap1, data, mitosis, centrosomal these of the onset of on the some Based at phosphorylates 1998). whereby, 2005; proposed al., al., been et et has Fry (Bahe model and 2003; spindle separation Fry, monopolar kinase-dead a and centrosome of Faragher centriole of formation defective the in expression causes to leads Nek2A results Fry, whereas of and Nek2A interphase, mutant O’Regan active in 2007; of al., separation and et Overexpression structure (O’Regan disjunction 2009). spindle fidelity centrosome for mitotic maintain required and is and to Nek2A Nek6 whereas phosphorylation activates function, Nek9 al., by 2005). et (Fry Mahjoub, Nek7 progression and cycle Quarmby cell These regulating 2012; Nek11. in to roles Nek1 play in members, kinases 11 which, of family, consists kinase cells, serine/threonine mammalian conserved a form Neks ctnnadprasohrtu a neie components], undefined far thus other perhaps and -catenin opeetpeauecnrsm eaain h kinase the separation, centrosome premature prevent To ora fCl cec 21)17 1142 doi:10.1242/jcs.151753 4111–4122 127, (2014) Science Cell of Journal b ctnn hc ipae them displaces which -catenin,

Journal of Cell Science COMMENTARY (PP1 s (as disjunction Nek PP1 centrosome inactivating centrosome-associated inducing by The and disjunction Nek2A. centrosome centrosome to Mst2–PP1 the of contributes from the recruitment CDK1 displacement Subsequently,form Moreover, centrosomal their symbol). phosphorylation. the in bolt by promoting lightning resulting Plk1 blue LRRC45, thereby the activates and Nek2A, Cep68 then with rootletin, which separation. interaction C-Nap1, AurA, and its phosphorylates of promote disjunction phosphorylation centrosome to the Mst2 regulate triggers to phosphorylates CDK1 kinases cascade. mitotic signaling of CDK1–AurA–Plk1–Nek2A activity Coordinated 2. Fig. rosidct h ieto fE5mtlt,adtelrega rosso h ieto fcnrsm oeet ,mte etil;D agtrc daughter D, da centriole; mother The M, poles. movement. spindle the centrosome along the of plus-end forming direction other, the the towards each show moves arrows from Eg5 gray away large Active centrosomes the cascade. duplicated and Plk1–Nek9–Nek6 the motility, the Eg5 propel and of to CDK1 direction force by the pushing regulated indicate a are arrows generates that and proteins microtubules motor antiparallel other and Eg5 by regulated erae t blt obn oPP1 Plk1 to by bind Mst2 to of ability phosphorylation its of contrast, decreases splitting premature By the centrosomes. prevent to C-Nap1 dephosphorylating oeettwrstemcouuepu-n oensure al., to et (Slangy plus-end bipolarity microtubule spindle and the its separation and Thr926, microtubules centrosome at towards antiparallel Eg5 Mardin to phosphorylates 1994; binding movement its CDK1 al., facilitates secondly, et which 2011); (Dohadwala al., centrioles PP1 et parental rootletin inactivates and the C-Nap1 and displace from and phosphorylates phosphorylate to it Nek2A allow in firstly, separation ways: centrosome three promotes CDK1 and Activated Tanenbaum separation. 2012; (see Schiebel, 2) and (Fig. Mardin 2010). bipolarity Medema, by spindle the mitotic reviews separation along of also centrosome myosin, maintenance for the and essential the and is propel dynein that which forces as apart, pulling centrosomes such and pushing motors, generates of with by microtubule together other Thr926 Nek6], movement of by position by Ser1033 to that at at The and Ser1033 modified below) activated (discussed is at accumulation. CDK1 [which KIF11) the and centrosomal Eg5 as phosphorylate phosphorylated known its to Plk1 also Nek6 promote (Eg5, allows by kinesin-5 which which mitotic a Nek6, bound phosphorylates Ser869, as activates Nek9 acts activated and at being this, CDK1 Nek9 Following pathway, phosphorylation. it phosphorylating this al., et In by promotes Rapley 2011). 2011; kinase al., al., priming et et (Bertran centrosome Sdelci Nek9 of 2008; induce activity kinase the and C-Nap1 2011). al., et phosphorylate (Mardin disjunction to Mst2–PP1 the Nek2A of formation nadto,CK n uAas otiuet centrosome to contribute also AurA and CDK1 addition, In regulating by separation centrosome to contributes also Plk1 c ;hr,PP1 here, ); c NkAcmlxta oneat e2-eitdpopoyaino -a1 h etooesprto aha ih edirectly be might pathway separation centrosome The C-Nap1. of phosphorylation Nek2A-mediated counteracts that complex –Nek2A c oneat e2 iaeatvt by activity kinase Nek2A counteracts c NkAcmlxadallowing and complex –Nek2A Microtubule c hrb rvnigthe preventing thereby ,

