NEK家族在細胞周期調控中的作用

李園園，郭磊，韓之明,3

綜 述

NEK家族在細胞周期調控中的作用

李園園1，郭磊2，韓之明1,3

1. 中國科學院動物研究所，干細胞與生殖生物學國家重點實驗室，北京 100101 2. 廣東省第二人民醫院生殖醫學中心，生殖力保護實驗室，廣州 510317 3. 北京干細胞與再生醫學研究院，北京 100101

NIMA相關激酶(NIMA-related kinases, NEKs)是絲氨酸/蘇氨酸激酶，在細胞周期調控中發揮著重要的作用，參與了中心體分離、紡錘體組裝、染色質凝集、核膜破裂、紡錘體組裝檢驗點信號、胞質分裂、纖毛形成及DNA損傷反應等多種細胞活動。本文結合近年來在該激酶家族的相關研究，從NEK家族的組成、結構特征及其在有絲分裂和減數分裂過程中的作用等多個方面展開綜述，以期為進一步研究NEKs在細胞周期調控中的作用提供重要基礎，也為腫瘤的臨床診斷和治療提供理論依據。

NIMA相關激酶；有絲分裂；減數分裂

細胞是生命活動的基本單位。細胞周期是一個非常復雜和精細的調節過程，該過程受到細胞內外各種因素的精密調控，細胞周期的紊亂與許多疾病的發生發展相關。研究顯示，許多蛋白激酶家族，如細胞周期蛋白依賴性激酶(cyclin-dependent kinases, CDK)、Aurora激酶、Polo樣激酶(polo-like kinase, PLK)和NIMA相關激酶(NIMA-related kinases, NEKs)，都參與了細胞周期調控的過程。近年的研究發現，NEK家族蛋白在細胞周期調控的過程中扮演了重要的角色，參與中心體復制和分離、紡錘體形成、染色體在赤道板上的排列、紡錘體檢驗點(spindle assembly checkpoint，SAC)調控、纖毛形成及DNA損傷反應(DNA damage response, DDR)等多種細胞活動。本文主要綜述了NEK家族成員的生物學特性及其在細胞周期調控中的作用，同時對NEK家族的未來研究方向進行了探討，以期讓相關科研人員更充分、更全面地了解NEK家族的研究進展，為進一步研究其在細胞周期調控中的作用提供有力的支撐，也為深入了解腫瘤發生機制及抗腫瘤藥物設計提供研究基礎。

1 NEK家族及其生物學特性

1.1 NEK家族的發現

NIMA (never in mitosis A)最早是在對曲霉屬真菌的有絲分裂突變體的研究中發現的[1,2]。20世紀80年代中期，Osmani等[3]通過調控基因的mRNA表達水平證明參與了曲霉有絲分裂的G2/M期轉換。進一步的研究證明，的過表達可以促進有絲分裂的提前發生，有絲分裂過程中NIMA與CDK1-cyclin B復合體是同等重要的調節因子[4,5]。在對曲霉的研究中發現，NIMA的降解是細胞完成正確的有絲分裂進程所必需的[6]。一系列的研究表明，NIMA激酶在曲霉和酵母()中參與了染色質凝集、紡錘體組裝和胞質分裂等多個細胞周期過程[7～11]。20世紀90年代初期，Letwin等[12]從小鼠()中分離出，發現編碼一種與NIMA相關的蛋白激酶，在結構、組成和表達上與NIMA存在較高的一致性，從而提出了在哺乳動物中可能存在一個基因家族。隨后的研究發現了小鼠和人()的細胞中均存在與相關的基因，證明了高等哺乳動物確實存在NEK家族[13,14]。研究已證明，NEKs存在于多種生物體中，從原生生物如衣藻()[15]、瘧原蟲()[16]等到多細胞真核生物如果蠅()[17]、非洲爪蟾()[18]、小鼠[13]和人[14]。

