Journal of Cell Science eateto iceity nvriyo ecse,LnatrRa,LietrL19N UK 9HN, LE1 Bayliss Leicester Richard Road, Lancaster and Leicester, Sabir of R. University Biochemistry, Sarah of O’Regan, Department Laura Fry*, M. Andrew of family NEK the by regulation cycle Cell Commentary s fNK steaetctresi ua cancer. human potential in the targets debate therapeutic the a as also is to NEKs we of treatment, contribute use targeting cancer NEKs because to we 2003; Moreover, approach how Here, proven division. al., of 2005). cell et Mahjoub, knowledge of O’Connell process and current 2011; Quarmby our al., 2007; review al., et et (Moniz O’Regan NEKs NIMA-related or the mitosis: (PLKs). in kinases roles kinases key have protein members less-well-characterised Polo-like whose family, another, and a is cyclin-dependent kinases there date, the However, Aurora include To regulate (CDKs), These that mitosis. identified. families kinases orchestrate been kinase protein have that mitosis of events number the small relatively that, dictate substrate turn, the of of in hundreds regulate many phosphatases, of understood protein counteracting status phosphorylation their Cell-cycle-dependent best with control. along the mitotic kinases, errors. of among without mechanisms mitosis is the undergo phosphorylation to redundant, Not the them often Reversible on mitosis. enable and that complex, occurs during developed mechanisms that have assembles segregation cells Typically, that surprisingly, errors resistance. of spindle of result drug microtubule-based a process as the of arise in instability selection chromosome malignant and drive of aneuploidy acquisition each and the at rapid to a lead properties with can instability, of tumours that provide gain potential defects evolutionary chromosome or these Together, loss division. exhibit frequent chromosomes. cell is many cancers too there meaning commonly, whereby aneuploid, many more are or, cells few Furthermore, cancer too human have of they organism. an majority of health vast the The to crucial is stability genome Maintaining Introduction cancer. in targets therapeutic as those potential on their microtubule-dependent emphasis particular coordinate consider with and to NEKs, control, evolved words: human have cycle Key the of NEKs cell functions that in the hypothesis involved review current are we Here, the that that cells. to members structures non-dividing have signalling microtubule-based led family and the members checkpoint has dividing cilia, assembly both family This within other function in spindle bodies. in NEK also processes NEKs breakdown, basal NEK8 several microtubule- for and envelope from the Roles that NEK1 nuclear nucleated response. of Interestingly, clear damage condensation, proposed. establishment are DNA been the is chromatin expressed. the also to as it have in are contribute cytokinesis implicated such entry, NEK9 and been NEK11 progression, and have mitotic mitotic to NEK11 NEK7 for and of NEK6, NEK1 NEK10 essential NEK2, aspects been NEK1, named particular, are have whereas proteins In spindle, NEKs, NEKs control. mitotic distinct or human cycle based kinases, genetically cell that NIMA-related in eleven evidence discovery, roles where that no important humans Since is entry. including there mitotic eukaryotes, Although for most required is in fungus that identified filamentous kinase the serine/threonine in mutants a cycle (NIMA), division cell for screens Genetic Summary 10.1242/jcs.111195 doi: 4423–4433 125, ß Science Cell of Journal ( correspondence for *Author 02 ulse yTeCmayo ilgssLtd Biologists of Company The by Published 2012. E,NM,Mtss etooe irtbl,Mttcside N aaersos,Cilia response, damage DNA spindle, Mitotic Microtubule, Centrosome, Mitosis, NIMA, NEK, [email protected] ) n te ls fpoenkns.NK0bek hsrl by its rule to this regards with breaks but NEK10 domain, kinase kinase. located and protein centrally kinase a of having serine/threonine class a with other of similarity any typical sequence are of closer that feature shares contains defining motifs that domain The the catalytic 1). all N-terminal an (Fig. is NEK11 family protein to this NEK1 encode that as Xenopus such 1998). al., Tetrahymena et protists, Wu 1998; from al., et Krien Hagan, and not 2004; Grallert al., are 2000; et al., Grallert they et 2002; Souza cytokinesis, (De viability and for chromatin required assembly including progression, spindle cycle cell the condensation, of to contribute aspects localises NEKs various yeast that to these Fin1 although protein However, spindle). yeast mitotic budding the to unrelated pombe a Schizosaccharomyces as complex Cdc2–cyclin-B in the subsequently progression with 1995). mitotic been Osmani, par of has a regulator on It master exit, it mitotic 1988). for puts essential al., is which NIMA (Osmani et of prematurely degradation Osmani that mitosis discovered 1991; enter al., Loss-of-function to attempting et 1983). cells to Morris, leads and in division (Oakley cell mutations for screen mutants genetic a in cycle colleagues and Morris never-in-mitosis Ron by the of is (NIMA) NEK A the of member founding The family kinase NIMA-related The sd h yeasts the do as Eshv o enietfe nawd ag forganisms of range wide a in identified been now have NEKs seglu nidulans Aspergillus ieadhmn.Hmnclsepeseee eleven express cells Human humans. and mice , omliellrekroe,including eukaryotes, multicellular to , nimA Aspergillus acaoye cerevisiae Saccharomyces as 2ars,weesoverexpression whereas arrest, G2 cause seglu nidulans Aspergillus e otedsoeyo ee-nmtssA never-in-mitosis of discovery the to led Chlamydomonas xrs igeNM-eae , NIMA-related single a express (called fin1 Aspergillus hc a identified was which , oeta hsis this that note ; , Aspergillus (called Plasmodium IAthan NIMA Drosophila kin3 P and (Pu 4423 and ) and , Journal of Cell Science otekns oano IAad ntewoe oec other. each to moderately whole, the only on and, family. NIMA are of NEK domain domains kinase the the to kinase to belongs NEK with conserved, clearly the it Generally, sequence a acid residue phenylanine a amino and NEKs. (Met86) several in residue present gatekeeper is bulky carb it However, follows: a inhibitors. ATP-competitive as has of coloured NEK2 design are the of inhibitor constrains severely pocket the which in ATP-binding combination, ( ( Atoms rare The red. red. 4A4X). a cyan. coloured code coloured is fluorine, (PDB is This is loop (Phe148). red; ADP ADP activation oxygen, and and the yellow; ( orange of orange acids. sulphur, conformation coloured coloured amino blue; inactive is is aa, an conformation’ site, included. induces ‘upward is active that kinases the inhibitor the the ‘hybrid’ in into of Tyr70 down function (ligh 2W5A). points and domains code localisation which 1) activation, (PDB Tyr97, condensation the chromatin 2WQN). about of code known (regulator (PDB is RCC1 what NEK7 (red), of motifs summary degradation A (green), (yellow). coiled-coils family. repeats (purple), (NEK) domains kinase kinase the protein are NIMA-related Shown human The 1. Fig. 4424 ora fCl cec 2 (19) 125 Science Cell of Journal , 05%iett nteaioai ee both level acid amino the on identity 40–50% ( A ceai iwo h lvnhmnNK,hglgtn hi oanorganisation. domain their highlighting NEKs, human eleven the of view schematic A ) oan hc suulyfudi iae htaepositively are that kinases in catalytic found the usually within is motif which (HRD) His-Arg-Asp domain, a human contain eleven kinase All NEKs their identity. sequence because 85% respect, than this more share in domains unusual are NEK7 and NEK6 D anfe iwo E2budt oetadselective and potent a to bound NEK2 of view Magnified ) C rsa tutr fhmnNEK2 human of structure Crystal ) B rsa tutr fhuman of structure Crystal ) le n armadillo and blue) t n ry nitrogen, grey; on, h base the t Journal of Cell Science 01 else l,20;Ri ta. 02.I em fa of terms In that 2002). found al., studies et early Roig sequence, 2007; consensus al., phosphorylation al., et et Bertran Rellos 2003; is al., it et 2011; some (Belham others kinase In in upstream modification. an whereas by activating autophosphorylated, targeted an is residue for this site NEKs, probable loop, activation a the within is residue which threonine or serine they a and possess 1996), all al., et (Johnson phosphorylation through regulated aepaea el oefo nepaeit ioi.This mitosis. into interphase from that move changes cells architectural the as in place participate NEK6, take entry. NEK2, NEK9 mitotic that and established for well NEK7 required been now absolutely has is it Nonetheless, NEK human entry mitotic single in No NEKs of role The emerging 3. are Fig. these higher in NEKs summarised that cell-cycle-regulated explore in are pathways of to and the control activity invested about cycle the details being control Furthermore, cell now 2). in (Fig. is functions roles effort clue have and first the eukaryotes might provided NEKs observation fission This that into 1994). al., introduced et when O’Connell also entry but mitotic cycle, cell yeast, of the of aspects stage any induces causes during only events mitotic not initiate NIMA of NEKs Overexpression human for 2002). functions al., Mitotic et (Roig NEK9 of C-terminus by the certainly NEK7 in and sequence NEK6 almost of a recognition NEKs the is by this example, Indeed, other and for regulation, illustrated, as 2010). the well as recognition, al., of substrate to et contribute regions Meirelles non-catalytic (Vaz the important recognition be might substrate that kinase extension for a N-terminal spindle of short solely the a consist with of They domain domain. independent C-terminal NEK7 a is and lack NEK6 that notably 2006). al., manner et (Hayes a (SAC) checkpoint in assembly mitosis degradation NEK2 early triggering thereby in APC/C, the of subunits with interaction core direct a mediates MR-tail the Unusually, complex/cyclosome(APC/C). anaphase-promoting and the which box by Pu recognition (MR)-tail, (Lys-Glu-Asn) allow dipeptide 2001; KEN methionine-arginine al., C-terminal a a both et and contains (Hames NEK2 that degradation 1995). regions for Osmani, non-catalytic protein the the within target motifs including destruction NEKs, contain Several 2012). al., et activation Aspergillus Zalli non-catalytic and/or 2011; localisation the al., et their that in (Bertran regulate finding autophosphorylate to the region NEK9 by C-terminal supported and to as a NEK8 protein, likely both the also usually in is elsewhere the autophosphorylation occur of motif, However, loop activation domain. oligomerisation the kinase within occur activation. an can and Autophosphorylation relatively autophosphorylation promotes one is which The coiled-coil, length, 1). feature in (Fig. divergent organisation common highly domain are and NEKs sequence the of substrates. regions NEK C-terminal on mapped been do have that motif sites this phosphorylation into as fall However, requirements, not 2002). strict al., not et are Lizcano these 2011; the al., at et (Alexander similar leucine, LxxS/T) hydrophobic or a a phenylalanine have preferring ideally NEK6 NEKs residue, and human NEK2 More 1994). both that al., with indicated et preference, (Lu have acid) position studies amino any at recent is phenylalanine ‘x’ for where FxxS/T, preference (i.e. strong a has NIMA ncnrs ihtecnevdctltcdmis the domains, catalytic conserved the with contrast In Xenopus IAadvrert E2 aeas ensonto shown been also have NEK2, vertebrate and NIMA oye rhmncls(uadHne,1995; Hunter, and (Lu cells human or oocytes Aspergillus 2 oiin(F/ position 3 el to cells 2 3 iasml h ehra h ne fmtsst facilitate mitotic by regulated to the is it mitosis how of and of tether establishment the onset of to the organisation is The the and NEK2 spindle. of at separation role tether The centrosome duplicate. the centrioles and two disassemble S proximity during the or place while in the close tether, remains G2 of and This centrioles ends in daughter proximal proteins. During and the mother filamentous held between recruited. of extends are linker, tether inter-centriolar are loose centrioles a two nucleation through the microtubule proteins which interphase, in to centrioles, involved called barrels, microtubule-based restricted be 1). not (Box might cells this dividing that to and microtubule organise, their the they exert and that NEKs structures centrosomes that of crucial hypothesis This regulation the 2006). through to al., functions led et has Wloga Mahjoub evidence 2005; 2002; of al., al., piece found et et Prigent Krien are 2002; 2000; al., (for al., et humans, et (MTOCs) Souza centres to De see microtubule-organising examples, fungi 2007). centrosome respective al., the from the in et at NEKs, step (O’Regan many key disjunction a Importantly, centrosome regulates namely it Fry core where 2003; cycle, a its al., 1998b), is et and NEK2 al., (Andersen phase. regulated, centrosome et G2 human cycle and the S cell of in component is peak activity NEK2 and NIMA, expression Like depth. any Aspergillus breakdown. envelope nuclear and pore disassembly nuclear (NPC) spindle condensation, complex chromatin mitotic potentially, and and, separation assembly centrosome in functions includes oprt oesr omto farbs ioa pnl hti aal of capable is that spindle bipolar robust a NEK9 of and formation NEK7 ensure NEK6, Our NEK2, to differentiation. mitosis, cooperate during and that progression is cycle understanding progression. cell current cycle during cell events in different NEKs to for Roles 2. Fig. ial,teei vdneta E1 E8adpsil E4 aekey have NEK4, cells. possibly post-mitotic and in NEK8 cilia transition. NEK1, in G2-M that roles the evidence at is all particularly there have signalling, Finally, NEK11 DDR