修光輝綜述 王廷華審校

(昆明醫(yī)學(xué)院神經(jīng)科學(xué)研究所,昆明650031)

細(xì)胞外信號(hào)調(diào)節(jié)激酶(Extracelluar signal-regulated kinase,ERK)是細(xì)胞內(nèi)的一類(lèi)絲氨酸/蘇氨酸蛋白激酶,1986年由Sturgill等首先報(bào)導(dǎo),最初其名稱(chēng)十分混亂,曾根據(jù)底物蛋白稱(chēng)之為 MAP2K、ERK、MBPK、RSKK、ERTK等。此后,由于發(fā)現(xiàn)其具有共同的結(jié)構(gòu)和生化特征,被命名為M APK。近年來(lái),隨著不同MAPK家族成員的發(fā)現(xiàn),又重新改稱(chēng)為ERK。ERK是MAPK家族中最先被發(fā)現(xiàn)并被人們了解最多的成員,主要包括兩種異構(gòu)體,ERK1和ERK2(分別為p44MAPK和p42MAPK),分子量分別為44,000和42,000,兩者的同源性為85%,而它們與底物結(jié)合的區(qū)域同源性越更高,統(tǒng)稱(chēng)為 ERK1/2。ERK信號(hào)轉(zhuǎn)導(dǎo)通路存在于大多數(shù)細(xì)胞內(nèi),并將細(xì)胞外刺激信號(hào)轉(zhuǎn)導(dǎo)至細(xì)胞及其核內(nèi),引起一系列細(xì)胞生物學(xué)反應(yīng),如細(xì)胞增殖、分化、轉(zhuǎn)化及凋亡等[1-2]。近來(lái),ERK信號(hào)通路在細(xì)胞凋亡過(guò)程中發(fā)揮著雙重的作用越來(lái)越被重視。

1 經(jīng)典的ERK信號(hào)通路的組成及功能

在哺乳類(lèi)細(xì)胞中已發(fā)現(xiàn)存在著三條并行的MAPK信號(hào)通路,分別為 ERK信號(hào)通路、JN K/ SAPK通路和p38MAPK通路,其中最為經(jīng)典的則是ERK信號(hào)通路[3-4]。

經(jīng)典ERK信號(hào)途徑大部分是Ras(rat sarcoma,Ras)依賴(lài)途徑。Ras是一種原癌基因ras表達(dá)的蛋白質(zhì),控制MAPK激酶鏈,被稱(chēng)為控制生長(zhǎng)和分化的信號(hào)途徑的分子開(kāi)關(guān)[5]。即活化的受體通過(guò)一系列磷酸化活化G蛋白,再經(jīng)過(guò)Ras進(jìn)一步激活三種信號(hào)轉(zhuǎn)導(dǎo)激酶[6]:MA PK,原癌基因表達(dá)產(chǎn)物Raf-1,核糖體 S6蛋白激酶 (ribosomal S6 kinase, RSK)。它們對(duì)應(yīng)答細(xì)胞基因表達(dá)的調(diào)節(jié)極為重要,尤其是MA PK是此信號(hào)通路的關(guān)鍵性轉(zhuǎn)換激酶。其轉(zhuǎn)導(dǎo)途徑過(guò)程大致如下:細(xì)胞信號(hào)與細(xì)胞膜上的特異性受體結(jié)合后,受體形成二聚體,二聚化的受體使其自身酪氨酸激酶磷酸化而被激活,激活的酪氨酸又與位于胞膜上的生長(zhǎng)因子受體結(jié)合蛋白2 (grow th facto r recep tor-bound p rotein 2,Grb2)的SH2結(jié)構(gòu)域結(jié)合,而 Grb2的SH3結(jié)構(gòu)域則同時(shí)又與鳥(niǎo)苷酸交換因子 SOS(Son of Sevenless,SOS)結(jié)合,后者使小分子鳥(niǎo)苷酸結(jié)合蛋白R(shí)as的GDP解離而結(jié)合GTP,從而激活Ras,激活的Ras進(jìn)一步與絲/蘇氨酸蛋白激酶 Raf-1的氨基端結(jié)合,通過(guò)未知機(jī)制激活Raf-1,Raf-1可磷酸化 M EK(MAPK kinase,MAPKK)上的二個(gè)調(diào)節(jié)性絲氨酸,從而激活M EK,M EK為雙特異性激酶,可以使絲/蘇氨酸和酪氨酸發(fā)生磷酸化,最終高度選擇性地激活ERK1/2[7]。經(jīng)典ERK信號(hào)轉(zhuǎn)導(dǎo)通路傳遞過(guò)程概括為:細(xì)胞外信號(hào)→細(xì)胞受體→Grb2-sos→Ras-GTP→Raf→M EK→ERK1/2→轉(zhuǎn)錄因子→相關(guān)基因表達(dá)→細(xì)胞增生、轉(zhuǎn)化。此外,ERK信號(hào)途徑也與其他信號(hào)途徑之間也可形成交聯(lián),從而發(fā)生相互聯(lián)系[8]。