1.2 NEK家族成員的結構特征

人類NEK家族由11種NIMA相關激酶組成[19,20]，這些激酶具有與曲霉NIMA相似的氨基末端催化區域，是含有典型的絲氨酸/蘇氨酸激酶序列的高度保守的激酶結構域，其氨基末端和羧基末端的調節結構域在序列組成和長度上有顯著差異。一般來講，NEK家族的氨基末端激酶區域是中度保守的，與NIMA的激酶區域的氨基酸序列有40%～50%的同源性。NEK10的激酶區域位于整個氨基酸序列的中段，與NEK家族典型的氨基末端催化區域不同。在NEK家族中，人NEK2和NIMA的同源性最高，能達到44%[21]。除此之外，NEK6和NEK7的激酶區域的序列一致性達到了85%以上[22]。人類NEK家族的催化區域均含有一個His-Arg-Asp(HRD)基序，在激活環中都有一個絲氨酸/蘇氨酸殘基，而這個殘基很可能是激活修飾的作用位點。在一些NEK家族成員中，這個殘基是自磷酸化的，而其他成員則是通過一個上游激酶進行磷酸化修飾的[23～26]。就磷酸化識別序列而言，NIMA的第3位殘基具有對苯丙氨酸的強烈偏好[27]，人類NEK家族也具有相似的偏好，例如NEK2和NEK6的第3位殘基更喜歡疏水殘基，尤其偏愛苯丙氨酸或亮氨酸[28,29]。

NEK家族成員具有保守的氨基末端催化區域，而羧基末端區域在長度、序列和結構上都存在很大差異(圖1)。其常見的特點就是寡聚化序列，通常是一種卷曲螺旋結構，可通過自磷酸化而被激活。一般而言，自磷酸化通常是在激酶結構域的激活環內進行，但是也可發生在蛋白質的其他區域，例如NEK8和NEK9羧基末端的非催化區域可以通過自磷酸化調控自身的定位和激活[23,30]。研究發現，包括曲霉NIMA和脊椎動物NEK2在內的幾種NEKs均顯示在非催化區域內存在靶向蛋白質降解的破壞基序[6,31]，例如NEK2含有一個KEN (Lys-Glu-Asn)- box和羧基末端MR (methionine-arginine dipeptide)- tail，均能被后期促進復合物/環狀體(anaphase- promoting complex/cyclosome, APC/C)所識別，其中MR-tail還可介導NEK2與APC/C的核心亞基CDC20直接作用，從而導致NEK2以一種不依賴于紡錘體組裝檢驗點的方式進行降解[32]。在NEK家族中，NEK6和NEK7僅由一個催化區域和短的氨基末端延伸區域組成[33,34]，而后者可能與底物識別有關[35]。NEK6和NEK7是NEK9的下游激酶，可以和NEK9蛋白中RCC1域和coiled-coil域之間的一個序列結合[25]。

圖1 人NEK家族的結構特征

2 NEK家族在細胞周期調控中的作用

作為蛋白激酶，NEK家族參與了細胞周期、細胞分裂、纖毛形成和DNA損傷反應等多種細胞活動(表1)。人和哺乳動物NEK家族在細胞有絲分裂和減數分裂過程中的作用主要有以下幾個方面。

2.1 NEK家族在有絲分裂中的作用

的過表達可以誘導處于細胞周期任何階段的曲霉細胞、酵母細胞、非洲爪蟾卵母細胞或人類細胞進入有絲分裂[82,83]，研究發現，人類NEK家族參與細胞周期進程和分化過程中的多個事件。在有絲分裂中，NEK2、NEK6、NEK7和NEK9相互配合調控雙極紡錘體的形成、染色質凝集、核膜破裂和胞質分裂等。NEK3除參與調控有絲分裂外，還可促進催乳素依賴性信號傳導[45]，而NEK1、NEK4、NEK5、NEK7、NEK8、NEK10和NEK11均與DNA損傷應答有關。