D CDK1 AurA

? M P PP1 Plk1 c CDK1 Proteinaceous γ to P Rootletin LRRC45 C-Nap1 P linker Cep68 Nek2A Eg5 M P P st 2 fCp9 irpstemttccnrsmllclzto of localization centrosomal and or mitotic depletion 2009). NEDD1 Interestingly, the NEDD1 2011). the al., disrupts Rhee, pericentrin, for and Cep192 et (Lee required of itself is Zhang Plk1 NEDD1, and Cep192, which of Plk1 2007; accumulation maturation, by centrosomal Ser1241 al., centrosome and Ser1235 initiates at et Nigg, pericentrin and of Phosphorylation a (Lane Steegmaier and formation the with separation spindle activity 1996; centrosome Both monopolar kinase impaired and 1996). Plk1 to maturation, RNA lead of Nigg, by inhibitor inhibition or and chemical the Plk1 (Lane and microinjecting interference by 1990s Plk1 of the depletion in past 3). (Fig. identified the the progression Over dissect mitotic maximum. the to normal in possible its when Plk1 it at mitosis, of made the functions also has during oscillates evidence is highest of increasing microtubules Plk1 is decades, of ability and anchor activity cycle the kinase and cell Consistently, is the nucleate it during Plk1. and to the microtubules, by centrosome increase organize regulated to to required centrosome tightly is the that of maturation capacity centrosome of for especially step PCM, formation the spindle of and incorporation maturation The centrosome in functions Plk1 uAPk–e2 inln acd shgl euae to regulated 2). (Fig. highly mitosis before separation is centrosome appropriate cascade CDK1– ensure the to van that signaling and conceivable and is AurA–Plk1–Nek2A below) it (Nam together, phosphorylates above) an Taken 2014). (discussed (discussed Deursen, separation through AurA Plk1 centrosome permit AurA before centrosome-associated finally, of activates mechanism, 2011); al., activation et undefined Smith triggers 1995; Mitchison, CDK1–cyclin-B2 and Sawin 1995; Nek9 Nek6 P Plk1 h rca oeo l1i etooemtrto was maturation centrosome in Plk1 of role crucial The P P P Displacement ora fCl cec 21)17 1142 doi:10.1242/jcs.151753 4111–4122 127, (2014) Science Cell of Journal

Pericentriolar material M c

tblnol nefrswt h itiuinbut distribution the with interferes only -tubulin D c sPP1 as , etooedsucini ihl euae ythe by regulated tightly is disjunction Centrosome c a neatwt nhshrltdMt to Mst2 unphosphorylated with interact can c tbln hra elto of depletion whereas -tubulin, c TR,i crucial a is -TuRC, c tbln AurA -tubulin, onby hown entriole. 2A 4115 shed Plk1

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Importin-α/β Importin- AurA TPX2 TPX2 c PP6 tbln and -tubulin, α T288 / homolog β RanGTP PP1 Eg5 c c Chromosome - - Nlp/dynein ulainadsaiiain ttecnrsm,AurA centrosome, the At microtubule in centrosomal role stabilization. as its to well and the related as in mainly nucleation entry, relevant are are mitotic formation that regulating centrosomes spindle at of formation spindle AurA context and of maturation functions centrosome in The A Aurora of Roles omlmttcsidefrain oee,teunderlying the elucidated. in fully however, function being from centrosome formation; far still and are spindle mechanisms lattice mitotic PCM appropriate normal the continuous the for the of essential that is Plk1 organization notion of activity the kinase al., prompts dynamic and et but evidence (Wang duplicate this microtubules to anchor All to capacity 2011). activity as has the well that as Plk1 has its PCM, centrosome Plk1 incorporate restoring the after by only by even phosphorylated Intriguingly, been rescued 2011). centrosome al., be the et Plk1 (Mahen can of of which defects activity kinase maturation, structural the of in (Kishi inhibition results formation Moreover, in spindle 2009). delay defective al., a et and induces and mitotic centrosome