2 ERK信號(hào)通路的作用機(jī)制

ERKs為脯氨酸導(dǎo)向的絲/蘇氨酸激酶,可以磷酸化與脯氨酸相鄰的絲/蘇氨酸。在絲裂原刺激后, ERKs接受上游的級(jí)聯(lián)反應(yīng)信號(hào),可以激活胞漿內(nèi)的下游底物,也可以直接轉(zhuǎn)位進(jìn)入細(xì)胞核。因此, ERKs不僅可以磷酸化胞漿蛋白如RSK、MN K和PLA 2等,而且可以磷酸化一些核內(nèi)的轉(zhuǎn)錄因子如cfos、c-Jun、Elk-1、A TF2和c-myc等,從而參與細(xì)胞增殖、分化、凋亡的調(diào)控。其主要機(jī)制有:①ERK調(diào)節(jié)c-fos:c-fos基因被稱(chēng)為即刻早期反應(yīng)基因 ( immediate early genes,IEG),可作為“分子開(kāi)關(guān)”或“第三信使”來(lái)控制下游基因程序,這些下游程序指導(dǎo)形成最終表達(dá)的蛋白質(zhì)。一旦c-fos下游基因程序被啟動(dòng),c-fos基因即關(guān)閉,故它在基因表達(dá)過(guò)程中至關(guān)重要[9]。ERK激活后,激活MAPK家族成員,進(jìn)而激活RSK,引起MAPK/cAM P反應(yīng)元件結(jié)合蛋白 (cAM P response element blinding p rotein, CREB)磷酸化激活并轉(zhuǎn)錄到核內(nèi),與cAM P反應(yīng)元件 (cAM P response element,CRE)結(jié)合,激活相關(guān)基因的轉(zhuǎn)錄,調(diào)節(jié)c-fos、SRF、Jun-B和Bcl-2等的表達(dá),這些蛋白質(zhì)通過(guò)抑制凋亡和促進(jìn)細(xì)胞分化,再生,損傷后修復(fù)等促進(jìn)神經(jīng)元的存活[10]。②ERK調(diào)節(jié)c-Jun:ERK激活后,經(jīng)過(guò)一系列級(jí)聯(lián)反應(yīng)激活A(yù)SK,然后激活Jun氨基末端激酶 (Jun N-teminal kinase,JN K),JN K一旦被激活,即從胞漿轉(zhuǎn)移至核內(nèi),引起一系列級(jí)聯(lián)反應(yīng),導(dǎo)致c-Jun等轉(zhuǎn)錄因子的激活[11]?；罨腸-Jun可聚合成同源二聚體或與c-fos聚合成異源二聚體形成活化蛋白-1(activato r p rotein-1,AP-1)復(fù)合物,而后AP-1再與其靶DNA相結(jié)合激活下游基因。③ERK調(diào)節(jié)Elk-1:ERK直接轉(zhuǎn)位到細(xì)胞核,引起轉(zhuǎn)錄因子 Elk-1的磷酸化, Elk與血清反應(yīng)因子 (serum response factor,SRF)和血清反應(yīng)元件 (serum response element,SRE)復(fù)合物相互作用,啟動(dòng)即刻早期基因c-fos的轉(zhuǎn)錄,進(jìn)而產(chǎn)生促進(jìn)細(xì)胞生長(zhǎng),發(fā)育,分化,再生及存活所需的結(jié)構(gòu)和功能蛋白;或者通過(guò)JN K對(duì)轉(zhuǎn)錄因子Elk-1氨基端得某些氨基酸位點(diǎn)磷酸化而使其激活,活化后的Elk-1可進(jìn)一步激活c-fos轉(zhuǎn)錄因子共同啟動(dòng)轉(zhuǎn)錄,促進(jìn)神經(jīng)元存活。④ERK調(diào)節(jié)A TF2:通過(guò)JN K活化c-Jun增加活化轉(zhuǎn)錄因子 2(activating transfaction factor 2,A TF2),與c-Jun一樣,A TF2也可結(jié)合到AP-1元件啟動(dòng)轉(zhuǎn)錄[12]。⑤ERK調(diào)節(jié)c-m yc和P53:JN K被認(rèn)為與一些凋亡相關(guān)蛋白的磷酸化有關(guān),ERK通過(guò)JN K磷酸化c-myc激活,發(fā)揮與凋亡相關(guān)的作用[13]。此外,ERK還可以磷酸化ERK通路的上游蛋白如 NGF受體、SOS、Raf-1、M EK等,進(jìn)而對(duì)該通路進(jìn)行自身的負(fù)反饋調(diào)節(jié)[14]。