2.1.1 有絲分裂起始

有絲分裂的起始和退出是由CDK1、cyclins、有絲分裂相關激酶和磷酸酶驅動的細胞周期轉換。在高等真核生物中，有絲分裂的起始導致多個細胞結構的改變，例如中心體分離、微管生長和收縮、核膜破裂以及染色質凝集等[84]。盡管沒有研究證明NEK家族是有絲分裂起始所必需的，但是已確定NEK2、NEK6、NEK7和NEK9參與調控了細胞從間期進入M期的中心體的分離、紡錘體的組裝、核孔復合物的去組裝和核膜破裂等。

表1 人和哺乳動物NEK家族的亞細胞定位和功能

研究發現，一些NEK家族成員在從真菌到人類的微管組織中心均有定位[9,17,85～87]。在人類細胞中，NEK2作為中心體的核心組分，參與調控中心體的分離[41,88,89]。在有絲分裂間期，兩個中心粒由一些蛋白質連接體結合在一起，而該連接體是由卷曲螺旋蛋白組成的，包括C-Nap1、rootletin、Cep68、centlein和LRRC45，而NEK2不僅可通過磷酸化連接蛋白[90～94]和中心粒相關蛋白GAS2L1[95,96]，還可通過失活驅動蛋白KIFC3[97]，共同調控有絲分裂前期的中心體分離和雙極紡錘體形成。在有絲分裂間期，NEK2與蛋白激酶MST-2和磷酸酶PP1形成三聚體結構，維持在一個去磷酸化的失活狀態。當有絲分裂啟動時，PLK1可通過磷酸化MST-2破壞這種結構，導致NEK2的激活。除此之外，NEK2也可通過自磷酸化而被激活[98]。在有絲分裂過程中，NEK5與NEK2的定位模式相似。人基因的敲降導致分裂間期NEK2減少、中心粒周圍物質(pericentriolar material, PCM)缺失、微管生長緩慢以及中心體連接蛋白rootletin被過度募集到中心體上，從而導致中心體的過早分離，分離的中心體之間相對較接近[50]，這個現象與過表達人基因的結果是一致的[41,91]，而且同時敲降和基因后中心體的過早分離被加重。我們推測，NEK5可能與NEK2協同調控中心體的分離。

研究發現，在有絲分裂的G1期和S期，NEK7可通過調控PCM的募集促進中心體的復制[99]。人基因的敲降導致PCM組分和原中心粒組裝相關蛋白PLK4、CPAP、SAS-6以及STIL不能被募集到中心體，從而調控中心體的復制[100]，而人基因和基因的過表達能夠誘導額外的中心體形成[101]。在有絲分裂中，人、和基因的敲降導致前期中心體的分離失敗、分裂中期形成脆弱的紡錘體、紡錘體兩極的距離減小以及微管密度降低[23,56,66]。事實上，對于這些紡錘體的缺陷最簡單的解釋是中心體和紡錘體兩極的微管成核作用減少。研究顯示，NEK9能與啟動微管成核的γ-tubulin環狀復合體(γ-tubulin ring complex, γ-TuRC)的多個組分互作，如磷酸化γ-TuRC的銜接蛋白NEDD1[73,102]，后者的激活促進了γ-tubulin被募集到中心體上，而的缺失會導致紡錘體組裝延遲、雙極紡錘體的形成減少和微管結構異常[102]。此外，NEK6和NEK7均定位到紡錘體兩極，NEK6在有絲分裂的中期和后期定位到紡錘體微管上[56]，NEK7可將γ-tubulin募集到紡錘體的兩極[66]。研究結果提示，這些激酶對微管成核的調控可能不僅是通過紡錘體兩極和紡錘體本身，還有可能是通過augmin復合體將γ-TuRCs募集到紡錘體的兩極[103]。除此之外，這些激酶調控紡錘體形成的另一種途徑可能是通過磷酸化微管相關蛋白進行的，例如Eg5作為一種驅動蛋白，參與了有絲分裂雙極紡錘體的形成和維持過程，而Eg5被募集到紡錘體微管上的過程依賴于CDK1對Eg5的磷酸化作用[104,105]。研究發現，NEK6也可磷酸化Eg5[106]，這一發現有助于闡明NEK6或NEK9在雙極紡錘體的形成和維持中的作用[23,106]。另一項研究顯示，EML4作為一種促進微管穩定性的微管相關蛋白參與微管動力學的調控，NEK6和NEK7可通過磷酸化EML4降低其與微管的親和力，從而促進染色體中板聚合[107]。NEK6和NEK7還可以直接將微管蛋白磷酸化，這一發現提示NEK6和NEK7可能通過磷酸化微管蛋白直接參與微管動力學的調控[56]。這些研究均表明，NEK6、NEK7和NEK9在紡錘體的形成中發揮了重要作用。