Artificial arrest the before 2013). prometaphase to al., just G2, Plk1 et PCM1 of Wang by tethering 2008; PCM persistent al., cycle the et to (Petronczki cell mitosis, recruited entry centrosomal to to is interphase the from Plk1 centrosome- cycle dynamic and hypothesis, highly is a centrosome of this Plk1 fulfilling of the activity localization with thus coupling factor, Consistent the limiting in progression. where a role as cycle, act crucial might cell Plk1 the associated of stage 2014). al., to et 2007). (Conduit al., Raff, owing PCM and defects and Lucas mitotic et centrioles 2010; between induces linkage thus Cnn (Conduit unstable of and an lack PCM maturation the the Consistently, anchor centrosome to helps PCM, facilitates entire scaffold the throughout Cnn-mediated there to this from centrioles. proximity diffuses close around and very centrioles scaffold in the localized a is assemble Cnn multimerized and Because multimerize to Cnn etooa ucin utb rcsl etitdt specific a to restricted precisely be must functions Centrosomal CDK1 ora fCl cec 21)17 1142 doi:10.1242/jcs.151753 4111–4122 127, (2014) Science Cell of Journal eoemttcety aGPrlae P2fo inhibition from TPX2 releases RanGTP entry, mitotic Before Plk1 A γ ur -TuRC A Nek9 Nedd1 Kiz, ASAP M D Pericentrin CEP192 γ Nedd1 -tubulin AurA ? Furthermore, . n of ent the d t). K. c -

Journal of Cell Science otiuet h ioi nr Dtrr ta. 2004). al., of recruitment et centrosomal the (Dutertre for required phosphorylation, entry is through latter the mitotic LATS2 partially and activates to the AurA CDK1 Furthermore, to activates then contribute phosphatase its to This leading Ser353, activation. at CDC25B phosphatase the phosphorylates COMMENTARY yl Pgceae l,20) hra jb neat ihand with interacts Ajuba primary whereas cell 2007), the the al., into of et re-entry (Pugacheva upon disassembly cycle centrosome instance, promote the liberates For to which AurA. cilium, AurA of AurA activates regulation functions the HEF1 NEDD9) other to centrosome-associated contribute as to the known Furthermore, microtubule shown of (also been also HEF1 2010). have drives Bora, Arpc1b, Ajuba, and al., as and such et cofactors, maturation (Joukov turn, in assembly centrosome which, AurA, of promotes activation the a enhances and feedback localization exhibits positive This centrosomal recruitment centrosome. AurA the the facilitate to activated Cep192 might of which addition, Cep192, for centrosomes In activity affinity higher the AurA. mitotic amplify centrosomal to dramatically of that AurA AurA of oligomers AurA formation or the targets induces homodimers the which (Joukov Cep192 interaction, direct is activity a 2010). centrosomal through Cep192 its al., the for that responsible et on Instead, found is 2002). effect that al., colleagues no cofactor et have and 2010; (Kufer to AurA Livingston al., appears of localization TPX2 et centrosomal of Dishinger depletion 2008; 2005). spindle, al., et Zhang, Wang readers 2005; and information, al., et more Clarke Peloponese discussed (for see not limitations are space can these to but owing function, Tsai aspects here many spindle 2008; regulate and effectors Zhang, centrosome its and and of RAN the Indeed, (Clarke 2003). is contains al., progression that substrates et that mitotic phosphorylated conceivable for its gradient consequently, crucial is AurA–TPX2 and, secondary it AurA active a is dynamics, to of that al., and contributes et gradient formation extensively Zeng RanGTP assembly 2003; chromosome the al., spindle the that et around Kufer fact (Bayliss 2003; established the al., dephosphorylation Considering et Eyers 2010). PP6-mediated 2003; al., not the et PP1- promoting but its preventing by and mediated, Thr288 AurA T-loop O its activates 2002; (Gruss of autophosphorylation al., microtubules TPX2 spindle et directly Subsequently, to Kufer then 2003). it 2001; importin- and target al., to manner et from AurA RanGTP-dependent with released mediated a interacts envelope are in is nuclear inhibition which After TPX2 3). cofactors, (Fig. breakdown, mechanisms diverse different with through interactions 3). (Fig. AurA its by