and in NEK10 implicated NEK1, been prolactin-dependent whereas to proliferation, contributes and NEK3 signalling mitotic mitosis, of breakdown Beyond aspects envelope cytokinesis. other nuclear and to condensation, contribute chromatin also including might progression, They SAC. the satisfying nhmncls etooe r opsdo two of composed are centrosomes cells, human In to related closely most the is NEK2 NEKs, human the Of G2-M checkpoint NEK11 NEK10 NEK1 Proliferation and signalling IAadi h is E hthsbe tde in studied been has that NEK first the is and NIMA NEK3 Esi elccerglto 4425 regulation cycle cell in NEKs G2 M S G1 G0 Mitotic progression NEK9 NEK7 NEK6 NEK2 ua Escontribute NEKs Human Cilliary function NEK4 NEK8 NEK1 Journal of Cell Science microtubules. e encaiid N rascue yI ciaeteknssAMadAR hc hshrlt n ciaeCK.CK hshrltsNK1on NEK11 phosphorylates bin CHK1 promotes CHK1. This NEK11. activate by and phosphorylation occurs for phosphorylate CDC25A this which in which ATR, Ser82) by (e.g. and pathway motifs ATM DSG the priming kinases however, thereby arrest; the Ser76, cycle activate on of cell CDC25A IR and to by it, leads activating caused This thereby breaks N ERK1/2. Ser273, activates Activated DNA and 2011). clarified. the phosphorylates al., been ( then and et yet 2011). which (Bertran microtubules ( al., MEK1, PLK1 (Eg5, 2011). et of by components al., activation Wei activation phosphorylate et causes and 2004; subsequently (Sdelci phosphorylation al., which formation subsequent et NEK7, for spindle Lou NEK9 and mitotic 2008; primes NEK6 al., which phosphorylate NEK9, et then in (Du can displace sites MAD1 t their of with NEK2 causing number allows interacting a rootletin, This and phosphorylates and 2011). 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Fry the 2003; al., and Fry, NEK2, et and Faragher Yang and 2005; CEP250) 1998a; al., the as et are known (Bahe sequence, (also rootletin in major C-Nap1 related two proteins, are coiled-coil However, which large elucidated. linker, fully the been of components yet not have NEK2 control. cycle cell in NEKs regulating Pathways 3. Fig. 4426 b TC,wihlast h bqiyainaddgaaino D2A hc,i un rvnsCK–ylnBatvto n ioi nr.MTs, entry. mitotic and activation CDK1–cyclin-B prevents turn, in which, CDC25A, of degradation and ubiquitylation the to leads which -TrCP, ora fCl cec 2 (19) 125 Science Cell of Journal B E2mgtas oaiet h ieohr fuaindsse hoaisdrn ioi n ar u oei h A through SAC the in role a out carry and mitosis during chromatids sister unaligned of kinetochore the to localise also might NEK2 ) C Spindleassembly A Centrosome disjunction disjunction Centrosome Inter-centriolar Mitotic entry Centriole pair linker CDK1 Eg5

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degradation Proteasomal etfo the from ment b Following -catenin a not has EK9 ding o Journal of Cell Science itne Brrne l,21;Kme l,20;ORgnand O’Regan 2007; al., of et failure Kim 2011; to weak al., leads interpolar of et and NEK9 (Bertran density formation microtubule distances or and/or reduced with NEK7 prophase spindles mitotic NEK6, in 2002; separation of al., centrosome loss through et confirmed revealed the have been (Roig which these has that studies, formation role depletion (RNAi) a that spindle interference Such RNA in 2006). evidence al., role et provided Yissachar a had microinjection proteins proteins antibody overexpressed using and studies functional early and mitosis investigated. be feedback to NEK9, a remains promotes phosphorylates of this NEK7) activity although possibility (and NEK6 the NEK6 kinases raises whereby that mechanism, also fact these NEK9 The with of 2009). interaction al., conformation et auto-inhibitory (Richards by NEK7 an and NEK6 of both activates disrupting domain activate a non-catalytic allosterically on NEK9 to the However, appears with that 2003). NEK9 interaction al., between for assumed direct et similarity (Belham level, kinase been manner second sequence upstream has same the high an it in the NEK7 as NEK7, of acts activity. and basis NEK6 NEK9 NEK6 the for level, important On first is NEK6. a that on loop activation Thus, the in site ob cie(ehme l,20;Rpe ta. 08 oge al., et Roig 2008; al., NEK6 et phosphorylate This can Rapley NEK9 2003; Furthermore, al., NEK6. NEK6 2002). et requires (Belham with and active mitosis be association during to prominent physical more is its interaction through identified n E8cudrsl rmtels facl yl ucino these of function cycle cell a of kinases. loss two the NEK1 from of result loss could or NEK8 mutation and the from result that of symptoms some disease Hence, the PKD. to Moreover, contribute or directly regulation 2012). could cycle orientation spindle al., cell re-entry aberrant et cycle signalling, ciliary cell Spalluto defective on besides 2005; resorption Mahjoub, cilia stimulate and to (Quarmby both or exit to cycle following contribute formation cell cilia somehow induce to either might plausible to NEKs processes evolved that these a coordinate suggested been have provides even has NEKs which It processes. why the ciliogenesis, of for in assembly explanation the and in spindle both mitotic involved and intimately Centrosomes 2011). are al., microtubules et (Coene been stability recently also in has implicated NEK4 Interestingly, 2011). cilia al., Mahjoub, of et and Thiel process Quarmby 2005; 2008; post-mitotic al., the et (Otto in function roles and/or assembly have of to thought identification are in NEKs the mutations then, Since to 1999). NEK8 al., led et Vogler have 2000; al., models PKD the in studiesmutations mouse and (PKD), two as disease kidney now on to polycystic is characteristic is referred disorders typical these A collectively it of 2011). inherited are al., and of et In which (Bettencourt-Dias surface, range ciliopathies disorders, wide cell 2007). a genetic the underlie al., human signalling cilia at defective regulating et initiated that in understood (Parker are roles that key length have pathways ciliary cilia be primary regulating might vertebrates, NEKs these in that considerably, suggested crucial expanded have has studies organisms functional and these al., in genes et of NEKs complement Wloga encoding the 2002; fungi, al., non-ciliated with et Compared Mahjoub 2006). 