NEK2、NEK6、NEK7和NEK9除影響紡錘體形成之外，也發揮其他的功能。例如，NEK2的剪接異構體NEK2C定位在細胞核中，這可能與NEK2在細胞核中的功能有關[108]。研究顯示，Nup98是核孔復合體(nuclear pore complexes, NPCs)的組成成分，CDK1和NIMA可磷酸化Nup98，從而促進Nup98從NPCs的解離。CDK1還可磷酸化NEK9的Ser869位點，進而激活NEK9，而NEK6和NEK7可通過與激活的NEK9結合而被激活[23]。因此，我們推測NEKs也可能參與NPCs的解體和核膜破裂[109]。除此之外，NEK9還可與BICD2相互作用。而BICD2作為一種動粒蛋白相關蛋白，在有絲分裂前期可與動力蛋白結合，促進核孔復合體的去組裝[110]。這些研究結果均表明，NEK家族在有絲分裂起始中發揮重要作用。

2.1.2 細胞周期檢驗點

細胞周期阻滯可發生在細胞周期的G1/S、S期和G2/M期，是由內源性因素(如停滯的復制叉)或者外源性因素(包括紫外線(UV)輻射、電離輻射(IR)、活性氧(ROS)和某些化療藥物)所造成的DNA損傷引起的。細胞周期由一系列的檢驗點所監控，當DNA出現損傷時，這些檢驗點蛋白被激活，進而導致細胞周期的延遲或阻滯。檢驗點的激活是由PIKK (phosphatidylinositol-3 kinase-related kinase)家族成員共濟失調毛細血管擴張突變(ataxia telangiectasia mutated, ATM)蛋白和共濟失調毛細血管擴張突變與相關(ataxia telangiectasia mutated andrelated, ATR)蛋白及其效應激酶CHK1/2 (checkpoint kinase 1/2)啟動的，ERK1/2 (extracellular signal- regulated kinase 1/2)和p38及其下游激酶MK2 (MAPK activated protein kinase 2)在細胞周期阻滯中也發揮重要作用。在NEK家族中，NEK2和NEK6作為DNA損傷反應的靶點，是受DNA損傷抑制的[58,111]，而其他的NEK家族成員在DNA損傷修復中發揮重要作用。

在有絲分裂的G1/S和G2/M轉換中，NEK1在DNA損傷修復中起作用[112～115]。當敲除的細胞暴露于IR和UV輻射時，CHK1和CHK2不能被激活。此外，NEK1的激活不依賴于ATM和ATR。這些研究結果提示，NEK1可能是作為損傷信號的獨立傳感器發揮作用。

研究發現，NEK2不僅可與SAC蛋白相互作用，還可促進動粒復合蛋白HEC1的Ser165位點磷酸化[116～118]。除此之外，在紊亂的染色體動粒上可檢測到磷酸化HEC1 (Ser165)的表達，而HEC1可將MPS1和MAD1/MAD2復合體募集到動粒上[119]。由此推測，NEK2可能參與紡錘體組裝檢驗點SAC蛋白完整性的調控。