progression controlled cycle are cell that of assembly aspects al., spindle importance regulating et and in the Peset centrosome emphasize 2005; the findings al., as of these et together, Kinoshita known Taken 2005; the 2005). al., (also et of (Barros MCAK activity KIF2C) the kinesin of counteracting stability microtubule-depolymerizing by the increase microtubules for the to ch-TOG functions of centrosomal turn of formation in affinity The which, the microtubules, CKAP5). (Fu enhances microtubule-stabilizing as centrosome complex the -dependent known with TACC3–ch-TOG mitotic (also interacts the a the ch-TOG it where factor to in 2010), phosphorylates exclusively al., and, et it AurA stabilize targets nucleating TACC3 To manner, 2004). microtubules, adaptor for al., et centrosomal maturation centrosomal Toji 2006; centrosome al., the et promote (Abe microtubules to tubulin lhuhTX srqie o agtn uAt h mitotic the to AurA targeting for required is TPX2 Although on depend AurA of functions pleiotropic the Interestingly, ¨ zlu ta. 05 sie al., et Tsai 2005; al., et ¨ a / b -mediated c - ioi rgeso yntol eitn h fiin function efficient the mediating correct only and not maturation by centrosome progression ensure been mitotic to has feedback sufficient mutual Plk1 be this to Therefore, once might 2014). sufficient mitosis, al., et are during (Bruinsma activity activated complex kinase AurA–Bora these Plk1 the that and sustain proposed of AurA-dependent been amounts Medema has for degraded it minimal responsible is Consequently, is Recently, Plk1. protein Bora of Bora activation residual degraded? the most mitosis, although is in that Bora found during maintained colleagues be when indeed Plk1 of is activity this kinase mitosis the If can degradation. how case, Bora the promotes Plk1 whereas 2008). Plk1, al., et when monopolar (Chan observed inhibited induce phenotype is and the activity poles Plk1 of reminiscent spindle al., Bora formation, of et the amounts spindle (Seki from excess threshold because AurA certain required sequester a be below might Bora This 2008a). of level protein the hshrltn oaa t SxTdgo opooeits promote to SCF degron by DSGxxT Moreover, degradation and 2011). its with Rhee, at interaction by and AurA Bora the of Lee function centrosomal phosphorylating for the 2009; for al., regulates et also required al., Plk1 Luca activated of accessible et (De is activation phosphorylation Eckerdt AurA Plk1 being the enhances 2006; further of and Plk1 Plk1 AurA, by entirety of TPX2 of activation of the initial localization results the contrast, centrosomal T-loop to which By leads the phase, this Plk1. AurA; G2 of by during phosphorylation centrosome Thr210 an Plk1 the of with on in that place interacts is take directly foremost might AurA, which (Macu Plk1, of of functions activator many the Plk1 Among and AurA between Feedback elto fNMhsn feto h AurA-mediated AurA the within sites Thr288. on activation CDC25B at effect different of not that that no abolishes suggesting but Ser89 but the has Ser353, Thr210, activation), Plk1 at at NPM of its AurA phosphorylation autophosphorylation for of with its necessary Depletion shown interacts is induces been NPM (which has 2012). and B23) al., PAK1 centrosome as et known of (Reboutier also activity (NPM, maturation AurA. of kinase nucleophosmin activation and the the in duplication (Zhao decrease of a Thr288 centrosome to at Inhibition owing delays it 2005). phosphorylating dramatically by al., serine/ at it et another activates AurA to that and binds of directly 1), AurA reported kinase phosphorylation (p21-activated colleagues PAK1 the kinase, threonine and induce Manser al., indirectly in Thr288. et mechanism, common they (Molli a share entry cofactors that these of mitotic all at substrate note, disturbing AurA Of a 2010). of thereby also activation the but centrosome, inhibits activator the Arpc1b of an depletion entry only and not AurA, mitotic in is and which, Arpc1b Macu CDK1, Finally, maturation 2006; of al., centrosome activation et the (Hutterer to to contributes leads to AurA this turn, with – cooperates Plk1 Bora transition Furthermore, activate G2–M 