2005; Quarmby, and (Bradley ciliated in studies as through such revealed eukaryotes, first unicellular were ciliopathies cilia in and NEKs for function Roles ciliary in NEKs 1. Box h iaeatvt faltreo hs Esi lvtdin elevated is NEKs these of three all of activity kinase The aeas enietfe nhmncloah ains these patients; ciliopathy human in identified been also have Nek1 and Nek8 Chlamydomonas ee Lue l,20;Uahaet Upadhya 2002; al., et (Liu genes and Tetrahymena nvitro in NEK1 and na on uC,wihiiitsmcouuenceto,and nucleation, microtubule initiates the which phosphorylates the of TuRC), components associates NEK9 multiple the Indeed, from mitosis. with in nucleation initiating poles spindle microtubule spindle in these frequently or reduction for centrosomes cells a explanation be and simplest with would The SAC defects arrest result. the a mitotic as activate apoptosis to changes lead these thereby Importantly, 2009). Fry, irs(ohm n iua 2010). Kimura, and recruit the (Goshima regulating specifically fibres by that possibly itself, complexes these spindle spindle augmin the that at within only speculate also not but we nucleation poles chromatin-mediated to microtubule Thus, control restricted 2005). might the not al., kinases is et or activity (Roig NEK9 centrosomes centrosome- that suggests which the pathway, from either NEK9 of through depletion Moreover, spindle 2009). microtubules Xenopus mitotic with Fry, co-sediment the and NEK7 and (O’Regan of NEK6 microtubules does both and but the itself, poles, with spindle at associate However, 2012). concentrate weakly al., obviously et Sdelci not 2005; does al., NEK6 et Roig 2007; al., recruit et to (Kim required be might NEK7 whereas Luele l,21) oevr E9itrcswt ID,a BICD2, with interacts NEK9 Moreover, 2011). NEKs mitotic al., the et and NPC CDK1 (Laurell nuclear both the by and of driven is release (NPCs) Nup98, component, and complexes phosphorylation as pore breakdown, contribute nuclear envelope also of might activated NEKs is disassembly known. NEK2 isoform not to which is this in pathway phase. for way MAPK the the function by M However, nuclear 2007). specific al., into et a which(Wu of variants, G2 idea splice other the nuclear from of supports functional absent cells a is stage that has as signal variant localisation chromatin pachytene splice NEK2C from the the HMGA2 Interestingly, might of from NEK2 release Thus, progress the DNA. the it for to of HMG2A phosphorylate contribute of control affinity and the chromatin can the HMGA2 decreases NEK2 the with under pathway. (MAPK) interact of the is kinase phosphorylation as protein HMGA2, mitogen-activated well and protein as NEK2 condensation, architecture chromatin of cells, activation al., these et Agostino In (Di spermatocytes 2004). meiotic come mouse have on condensation chromatin studies in from Data NEK2 progression. for mitotic role in a supporting functions additional have also might 2009). Fry, phosphorylating (O’Regan and of phosphorylation tubulin capable through dynamics are microtubule NEK7 bearing and worth in also NEK6 tubulin is function It that formation 2008). of mind al., spindle its et monopolar in depletion Rapley to for 2011; why lead al., et required can (Bertran explain NEK9 by be or could NEK6 phosphorylated to and either This also appears Sawin separation. is this 1995; its centrosome Eg5 al., on and However, depends et NEK6, 1995). microtubules (Blangy spindle CDK1 Mitchison, apart. to by poles spindle Eg5 phosphorylation driving of thereby another manner, Recruitment one anti-parallel across an microtubules plus-end-directed slides a in and is Eg5 crosslinks family. that kinesin motor KIF11), BimC protein the kinesin-like of as member known a (also microtubule-associated Eg5 of as such phosphorylation proteins, is formation spindle nte ot hog hc hs iae ih control might kinases these which through route Another eodsidefrain E2 E6 E7adNEK9 and NEK7 NEK6, NEK2, formation, spindle Beyond nvitro in g xrcspeet irtbl se formation aster microtubule prevents extracts egg hc asstepopc fdrc euainof regulation direct of prospect the raises which , Esi elccerglto 4427 regulation cycle cell in NEKs c TR dpo rti,NEDD1/GCP-WD, protein, adaptor -TuRC c tblnrn ope ( complex ring -tubulin c c tblnt h poles the to -tubulin TRst spindle to -TuRCs nvitro in which , c - Journal of Cell Science ean ihfo hs oteG- rniin(Noguchi transition G2-M the expression to phase its S and from a exhibits high pattern, NEK11 MEK1 remains treatment. expression of UV to activation cell-cycle-dependent response impairs in G2-M depletion ERK1/2 and/or and of NEK10 phosphorylation (ERK1/2) Indeed, does to it arrest. 1/2 2011). leads activity, kinase Stambolic, which kinase extracellular-signal-regulated RAF1 activation, and alter MEK1 interaction (Moniz not promote the does MEK1 for to NEK10 required and not Although is NEK10 but RAF1 where irradiation, between with RAF1, complex UV trimeric and a to MEK1 forms NEK10 response factors, growth In mitogenic signal. checkpoint. damage DDR the of transducer NEK1 independent that an as suggests the act which might on kinases, and (ATR) telangiectasia dependent ataxia protein not or Rad3-related (ATM) is mutated activation telangiectasia this ataxia in NEK1 early NEK1 (UV) However, places ultraviolet as which pathway. (IR), known to radiation also response ionising CHK2; in and light and activation (CHK1 CHEK2) failure G2-M 2 causes and and and NEK1 al., CHEK1 1 of et G1-S kinase cells Pelegrini the Depleting checkpoint 2008; 2004). of al., at al., et et breaks Chen Polci 2011; strand 2010; al., DNA et (Chen of DNA-damage- sensing transitions repair in the Lee both roles the 2004; in involved integral al., and is more NEK1 et signalling. have (Fletcher targets (DDR) others response damage checkpoint 2008), are DNA al., Whereas NEK6, by et damage. and inhibited DNA NEK2 are to checkpoints as that response of such in series NEKs, cycle a some cell by the monitored arrest is that checkpoints progression cycle cycle cell in Cell NEKs of role The derived fibroblasts and Rapley stages, from 2009; post-natal Furthermore, early Fry, or and 2008). embryogenesis during O’Regan late al., maximal 2007; is in al., et NEK6 midbody et of activity the (Kim kinase kinase cytokinesis at expressing the reduced concentrate and cells with cells NEK7 mitotic in NEK7 and or phenotype NEK6 NEK6 activity. common of abscission most mutants this, hypomorphic the with Consistent are 2009). defects Fry, when al., and beyond et Second, (Kim O’Regan progressing abscission 2005). 