3 ERK信號(hào)轉(zhuǎn)導(dǎo)通路的調(diào)節(jié)

ERK被細(xì)胞外刺激激活后,其活性增高持續(xù)時(shí)間的長(zhǎng)短決定著細(xì)胞對(duì)刺激的反應(yīng)形式:ERK的短暫激活導(dǎo)致細(xì)胞增殖,而ERK的持續(xù)激活則導(dǎo)致細(xì)胞的死亡。因此,ERK的滅活與其被激活同樣重要,而且也是受到嚴(yán)格調(diào)控的。ERK調(diào)節(jié)位點(diǎn)的絲/蘇氨酸及酪氨酸殘基被其上級(jí)雙重特異性激酶磷酸化激活,一組雙重特異性蛋白磷酸酶可使同樣位點(diǎn)的蘇/絲氨酸及酪氨酸殘基去磷酸化,從而滅活ERK[15-16]。目前已知的雙特異性磷酸酶有:M KP-1 (CL100)、M KP-2、hvH3、hvH5、PAC-1、M KP-3、PP2A、Pst-1、Pst-2。ERK的滅活隨其在細(xì)胞中的位置不同,由不同的磷酸酶滅活。PP2A、Pst-1、Pst-2可迅速滅活胞漿中的ERK。持續(xù)的ERK的激活,常伴有ERK轉(zhuǎn)位到核,此時(shí)核中的ERK由位于細(xì)胞核中的雙特異性磷酸酶M KP-1、PAC-1等滅活。不同的ERK為不同的雙特異性磷酸酶選擇性滅活。此外,ERK的抑制劑PD98059和 U 0126不僅能抑制ERK,也能抑制 M EK從而抑制 ERK的功能[17-18]。

4 ERK通路與神經(jīng)細(xì)胞存活

ERK信號(hào)途徑是神經(jīng)科學(xué)領(lǐng)域中重要的信號(hào)途徑,在大量研究中,發(fā)現(xiàn) ERK通路是神經(jīng)營(yíng)養(yǎng)因子對(duì)神經(jīng)元的存活、增殖、分化、抑制凋亡的生物學(xué)特性的主要作用機(jī)理之一[19]。目前對(duì)其激活過(guò)程及生物學(xué)意義已有了較深入的認(rèn)識(shí),大部分神經(jīng)營(yíng)養(yǎng)因子受體,特別是受體酪氨酸激酶(RTK)、G蛋白偶聯(lián)的受體,和部分細(xì)胞因子的受體,都可激活ERK信號(hào)轉(zhuǎn)導(dǎo)途徑[20],從而發(fā)揮促進(jìn)神經(jīng)元存活,增殖,抑制凋亡的作用。ERK信號(hào)通路在神經(jīng)生長(zhǎng)因子介導(dǎo)的細(xì)胞增殖過(guò)程中發(fā)揮重要作用已經(jīng)為人們所公認(rèn),其激活、失活和抑制 ERK信號(hào)轉(zhuǎn)導(dǎo)在細(xì)胞增殖和存活中發(fā)揮著重要的作用。但是ERK通路在神經(jīng)細(xì)胞死亡中的直接作用,越來(lái)越受到了研究人員的關(guān)注,正呈方興未艾之勢(shì)。

5 ERK通路與神經(jīng)細(xì)胞死亡

5.1 ERK通路與神經(jīng)細(xì)胞死亡模型

神經(jīng)細(xì)胞死亡是神經(jīng)系統(tǒng)發(fā)展中的常見(jiàn)現(xiàn)象,更是所有神經(jīng)變性疾病的主要標(biāo)志。在神經(jīng)細(xì)胞死亡過(guò)程中,來(lái)源于胞膜、胞漿、線粒體或胞核內(nèi)的死亡信號(hào)發(fā)揮著重要作用,它們以瀑布式蛋白反應(yīng)促使一種凋亡式的細(xì)胞死亡,包括DNA的斷裂和細(xì)胞的皺縮[21]。各種細(xì)胞死亡模型被發(fā)現(xiàn)存在于神經(jīng)機(jī)能紊亂或腦卒中的模型當(dāng)中,例如在AD(A lzheimer’s disease,AD)中的基底前腦的膽堿能神經(jīng)元和PD(Parkinson’s disease,PD)中紋狀體系統(tǒng)的多巴胺神經(jīng)元大量細(xì)胞受損死亡,ERK信號(hào)在其中發(fā)揮著關(guān)鍵的作用[22]。此外,研究表明在腦缺血模型中也發(fā)現(xiàn)了ERK的激活介導(dǎo)了神經(jīng)細(xì)胞的大量死亡[23-24]