2003). the al., accelerate to et phase (Hirota G2 late in AurA activates itntptwy o uAatvto lutaeahighly cycle. induce cell a the to a during for cofactor function illustrate manner regulated AurA-mediated given spatiotemporally particular a activation each in activity allows kinase AurA AurA that phosphorylating network for by controlled these pathways functions together, Taken distinct different substrates. centrosome-associated apparently distinct its fulfill tapasprdxclta oamdae h ciainof activation the mediates Bora that paradoxical appears It oercnl,anvlmcaimo uAatvto by activation AurA of mechanism novel a recently, More ˚ e ta. 08 eie l,20b.I hscs,Bora case, this In 2008b). al., et Seki 2008; al., et rek ora fCl cec 21)17 1142 doi:10.1242/jcs.151753 4111–4122 127, (2014) Science Cell of Journal ˚ e ta. 08 eie l,2008b). al., et Seki 2008; al., et rek b -TrCP hrb keeping thereby , 4117

Journal of Cell Science etooefntosta eutfo yrgltdmitotic dysregulated from result that abnormal However, functions fidelity. spindle above, mitotic centrosome bipolar discussed the as ensure controlled, to tightly are functions Centrosome spindle- inducing in defects role assembly kinase kinases: mitotic adequate of maintaining Dysregulation by also but Plk1. mitosis, of activity in AurA of COMMENTARY 4118 Plk4, of depletion to and similar (Tanenbaum Furthermore, formation 2010). spindle the initial enhances monopolar Medema, proteins for of motor power of probability bipolarity, mislocalization the spindle centrosomal of provide maintenance the that the microtubules and proteins of Because separation motor the centrosome dynein. by mislocalization generated and along forces Eg5 movie the pulling as and AurA pushing such to the or proteins centrosomal leading motor Plk1 and microtubule nucleation, of maturation inhibition centrosome microtubule al., disturbs Alternatively, et Steegmaier dramatically 4A). 2011; (Fig. al., et Smith or 2007) 2011; centrosome- mitotic al., interference the et induced and of (Mardin RNA for monopolarity spindle Plk1 consequent cause by the the by and likely AurA defects As the regulated separation or is Eg5. are inhibitors Plk1 and Eg5 chemical of Nek2A and inactivation of Nek2A AurA, both activity is process of the this and activities on mitosis, of dependent for onset centrosomes the partly duplicated factors, at joint separation the timely liberate particular their to centrioles away parental move when connecting to For has linker manipulated. observed proteinaceous experimentally the are frequently instance, kinases, be mitotic especially can they Tanenbaum 2007; al., et Steegmaier 2010). 2011; Fry, Medema, and and al., (Faragher et spindle Mardin monopolar frequently the a 2003; kinases, of of mitotic formation of bipolarity the inactivation induces ensure the to and to separation due duplication, MTOCs maturation, centrosome as of Failure act spindle. mitotic into and incorporated poles are centrosomes opposite duplicated the mitosis, Before spindles, formation mitotic spindle Monopolar aberrant 4). (Fig. of spindles is multipolar that formation and cycle monopolar the including centrosome abnormal by an accompanied induce typically kinases B Multipolarspindleassembly A Monopolarspindleassembly lhuhmnplrside r o htcmo nnature, in common that not are spindles monopolar Although Key Chromosome Microtubule Daughter centriole Mother centriole PCM rcngttruhtecl yl ihfie yoiei,leading cytokinesis, failed with 2007). cycle activation (Fukasawa, cell checkpoint multiploidy the spindle to through of get consequence 2010). can cell-cycle a al., or a as et undergo die Hatch either and 2005; spindle arrest spindle al., monopolar monopolar a et a containing Habedanck of Cells 2012; assembly al., the et for (Bahtz eventually pole duplication, means single centrosome some a by of generates centrosome pericentriolar solitary failure the remaining the in or and results Cep152 protein GCP6 centriolar component the of depletion sebycekon SC n eut ntefiueof failure the spindle in the (Anand results amplification override centrosome and to drives then able (SAC) which al., cytokinesis, is et checkpoint (Mundt