2007; complete in to al., fail succeed frequently they et cells metaphase, NEK7-depleted (Fletcher or exit NEK6- results mitotic RNAi by delayed depletion its be in and degradation mitosis, APC/C-mediated also late the short into might persists a lacks motifs, NEK2B, that NEKs First, variant division. cell vertebrate splice of NEK2 stages that final 2005). the its evidence al., in involved and some et (Prigent cells, is formation furrow mitotic There cleavage at late anillin of and sites of actin ectopic of mislocalisation midbody the in the results overexpression in to Meanwhile, 2004). localises al., cytokinesis NEK2 et regulating (Grallert in yeast role fission key a in has Fin1 above, mentioned As cytokinesis and NEKs 2002). al., et (Holland onset mitosis envelope at nuclear facilitates breakdown and with associates that protein 4428 hs iae ol euaetednmc fcnrlspindle 2009). of Fry, regulation central and the (O’Regan in of assembly role spindle their dynamics during to microtubules manner the similar a regulate in microtubules could Alternatively, cytokinesis. kinases for is required these directly it activity are or Mechanistically, that localisation factors the 2010). of regulate NEK7 al., and NEK6 et that possible (Salem failure cytokinesis E1 n E1 aebt enipiae nteG2-M the in implicated been both have NEK11 and NEK10 Nek7 ora fCl cec 2 (19) 125 Science Cell of Journal 2 / 2 mro hwdfcsta r niaieof indicative are that defects show embryos Nek7 koku iedei late in die mice -knockout Drosophila , ae hr sltl vdneta aiuaino E2expression NEK2 of to manipulation However, that regulate evidence 2008). might little al., is site there et date, this misaligned (Du at binding of phosphorylation kinetochore kinetochore–microtubule for Hec1, required kinetochores phosphorylation not of this Although the localisation NEK2. that by phosphorylated suggested mediated on been is is event has present HEC1 it and Specifically, when chromosomes al., 2011). et Ser165 Lou al., 2008; complex on al., et et kinetochore (Du Wei NDC80) the 2004; as known phosphorylate (also HEC1 and protein components SAC 2009). al., et thereby (Melixetian surrounding and arrest degradation G2-M motif proteasomal causes for the CDC25A SCF( the in targets for of which binding notably to it Asp-Ser-Gly leads CDC25A, This within primes Ser82. of NEK11 Ser76 motifs active on (DSG) by CDC25A phosphorylation of further Ser273, al., et on Phosphorylation (Melixetian it Ser76 2009). on 2002). phosphorylating CDC25A by phosphorylating al., also NEK11 CHK1, while et phosphorylate activates Noguchi ATR then and 2009; ATM which IR, al., to et exposure and ATM Following (Melixetian the of stresses, kinases inhibition genotoxic the following ATR and lost is inhibitors activation in this replication increases and specifically DNA activity to NEK11 response However, 2002). al., et eut ni pnn padtu h ciaino notherwise an of Second, activation 2004). the al., et thus (Noguchi which and NEK11 of up conformation NEK11, inhibited opening it phosphorylate in arrest, can results G1-S to response NEK2 in for First, roles autophosphorylated suggested. are Interphase been seen. also there be have to NEK2 whether perhaps remains sites, are or specific that to during NEK9 localised activators present of NEK7 is interphase-specific independent that alternative activity is is of this that Whether level mitosis. interphase basal in a activated specifically through is achieved it that current the to interphase is when activity, has view kinase This contribution NEK7 its on that dependent 2008). are suggests its that directly functions it al., because explain PCM et intriguing, is could (Loncarek of result efficiency amount this duplication the and influences because phase duplication, S centrosome and in centrosomes to G1 (PCM) material promotes pericentriolar also of its recruitment NEK7 the 2011). whereas a al., in centrosomes, et (Kim centrosomes of manner additional kinase-dependent loss of formation to induces leads duplication overexpression centrosome depletion to its not contributes because a NEK7 do to that has fused proposed it proteins Nevertheless, are been 2011). they al., et recombinant unless (Kim location motif centrosome-targeting this and in 2007; concentrate centrosomes, proteomicobviously al., a of in et detected not was (Kim analysis it although centrosomes 2006), al., interphase et be Yissachar at can NEK7 detected interphase. during weakly cycle control. centrosome and cycle the regulating cell Quarmby focus in by the implicated review NEKs However, more those excellent 2005). on in the is Mahjoub, discussed here in and is and ciliopathy-related (Quarmby 1 function to Mahjoub Box NEK lead in of can detail aspect as NEK8 ciliary This such and of disorders. organisms, NEK1 unicellular aspects in for mutations regulating have both family in true NEK Chlamydomonas is cells the This of non-dividing function. members in some above, roles to interphase? in alluded function As also NEKs ‘mitotic’ Do integrity. SAC with interferes obviously activity or E2mgtas aearl nteSC si a neatwith interact can it as SAC, the in role a have also might NEK2 eetdt a ugse htNK ih aearl in role a have might NEK7 that suggested has data Recent and Tetrahymena n o aml,where mammals, for and , b TC)uiutnligase, ubiquitin -TrCP) Journal of Cell Science lotrcrgltr ehnssand mechanisms regulatory Allosteric for remain roles 2007). putative essential these al., for unknown. et is details (Jeong mechanistic centrosome the which However, the to protein, duplication, centrosome this centriole-specific of recruitment the daughter limits and centrobin phosphorylates NEK2 oral ei u aeteptnilt eelmn more many reveal to potential the have but begin really well. as to these of this number that a possible to is applies it regulation thus NEKs, of domains, mode eleven catalytic (Richards their of in down out position Eight or this 2010). up al., this switched et have and be Whelligan that 2009; can inhibitors indicates al., and et ATP-competitive which flexible conformation, is of residue Tyr-down of presence structures a Nonetheless, the revealed inhibitory. not in the is of it out NEK2 is, and of upwards that presence points site, the residue In active this Tyr70). too, of 1C, it, side-chain (Fig. that the position revealed ADP, this has at structure tyrosine NEK2 activate a of has to Analysis domain of ability phosphorylation. kinase its loop the activation the of of activation allosteric through independent at has kinases is an it residue these that induces data, NEK6) tyrosine NEK9 these (and of NEK7 that a basis proposed the has On been which (Tyr108). were position results NEK6, equivalent Similar but mutant. with NEK7, Y97A a wild-type NEK7 obtained of active form activity already longer the kinase not the no fragment stimulates C-terminal NEK9 a to can of of leads addition Leu180, but the of Strikingly, backbone activation. ring some the residue, with aromatic phenylalanine bond a hydrogen the stabilising to the Tyr97 activates retains of alanine which mutation to the residue site Even this active an kinase. of for active required mutation are Indeed, the conformation that interactions kinase. ‘Tyr-down’ key into This of 2009). number a downwards al., blocks et points (Richards the within 1B) located for lobe, (Fig. is conformation which N-terminal Tyr97, inhibited of the side-chain new the a which in revealed kinase, has site, active family. NEK other inhibitors the targeting of inhibitors NEK2 chemical members designing of generation of to the experience types facilitate will cell the different and in mitosis delineated, during be NEK2 of roles enable will precise inhibitors of the available progression the mitotic that with the studies indicates in Further inhibitor