研究還發現，NEK8可通過RAD51蛋白和DNA損傷修復調控復制叉的穩定性[71]，而NEK10和NEK11參與調控G2/M期的DNA損傷反應檢驗點。當細胞暴露于UV輻射時，NEK10與MEK1、RAF1形成一個三聚體的結構，NEK10可通過促進MEK1的激活，進而導致G2/M期阻滯和ERK1/2的磷酸化[75]，敲降人基因可以抑制MEK1和ERK1/2的磷酸化。當發生DNA損傷和遺傳毒性應激時，NEK11活性顯著增加，而當抑制ATM和ATR激酶時，NEK11不能被激活[79,80]。當細胞暴露于IR輻射時，ATR和ATM激活CHK1，CHK1的激活促進NEK11和CDC25A的磷酸化，而NEK11的激活可進一步磷酸化CDC25A，這一過程促進SCF泛素連接酶復合物與CDC25A的結合，從而促進CDC25A的降解，最終導致G2/M期阻滯[79]，使細胞有充足的時間進行DNA修復，不會過早進入有絲分裂。

2.1.3 胞質分裂

胞質分裂發生在細胞分裂后期姐妹染色單體分離之后, 是細胞周期和生物個體發育過程中的一個重要環節, 直接關系到遺傳物質和細胞質組分能否在2個子細胞中正常分配。胞質分裂是由許多亞細胞結構和生物分子相互協調作用的結果。動物細胞胞質分裂過程主要包括分裂溝的定位、胞質分裂結構收縮的組裝、分裂溝的產生和收縮、分裂溝膜泡的融合以及中間體的形成和剪切。

在真核生物中，NEK家族也參與胞質分裂的調控。在裂殖酵母中，Grallert等[11]發現FIN1在胞質分裂中起重要作用。在果蠅中，NEK2定位在有絲分裂后期的中體上，它的過表達可導致actin和anillin在卵裂溝的形成部位發生錯位[17]。人NEK2剪接異構體NEK2B的敲降可導致細胞無法完成胞質分裂而形成多核細胞[120]。NEK6和NEK7也定位在有絲分裂后期的中體上，在胞質分裂中NEK6的激酶活性達到最大[56,66,106]。人或基因敲降的細胞可成功進入中期，但不能完成胞質分裂，而且人或的等位基因突變體細胞也經常出現胞質分裂的失敗[56,66]。研究還發現，來自小鼠敲除胚胎的胚胎成纖維細胞也表現出胞質分裂失敗的缺陷[121]。除此之外，NEK6和NEK9還可介導與胞質分裂有關的驅動蛋白MKLP2和KIF14的定位和募集[122]。以上證據均表明，NEK家族可能通過胞質分裂相關因子的定位和活性改變調控胞質分裂[56,122]。

2.2 NEK家族在減數分裂中的作用

如上所述，NEK家族在有絲分裂過程中發揮重要的調節作用。減數分裂作為一種特殊的細胞分裂方式，是真核生物和二倍體生物有性生殖和配子產生所必需的。在減數分裂中，染色體的錯誤分離有可能導致非整倍體受精卵或后代的產生。與有絲分裂相比，人們對NEK家族在減數分裂中的作用了解較少。近些年的研究發現，一些NEK家族成員，如NEK1、NEK2、NEK5、NEK9和NEK11，在減數分裂中也發揮重要的作用。