AurA to spindle lines assembly excess bipolar appear cell normal whereas not a cancer does 1997), of various formation Plk1 the of of disturb features PCM Overexpression 2007). common (Fukasawa, are and AurA, and 2008; splitting 2008). al., al., et et supernumerary Yang (Basto centriole 2007; multipolarity that Fukasawa, spindle likely in result highly premature disintegration assembly is the It to lead centrosomes, spindles. to potential multipolar the have of also defects functional centrosome spindle, the mitotic of the of monopolarity than Other formation spindle Multipolar uha ien e9 telretioomo IF)adCep57, prevent and components, to PIBF1) of PCM order isoform In largest some (the 4B). of Cep90 (Fig. ninein, activity 2007) as Nakamura such the al., 2012; et multipolarity, al., Thein spindle et 2009; trigger to al., (Matsuo MTOCs et as formation serve as spindle also splitting, can multipolar PCM, centriole fragmented premature the from as well resulted to has ability that their centriole to owing 4B). spindle (Fig. bipolar organization multipolar microtubule functional a initiate trigger of a preferentially centrosomes formation assembling amplified the the of 1), supernumerary (Box capable have spindle that Sonnen cells are 2007; the al., of inappropriately centrosomes et some Peel Although to 2007; 2013). al., al., sufficient Hatch et et 2005; Kleylein-Sohn is 2010; al., ectopic al., et STIL, et (Habedanck Furthermore, reduplication such and components centrosome biogenesis, 2002). centriole SAS6 induce centrosome of steps Cep152, al., other initial the as of for et required and are Meraldi that Plk4 of 2003; overexpression al., et h infcn peuaino ioi iae,sc sPlk1 as such kinases, mitotic of upregulation significant The uigmtss h xr etooe htcnanol one only contain that centrosomes extra the mitosis, During ora fCl cec 21)17 1142 doi:10.1242/jcs.151753 4111–4122 127, (2014) Science Cell of Journal cnrsmlPMcnas c setaplst induce to poles (right). extra assembly as spindle act multipolar formed also newly can or PCM disintegration acentrosomal pole spindle from spindle PCM resulting multipolar acentrosomal a fragmented assemble Furthermore, to (middle). MTOCs impaired can as centrosomes deficient act These centriole. centrosomes single the a of of containing formation each the with in centrosomes results supernumerary mitosis centrioles into of entry spindle splitting before multipolar premature induce Aberrant can (left). that formation MTOCs extra centrosomes as spindle. Overduplicated act monopolar assembly. a spindle assembling Multipolar for (B) serve pole also single can a single centrosomes as a unseparated forms Right, a centrosome pole. of single spindle formation the the as to spindle, leads monopolar duplication centrosome of failure of defects bipolarity. induce spindle abnormalities Centrosomal 4. Fig. A oooa pnl seby Left, assembly. spindle Monopolar (A)

Journal of Cell Science COMMENTARY osrcino outfcsdsidepls(i.3.Evidence 3). the (Fig. for poles kinases spindle 2012). essential focused al., are et robust of AurA Wu of 2012; stabilizing and construction al., Plk1 and et both Logarinho Furthermore, bundling 2011; tensions Rhee, microtubule the and withstand (Kim to facilitate and microtubules to centrosomal coordinated is ae ) hs h itntaiiyo cuaeyduplicated accurately centrosomes. additional of contain also ability that to cells contribute in distinct partially bipolarity might spindle (see the microtubules 2008) nucleate erratically to al., Thus, centrosomes et are subsequent B). (Basto matrix asters panel cytoplasmic and microtubule the within robust bipolarity dispersed without spindle centrosomes 2012). induces the al., et corrects Marthiens the so 2007; clustering (Fukasawa, inactivate cytokinesis and centrosomal to the attachment SAC finally, –microtubule Quintyne 2005); 2008; aberrant extra al., al., the et centrosome- (Kwon drive groups et to the distinct forces two pushing into crosslink centrosomes focused minus- microtubule generates motors the which towards ends, protein move and microtubules prolonged the this anchored during delay, second, et 2013); Chiroli Kapoor, mitotic 