cells. role A549 essential irreversible an have the not of does NEK2 use the with Consistent studies, active activity. RNAi the catalytic within inhibiting Cys22 irreversibly with thus linkage covalent site, a form third of a to whereas reacts Two kinase, one the kinases. to NEK2 mitotic reversibly bind other scaffolds inhibitor over in the selectivity potency and improved changes have NEK2 they that were addition, against compounds design In the structures to inhibitors. possible the it Crystal revealing made by induced 2010). are in al., that conformation et important Whelligan particularly 2012; Innocenti 2011; al., Taunton, and et their (Henise NEK2 selective into target 1). first that the (Fig. insights inhibitors of generation mechanisms the provided enabled 2009; have regulatory have they Furthermore, al., and that flexibility inactive et proteins revealed conformational these Richards have structures of 2007; These states 2009). al., al., et et Westwood (Rellos have domains catalytic determined NEK7 and been NEK2 the of structures Crystal inhibitors chemical tutrlsuiso h o-aayi oan fNK r yet are NEKs of domains non-catalytic the of studies Structural vacant a with or ADP to bound either NEK7, of structure The , 0 fhmnknssi oa,hv yoiersdeat residue tyrosine a have total, in kinases human of 10% ewe hs w eitr narltvl lwtimescale slow relatively interchanges a motif on this registers whereby s two (17 data model NMR these the that a and between zipper registers, support leucine two of unusual strongly one rather sequence through a dimerise to adopts could According motif trans- 1999). this by al., analysis, probably promotes et NEK2, motif (Fry the of This autophosphorylation of 2011). activation downstream al., and just the et homodimerisation lies on (Croasdale which domain performed NEK2, catalytic been of have motif coiled-coil studies magnetic (NMR)-based nuclear and resonance Biophysical regulation. of modes important erpty orrsossi usto ainsaddrug and patients as of such interfering subset effects, by arrest side a 2004). mitotic induce by in Wilson, poisons limited Microtubule responses and resistance. is poor (Jordan including use are cancers, tumours neuropathy, clinical alkaloids many lung their of vinca and However, treatment and ovarian the taxanes breast, in as therapies such effective poisons Microtubule post- targets anti-cancer or as NEKs interactions other. favouring the that over by register possibility NEK2 one of regulate the adoption other could the up modifications on opens protein; translational full-length it the of hand, structure crystal a obtain eas hyaeivle nseii set fmicrotubule of aspects to specific either in used involved targets be are drug attractive are could they family (Jackson NEK the treatment because poisons of microtubule Members to, a 2007). al., alternative et an such as in microtubules or and of complement, functions cells, the affect not nerve do similar death. a but trigger cell response that cellular to compounds from leads benefit clearly eventually would Patients which dynamics, microtubule with lal ihpirt fw r oudrtn o E niiosmight treatments. inhibitors NEK clinical how effective understand is as to studies developed are be we mechanistic if for priority high compounds a clearly selective of Nevertheless, development function. ciliary the in to implicated undesirable been be have would safe that it NEKs and that inhibit the successful predict a might we of Because although profile inhibitor, selectivity NEK how 2008). desired clear the yet not Taylor, define is could it we characterised, and poorly are NEKs (Gascoigne many of functions fates inhibitors kinase diverse mitotic with checkpoint treated have cells cycle Furthermore, and cell pathways, in 2011). death roles cell al., complex and and et varied low have very (Komlodi-Pasztor kinases a duplication mitotic have which cell tumours, of solid of rate sufficient therapy therefore a effective form the has not most for might It basis alone cells, the mitosis inhibitors. targeting marrow kinase that shown suggested bone mitotic been have to patient malignancies responses in encouraging haematological targets their indeed, against and, that active shows anti-mitotic toxicity are fact haematological The of they cause models. animal inhibitors these and development kinase cell mitotic in on allow studies the that from promise ex trials the in To to to up crucial made lived clinical activity. is it be from anti-tumour drugs, to cancer Results modest progress B. shown further Aurora have PLK1, CDK1, and compounds for inhibitors A selective in of resulted Aurora number has a of research cancer development chemistry potential is the medicinal as there Intensive kinases consequence, targets. mitotic a drug in As interest patients. considerable provide cancer currently to chemotherapeutics for new therapies for effective need ever-present an targets is anti-cancer There as kinases Mitotic 2. Box 2 1 .O n ad hsage hti ilb hlegn to challenging be will it that argues this hand, one On ). Esi elccerglto 4429 regulation cycle cell in NEKs li h hs opud aenot have compounds these why plain Journal of Cell Science lentv praht rgdsg ih erequired. be an might particularly design that drug are suggests to kinases which approach two inhibitors, alternative identical these ATP-competitive is Furthermore, NEK6-selective to site NEK7. insensitive maximal active of developing the for because that are challenge, druggable, to required a kinases be is Although as will compounds 2010). that regarded al., event et generally an (Jeon Ser727, activity transcriptional on the phosphorylation STAT3 affect through cell might of cancer that NEK6 a non- example, of mechanisms a programme For reflect transcriptional NEK6. molecular could of and The cellular function unknown, mitotic 2010). are p53-dependent observations al., these inhibits underlie et also (Jee 2010). NEK6 senescence al., et of (Nassirpour fibroblasts normal Overexpression by cell cancer tolerated in anchorage- is death but promotes to lines leads and activity NEK6 protein of NEK6 depletion also tumour-promoting growth; target. independent is a drug There as cancer cancers. NEK6 potential other of and and support cholangiocarcinoma further these in The evidence in enable as 2010). studies should al., validation well inhibitors et target Suzuki NEK2-selective as 2007; of al., 2008), al., availability et et potential al., (Kokuryo Tsunoda a cancer 2004; et is colorectal al., NEK2 et Wu family. (Hayward the cancer 2009; breast of in members been target few have drug a studies on validation out target carried limited only another and unexplored is which 2). (Box checkpoint, discovery drug cancer damage for pathway DNA target precedented the and/or function 4430 pair Centriole A C odt,teptnilo Esa nicne agt srelatively is targets anti-cancer as NEKs of potential the date, To linker centriolar Inter- Minus end ora fCl cec 2 (19) 125 Science Cell of Journal NEK2 Microtubule