在哺乳動物生殖細胞中，NEK1高表達，并參與減數分裂中紡錘體形成的調控[36]。在敲除小鼠的精母細胞和卵母細胞中，第一次減數分裂的紡錘體組裝和染色體排列異常，調控紡錘體動力相關蛋白-肌球蛋白X (myosin X, MYO10)和α-adducin的定位和表達改變[64,123,124]。我們推測，NEK1可能通過與MYO10和α-adducin的相互作用調控紡錘體的形成。在小鼠卵母細胞中，NEK2是微管組織中心的組成成分，它的敲降導致第一次減數分裂紡錘體兩極的異常和染色體排列異常[42]，研究證明centrobin/Nip2是NEK2的作用底物，在微管組織中心發揮重要作用[125,126]，而且在卵母細胞中敲降與敲降的表型是一致的[42]。這些結果提示，NEK2可能通過磷酸化centrobin參與調控卵母細胞減數分裂I中紡錘體組裝。在小鼠精母細胞減數分裂過程中，NEK2可磷酸化染色質結構蛋白HMGA2，通過降低后者與DNA的親和力調控染色質的凝集[127]。我們最近的一項研究發現，NEK5在減數分裂G2/M轉換過程中發揮了重要作用，在敲降的卵母細胞中MPF活性降低，導致了卵母細胞減數分裂恢復的失敗[51]。同時，我們還發現NEK5定位在MI～MII期紡錘體上，推測NEK5也可能參與減數分裂紡錘體的組裝。在敲降的小鼠卵母細胞中，紡錘體組裝和染色體排列異常，γ-tubulin在紡錘體兩極的定位異常，SAC被激活[128]。在小鼠卵母細胞中敲降影響了MI期紡錘體的遷移，導致卵母細胞的均等分裂[81]。上述研究結果表明，在生殖細胞中NEK1、NEK2、NEK5和NEK9等是保證減數分裂正常進行和染色體正確分離的關鍵蛋白，其表達的改變會導致紡錘體組裝相關因子的定位和活性改變進而干擾紡錘體組裝和減數分裂細胞周期進程。

3 結語與展望

自發現以來，NEK家族一直是細胞生物學的研究熱點，研究證明NEK家族在細胞周期調控中發揮著關鍵的作用，但其在減數分裂中的功能和分子機制還有待于進一步深入的研究。細胞周期高度有序的運轉是通過G1/S期轉換、G2/M轉換和中/后期轉換等多個過程的調控來實現的。細胞周期紊亂是腫瘤發生的主要原因，細胞周期相關蛋白的表達異常在腫瘤細胞增殖中扮演著重要角色。因此，對NEK家族的生物學功能及其在細胞周期調控中作用的研究，不僅可以更深入地了解細胞周期過程及調控機制，還有助于闡明NEK家族在腫瘤發生發展中的作用機制，對腫瘤的臨床診斷和治療也具有重要意義。

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Roles of NEK family in cell cycle regulation

Yuanyuan Li1, Lei Guo2, Zhiming Han1,3

As a serine/threonine kinase, NIMA-related kinases (NEKs) play important roles in the regulation of cell cycle, and involve in several cellular activities such as centrosome separation, spindle assembly, chromatin condensation, nuclear envelope breakdown, spindle assembly checkpoint signaling, cytokinesis, cilia formation and DNA damage response. In this review, we summarize the component, structural characteristics and functions of NEK family in mitosis and meiosis based on the relevant researches in recent years, providing a reference for the further study on the roles of NEKs in the regulation of cell cycle and a theoretical basis for the clinical diagnosis and treatment of tumors.

NIMA-related kinases; mitosis; meiosis

2021-03-27;

2021-05-12

國家重點研發計劃資助項目(編號：2018YFC1004000，2019YFA0109900)和國家自然科學基金項目(編號：31970509)資助[Supported by the National Key R&D Program of China (Nos. 2018YFC1004000, 2019YFA0109900), and the National Natural Science Foundation of China (No. 31970509)]

李園園，博士，專業方向：發育生物學。E-mail: liyuanyuan891116@163.com

韓之明，博士，副研究員，專業方向：發育生物學。E-mail: hanzm@ioz.ac.cn

10.16288/j.yczz.20-421

2021/6/25 13:16:28

URI: https://kns.cnki.net/kcms/detail/11.1913.R.20210625.1123.002.html

(責任編委: 史慶華)