2008; and al., et Foley (Basto activates 2009; delay al., centrosomes mitotic in extra results which the and SAC, the from emanate between as attachment that is of clustering incorrect microtubules A centrosomal the panel this (see et first, explain 2008) Kwon to follows; al., 2008; model et al., One Yang figure). et 2005; the al., (Basto et SAC Quintyne the 2008; (such and termed sections al., proteins kinesin) motor two and integrity, dynein mechanism, into microtubule as of with centrosomes regulation such supernumerary the multiple formation survive under spindle the One multipolar grouping to use prevent by can characterized. order from clustering, far cells centrosomal are fully In these and multipolarity, cancer being 2013). spindle failed block to al., al., and centrosomes, mechanisms et Karna et arrest 2009; supernumerary is al., mitotic Marthiens et that cell subsequent Ganem 2011; for spindle 2007; detrimental mitotic to (Fukasawa, be cytokinesis the owing might of centrosomes proliferation multipolarity excess hand, by and mediated aneuploidy, other of the generation hand, Excess on the one on promote generated. tumorigenesis; centrosomes in are multiple roles dual centrosomes play might supernumerary centrosomes mechanisms represent which to thought are by fusion cell and cytokinesis of reduplication, Centrosome excess with spindle mitotic bipolar centrosomes a Building 1. Box nrgigy twsas on httennpl-soitdextra non-pole-associated the that found also was it Intriguingly, A Key Centrosome enovo de xr etil omto,failure formation, centriole extra B Chromosome Microtubule irtbl-eitdtnin hrb nuigPCM of basis structural inducing molecular al., of detailed et Luca the balance (De thereby Nevertheless, formation the 2008). spindle multipolar and and of tension, disturbs fragmentation activity dynamics probably accumulation kinase microtubule which microtubule-mediated AurA MCAK, centrosomal centrosomal of of the loss dissociation al., the and that et ch-TOG Marumoto shown stimulates 2008; been also al., dramatically has antibodies et It AurA Luca by 2003). of down (De knocked microinjection multipolarity been has exhibit or AurA (Eot- formation, which interference spindle in unclear cells RNA monopolar manner; the than remains of Other microtubule-dependent fraction 2010). a mechanism Plk1- al., a maintain et underlying and to Houllier in the the sufficient ASAP, integrity promotes is however, formation of pole Plk1 ASAP spindle localization of spindle Furthermore, phosphorylation spindle multipolar 2006). mediated and induces al., from centrosome PCM et and the of (Oshimori centrioles dissociation and fragmentation the causes depletion Kiz therefore, from forces; of centrosomes traction mature tethering microtubule Oshimori protect for under to bond 2010; collapsing centrioles a to al., as tightly acts PCM et then including the Kiz (Eot-Houllier Phosphorylated 2006). substrates, ASAP al., et by and mainly centrosomal (Kiz) integrity Kizuna pole different spindle maintains phosphorylating Plk1 that shown has o C opnnsaergltdb ioi iae to kinases mitotic obscure. by remains bipolarity regulated spindle maintaining are in roles components perform PCM how ehgl hlegn odtrieterl htdfcsin defects that we date, role To the tumorigenesis. determine in have to function challenging centrosome will it highly cells, cancer be in frequently occur amplification, between centrosome relationship the to of PCM. tool the control powerful and centrioles a spatiotemporal be the to cell prove dissect next could analysis the imaging and single- molecular with duplication combined microscopy centrosome super-resolution Perhaps restart cycle. to upon centrioles exit from PCM mitotic the what of determine dissociation of the to are promotes interesting regulation exactly that be the will forces it under the Moreover, microtubules kinases? sustain mitotic spindle to the maintained from integrity generated its centrosome is entities the how around the PCM and are the what of organization remain; the questions determine of that number a PCM the ordered but highly structure, gain and elegant the to of able cell understanding