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Eg5 NEK7 P P α β P P Tubulin Glu NEK6 B Tubulin C-terminaltails Glu NEK7 IAadteyatNK.Tehptei sta those that is hypothesis The of NEKs. example, orthologue for the yeast cilia, sub- without probably the same organisms indeed the and into is fall NIMA NEK2 be NEK5 can whereas and NEKs NEK3 family, the similarity. NEK1, some functional that example, predict al., which For might indicated et that also of sub-families (Parker into cell, has cilia NEKs, divided last analysis regulated ciliated five This others the a and as 2007). division was that many cell which as regulated indicated themselves eukaryotes, expressed has of probably microtubules analysis ancestor or common Phylogenetic microtubule- MTOCs of 4). regulation (Fig. the processes, is processes dependent cilia two that to theme these have contribute common The NEKs underlies others 2005). human Mahjoub, whereas and some (Quarmby progression, that function mitotic established in well been roles now has It perspectives future and Conclusions Es(rde n urb,20;Mhobe l,20) For 2002). al., et the Mahjoub of some 2005; two for Quarmby, the case and coordinate the (Bradley directly be NEKs to might seems NEKs interesting as is some events, it that However, process. consider each possess to to cilia course, devoted of are cells, that complex Human NEKs NEKs. with cilia-related of repertoire example, organisms for whereas arrangements, NEKs, cilia-related erpiayclai eue oprdwt hti wild-type in that the with but compared reduced mitosis, is from with cilia derived primary linked MEFs bear intimately of is percentage NEK7 example, NEK1 Glu NEK6 P +TIP NEK8 +TIP P P +TIP cilium Primary NEK7 Plus end Tetrahymena idctdb Gu)teCtria tails tubulin. C-terminal of the ‘Glu’) by polyglutamylate (indicated that those as enzymes, such tubulin-modifying or Eg5, as such proteins, of motor activity microtubule-based the modulate could or they dynamics, microtubule proteins, regulate tracking to +TIP as such proteins, b phosphorylate could and NEK7 NEK6 example, For microtubules themselves. regulating in roles direct 2011). al., et (Yim ( 2 polycystin proteins as of such stability the regulating such as routes alternative ciliary through on function impact might they length. However, ciliary control to basal bodies and/or microtubules axonemal regulation of through possibly have cilia, NEK8, in and roles NEK1 as such NEKs, ( assembly. robust spindle to bipolar contribute NEK9, the of under control NEK7, and NEK6 whereas centrosomes, interphase the cohesion between of loss promotes NEK2 spindle. mitotic microtubule-based cells. ( in organisation microtubule aspects of different to contribute to have evolved might NEKs how illustrates in NEKs organisation. for microtubule roles Potential 4. Fig. C A tblno microtubule-associated or -tubulin eseuaeta Escudhave could NEKs that speculate We ) the of assembly regulate can NEKs ) Nek7 Aspergillus aeepne the expanded have , koku iethat mice -knockout Chlamydomonas aels the lost have , B hsdiagram This a Some ) -or Journal of Cell Science etnor-is . idbad,F,Plmn . od,G n oih,S A. S. Godinho, and G. Woods, D., Pellman, F., Hildebrandt, M., Bettencourt-Dias, Regue S., Sdelci, T., M. Bertran, ehm . og . adel .A,Aym,Y,Km,B . ob .and M. Comb, E., B. Kemp, Y., Aoyama, A., J. Caldwell, J., Roig, C., Belham, amna,S,Kpa,D . eua .G,Gdig,T . r ’ol,E T., E. O’Toole, Jr, H., T. Giddings, G., J. Deluca, D., D. Kaplan, S., A. Bahmanyar, E. Nigg, and F. Leiss, J., C. Wilkinson, D., Y. Stierhof, S., Bahe, Salt ta. 02.Aohrmttckns,Arr A, , been mitotic recently Another has mitosis 2012). of NEK2 onset al., the and et at disassembly function, (Spalluto cilium cilia promote both to in and roles proposed has DDR 2007). NEK1 al., that et evidence the Miller good 2009; is al., there of et Furthermore, status (Chang acetylation neurons prolactin-mediated the in in regulates microtubules role potentially a also has but NEK3 signalling, 2010). al., et (Salem cells nesn .S,Wlisn .J,Myr . otne,P,Ng,E .adMann, and A. E. Nigg, P., Mortensen, T., Mayor, J., C. Wilkinson, S., J. Andersen, Ehrenberger, R., J. Hutchins, B., Hegemann, A., B. Joughin, D., Lim, J., Alexander, References Cancer Centre. Leicester Medicine the Cancer of Experimental members UK are and authors Research UK; Cancer The Research Society. Trust; Cancer Royal from Wellcome the Research support Cancer the acknowledges International by R.B. for (AICR). Association supported the is and UK; A.M.F. Research of work and The manuscript Funding the to space on had not comments have we work for whose cite. authors Yeoh to apologise Sharon sincerely thank as them We exploit fully to Acknowledgements position a in be clear we targets. become therapeutic will disease then human only Only to mechanisms and contribute family. the NEKs will kinase understanding terms which this in this through go of of to development biology way the long basic with very the a still understanding is of there summary, inhibitors In cell-permeable would tools. of that Finally, as development challenge the inhibitors. huge from and benefit a NEK clearly interactions is of treatments lethal as combination effects synthetic roles, potential side windows, physiological therapeutic potential key defining their the the defining as be Meanwhile, in will well NEKs step inhibitors. different important the specific for an animals of design knockout mechanisms of their to development understand and to required activation the of clearly detail with is structural interfere NEKs greater selectively the However, to cells. cancer potential of the mitotic proliferation the has of NEKs inhibition DDR functions, or could what their about from they know Furthermore, that currently biomarkers. we suggests prognostic types important tumour as act various in NEKs mitotic Pugacheva 2005; Golemis, 2007). and al., be (Pugacheva et happens NEK2 also of which protein regulator Cas-L), scaffolding and a adhesion HEF1 focal as requires known the (also this by NEDD9 and A Aurora entry, of mitotic activation with resorption cilia coordinates 21) etooe n ii nhmndisease. human in cilia and Centrosomes (2011). e9i l1atvtdkns htcnrl al etooesprto through separation centrosome early controls that Eg5. kinase and Plk1-activated Nek6/7 a is Nek9 kinases. Nek7 and Nek6 the activates J. Avruch, 105. aei saNk usrt novdi etooeseparation. centrosome I. in A. involved Barth, and substrate J. Nek2 W. Nelson, a J., is P. Casey, Catenin D., E. Salmon, M., Winey, obndwt oiieadngtv eeto fpopoyainmtf stebasis M. al. the is et motifs A. phosphorylation signaling. E. of mitotic Nigg, selection context-dependent negative O., for and Hudecz, positive F., with Sessa, combined F., Ivins, T., om etil-soitdflmnsadfntosi etooecohesion. centrosome in functions and Biol. filaments centriole-associated forms profiling. correlation rmacne ilg esetv,oeepeso fthe of overexpression perspective, biology cancer a From 20) rtoi hrceiaino h ua etooeb protein by centrosome human the of characterization Proteomic (2003). 