been superficial just some the Furthermore, have progression? we between microscopy, mitotic super-resolution substrates using normal coupling and the centrosome-associated cycle centrosome ensure of to phosphorylation between maintained dephosphorylation balance the centrosome is and uncontrolled How kinases? preventing mitotic substrates in particular of dephosphorylating role by centriole perhaps a of amplification, have onset PP2A, PP1 the as such and at phosphatases, whether activity is question Another kinase biogenesis. Plk4 what unclear monitor remains it factor(s) duplication, centrosome for although crucial instance, is For Plk4 of unknown. largely remain cell progression and understanding formation cycle spindle mitotic to in cycle spindles. our centrosome function the mitotic kinase coupling and underlying bipolar mechanisms enhanced of exact separation the assembly Nevertheless, the duplication, greatly in function centrosome centrosome have in involved kinases, maturation Aurora are and of Plks characterization CDKs, that and Neks, identification including the kinases, mitotic decades, past the Over perspectives future and Conclusions ept h atta etooeanraiis especially abnormalities, centrosome that fact the Despite ora fCl cec 21)17 1142 doi:10.1242/jcs.151753 4111–4122 127, (2014) Science Cell of Journal 4119

Journal of Cell Science etnor-is . orge-atn,A,Cretr . iabli M., Riparbelli, L., Carpenter, A., Rodrigues-Martins, M., Bettencourt-Dias, M. D. Glover, and M. Bettencourt-Dias, Regue S., Sdelci, T., M. Bertran, W. J. Raff, and A. A. Hyman, K., Kinoshita, P., T. Barros, Lehmann, C., Antony, U., Haselmann-Weiss, M., Arnold, J., Seidler, R., Bahtz, T., E. O’Toole, Jr, H., T. Giddings, A. G., J. E. Deluca, Nigg, D., D. and Kaplan, F. S., Bahmanyar, Leiss, J., C. Wilkinson, D., Y. Stierhof, S., Bahe, Delouve P., Hergert, J., Azimzadeh, als,R,Sro,T,Vro,I n ot,E. Conti, and I. Vernos, T., Sardon, and R., A. Bayliss, Khodjakov, A., Franz, N., Peel, T., Vinadogrova, K., Brunk, R., Basto, J. Gopalakrishnan, and T. Avidor-Reiss, A. E. Nigg, and C. Arquint, nn,S,PnhnLw,S n ektrmn .R. A. Venkitaraman, and S. Penrhyn-Lowe, S., Anand, omto,btta tisedidcsaotssadtissue mouse and during of apoptosis to division leading asymmetric induces thereby the cells, instead disturb stem neural also it tumor might induce and that degeneration to but insufficient that is formation, argue alone studies other amplification 2008), al., centrosome et (Basto Raff initiate flies Although can in amplification tumorigenesis progression. centrosome cancer that reported of colleagues and consequence the are the aberrations or centrosome whether cause idea concrete no have still COMMENTARY 4120 T. Yamamoto, and J. Fujimoto, K., Haraguchi, M., Ohsugi, Y., Abe, References and 91313302 31030044, numbers [grant 31371365]. [grant Science (NSFC) Natural China China National of of and the Technology Foundation and Research and 2014CB138402]; Basic Science and Key of 2010CB833705 State Ministry numbers the the from of grants Plan by Development supported was work This Funding interests. competing no declare authors The interests Competing spindle limitations. mitotic space in to centrosome due the cited of be other functions that cannot apologize the formation the We to comments. all relating valuable and works for illustration excellent laboratory scientific our for of editing, China) members copy Chengdu, other for University, China) (Sichuan Beijing, University, Li (Peking Si Bruce Iain thank sincerely We Acknowledgements the disturb cancer for to separation avenues new centrosome provide therapy. sufficient might ablating the insights by Such are investigate clustering. spindle or to that bipolar be of will inhibitors formation to research Therefore, of future 2013). and al., for mechanisms et spindles area Marthiens attractive bipolar 2009; an excess al., harbor functional et that (Ganem cells assemble survive of ability to the from centrosomes stem might difference partially This least 2013). at al., et (Marthiens development brain emn,L,Gt,M . am,N,Blox . alii .adGoe,D M. 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