171 27-33. , 20) ioi acd fNM aiyknss Nercc1/Nek9 kinases. family NIMA of cascade mitotic A (2003). MOJ. EMBO Nature 30 426 2634-2647. , ,L,Arc,J,Cels .adRi,J. Roig, and C. Caelles, J., Avruch, L., ´, 570-574. , .Bo.Chem. Biol. J. c.Signal. Sci. rnsGenet. Trends 4 278 ra42. , 34897-34909. , 21) pta exclusivity Spatial (2011). 27 ee Dev. Genes 307-315. , 20) Rootletin (2005). 20) beta- (2008). 22 (2011). .Cell J. 91- , rsr . tehf .D n ig .A. E. Nigg, and D. Y. Stierhof, S., Graser, M. I. Hagan, and V. Simanis, S., Bagley, A., Krapp, A., Grallert, A. Kimura, and G. Goshima, S. S. Taylor, and E. K. Gascoigne, A. E. Nigg, and L. Arnaud, M., A. Fry, ae,M . iaa . atm .L,Lno,C,Mo . aao .adFry, and H. Yamano, G., Mao, C., Lindon, L., S. Wattam, Y., Kimata, J., M. Hayes, M. A. Fry, and R. Bacchieri, H., Yamano, L., S. Wattam, S., R. Hames, M. I. Hagan, and A. Grallert, A. E. Nigg, and P. Meraldi, M., A. Fry, lny . ae .A,d’He A., H. Lane, A., Blangy, r,A . ao,T,Mrli . tehf .D,Tnk,K n ig .A. E. Nigg, and K. Tanaka, D., Y. Stierhof, P., Meraldi, T., Mayor, M., A. Fry, J. R. Muschel, and J. J. T. R. Yen, J., Muschel, G. and Cerniglia, J. L., Fletcher, T. Yend, A., E. Nigg, J., G. Cerniglia, L., Fletcher, eSua .P,Omn,A . u .P,Sot,J .adOmn,S A. S. Osmani, and L. J. Spotts, P., L. Wu, H., A. Osmani, P., C. Souza, De M. L. Quarmby, and A. B. Bradley, aahr .J n r,A M. A. Fry, and J. A. Faragher, radl,R,Iis .J,Mset . aie,T,Sot .J,Hry . Smerdon, T., Hardy, J., D. Scott, T., Daviter, F., Muskett, J., F. Ivins, R., Croasdale, E., Bolat, J., Reeuwijk, van J., C. Gloeckner, K., Boldt, A., D. Mans, L., K. L. Coene, P. Chen, and J. D. Riley, F., C. Chen, Y., Chen, J. D. Riley, and X. Jiang, F., C. Chen, L., P. J. Chen, Y., Milbrandt, Chen, and H. R. Baloh, J., Chang, u . a,X,Yo . ig . u . e,S,Jag . hn,Y,Wn,W., Wang, Y., Zhang, K., Jiang, S., Pei, Q., Wu, X., Ding, J., Yao, X., Cai, J., Du, eie .C n ano,J. Taunton, and C. J. Henise, T. P. Cohen, and M. H. Barker, X., Luo, R., N. Helps, iAotn,S,Fdl,M,Cifi . uc,A,Rsi . eei,R n Sette, and R. Geremia, P., Rossi, A., Fusco, P., Chieffi, M., Fedele, S., Agostino, Di oln,P . in,A,Gra . ono,R . ils . is .E,Rauch, E., J. Sims, C., Willis, S., R. Johnson, K., Garka, A., Milne, M., P. Holland, Fry, and M. I. Hagan, R., M. Pillai, J., A. Faragher, B., R. Clarke, G., D. Hayward, neln aito olwn rlne xouet niioi drugs. antimitotic to 111-122. exposure prolonged following variation interline neato ihteAPC/C. the with interaction M. A. activity. SIN modulating cohesion. centrosome in for NIMA required for role a over reveals occurs body Dev. and spindle-pole Genes pombe cycles S. the cell of maturation consecutive that shows kinase NIMA SPB. of the for Polo of affinity an and formation J. spindle regulates Fin1, kinase, spindle. the 49. within generation microtubule dependent motif. dimerization zipper leucine unusual 274 an on depends Nek2, kinase, regulators. cycle cell of family NIMA the of 17 member a kinase, protein Nek2 -eitddsrcino h etooa iaeNkAocr nerymtssand mitosis D-box. early A-type in cyclin occurs a Nek2A kinase upon centrosomal depends the of destruction C-mediated of substrate Nek2. candidate kinase and protein Nek2B. protein cycle-regulated coiled-coil and cell centrosomal the Nek2A novel a for C-Nap1, (1998a). regulation cycle cell in Acta Biophys. roles distinct reveals eae oo seta o ioa pnl omto nvivo. kinesin- in a formation spindle Eg5, bipolar human for of essential association motor spindle related regulates p34cdc2 by Phosphorylation niiino etooesprto fe N aae oefrNek2. for role a damage: DNA 162 after separation centrosome of Inhibition spindles. mitotic bipolar of formation for 14 required is and disjunction ioi itn 3popoyainb h IAkns nAprilsnidulans. Aspergillus in kinase NIMA the by phosphorylation H3 histone Mitotic dynamics. exchange conformational atypical 286 exhibits M. kinase Pfuhl, Nek2 and of M. A. Fry, J., S. al. et P. F. kinase. Cremers, serine/threonine 3592-3605. Nek4 cilium A., to with linked interaction T. are through RPGRIP1L Peters, integrity and RPGRIP1 J., homologs S. protein ciliopathy-associated Letteboer, of S., independent pathway Roosing, a through control ATR. checkpoint and and ATM response damage DNA neurons. in acetylation microtubule Chlamydomonas. regulates in size cell and length flagellar both irtbl tahetstability. attachment microtubule al. et Y. Shi, eae iae1fntosi N aaersos n hcpitcontrol. checkpoint and response damage DNA in functions Cycle 1 kinase related h is eoi iiini os spermatocytes. mouse in division meiotic first the C. hrceiaino e8 oe IArltdkns,adiscniaesubstrate candidate its and kinase, NIMA-related novel a Bicd2. Nek8, of characterization C.T.,Bird,T.A.andVirca,G.D.activity. complexed is centrosomes, 1. to phosphatase localized protein kinase to protein cell-cycle-regulated a (Nek2), cancer. breast human in expression M. A. 102 470-481. , 2876-2889. , 21 20) hshrlto fhg-oiiygoppoenA yNk iaeduring kinase Nek2 by A2 protein group high-mobility of Phosphorylation (2004). 16304-16310. , 128-135. , 27537-27547. , 293-302. , 3096-3107. , 7 20) al ioi erdto fNkAdpnso Cdc20-independent on depends Nek2A of degradation mitotic Early (2006). .Bo.Chem. Biol. J. 3194-3201. , 20) h etooa iaeNk ipaseeae eeso protein of levels elevated displays Nek2 kinase centrosomal The (2004). .Md Chem. Med. J. 18 20) h ioi hcpitkns E2 euae kinetochore regulates NEK2A kinase checkpoint mitotic The (2008). 1744 1007-1021. , elCycle Cell 89-92. , Esi elccerglto 4431 regulation cycle cell in NEKs 277 54 ice.J. Biochem. 16229-16240. , 4133-4146. , rn . apr . rs,M n ig .A. E. Nigg, and M. Kress, M., Harper, P., ´rin, 10 a.Cl Biol. Cell Nat. 21) reesbeNk iaeihbtr ihcellular with inhibitors kinase Nek2 Irreversible (2011). 655-663. , 21) e okisd h pnl:microtubule- spindle: the inside look New (2010). 20) cioacaoye ob NIMA-related pombe Schizosaccharomyces (2002). 21) nudcddcie ol h ecn zipper leucine the coil: coiled undecided An (2011). Oncogene .Cl Sci. Cell J. 20) IArltdkns,Ckp regulates Cnk2p, kinase, NIMA-related A (2005). 20) acrclsdslypoon nr-and intra- profound display cells Cancer (2008). acrRes. Cancer 20) e2 iaesiuae centrosome stimulates kinase Nek2A (2003). 19b.Acnrsmlfnto o h human the for function centrosomal A (1998b). 349 MOJ. EMBO 19) ciiyo h ua centrosomal human the of Activity (1999). 20) e6 n e25(d5a2 are (Cdk5rap2) Cep215 and Cep68 (2007). 509-518. , 20) h IAfml iaeNek3 kinase NIMA-family The (2009). 8 27 607-614. , .Cl Biol. Cell J. .Cl Sci. 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