在以往的研究中,M APK三條信號(hào)中JN K和P38促進(jìn)細(xì)胞死亡,而 ERK抑制細(xì)胞死亡[25]。然而,這種觀點(diǎn)已經(jīng)太過(guò)簡(jiǎn)單化了。大量研究表明,在體內(nèi)外的神經(jīng)細(xì)胞死亡模型中,ERK的激活發(fā)揮著促進(jìn)細(xì)胞死亡的作用。Bhat[26]最早發(fā)現(xiàn)在少突膠質(zhì)細(xì)胞株CG4 H2O2誘導(dǎo)死亡模型中發(fā)現(xiàn)ERK促進(jìn)細(xì)胞死亡。Stanciu等[27]在谷氨酸誘導(dǎo)的細(xì)胞死亡模型中發(fā)現(xiàn)神經(jīng)細(xì)胞的死亡可被 ERK抑制劑所阻斷。de Bernardo等[28]發(fā)現(xiàn)ERK信號(hào)促進(jìn)細(xì)胞死亡與ROS(reactive oxygen species)的激活有關(guān)。這種現(xiàn)象同樣被大量發(fā)現(xiàn)在腦損傷和腦缺血的模型中[29-30]。這些發(fā)現(xiàn)說(shuō)明了在這些死亡模型中 ERK信號(hào)途徑被激活,促進(jìn)了神經(jīng)細(xì)胞的死亡,而抑制ERK信號(hào)的激活則阻斷了神經(jīng)細(xì)胞的死亡,而這種神經(jīng)細(xì)胞的大量死亡,可能聯(lián)系著ERK信號(hào)激活了大量的ROS或其他有害刺激的產(chǎn)生。

5.2 ERK信號(hào)促進(jìn)細(xì)胞死亡的機(jī)理

ERK信號(hào)促進(jìn)細(xì)胞死亡是近些年研究中重要發(fā)現(xiàn),也是未來(lái)研究的重點(diǎn)與難點(diǎn)。研究發(fā)現(xiàn),在細(xì)胞中由ROS介導(dǎo)的氧化應(yīng)激誘導(dǎo)著ERK的激活,并且被大量報(bào)道,其中也包括神經(jīng)細(xì)胞[31]。這些報(bào)道中發(fā)現(xiàn)氧化應(yīng)激介導(dǎo)的細(xì)胞死亡需要的是持續(xù)的ERK信號(hào)的激活。持續(xù)的ERK信號(hào)激活促使了細(xì)胞的死亡,而短暫的ERK信號(hào)激活促使了細(xì)胞的存活[32]。也有研究發(fā)現(xiàn),僅僅是單純的ERK的持續(xù)激活也是不夠的,還依賴(lài)于ERK激活的強(qiáng)度[33],加入的神經(jīng)營(yíng)養(yǎng)因子[34],這說(shuō)明持續(xù)的ERK激活協(xié)同了其他的信號(hào)或細(xì)胞元件促使了細(xì)胞的死亡或者通過(guò)還不清楚的機(jī)制來(lái)征募不同的下游分子來(lái)促進(jìn)細(xì)胞存活還是細(xì)胞死亡。

ROS介導(dǎo) ERK的持續(xù)激活導(dǎo)致了細(xì)胞的死亡,其機(jī)理還不是很清楚。但是,研究發(fā)現(xiàn),ERK激活后一方面磷酸化胞漿底物,另一面進(jìn)行核轉(zhuǎn)移。持續(xù)的ERK激活被發(fā)現(xiàn)都屬于ERK轉(zhuǎn)移進(jìn)入核后,核轉(zhuǎn)入的ERK發(fā)揮著促進(jìn)細(xì)胞死亡和調(diào)節(jié)基因轉(zhuǎn)錄[35-36],而且ERK這種促進(jìn)細(xì)胞死亡方式并不是通過(guò)凋亡途徑[37]。凋亡途徑下的細(xì)胞死亡胞膜完整,核固縮,而ERK激活促進(jìn)細(xì)胞死亡表現(xiàn)了壞死的胞膜損傷和凋亡樣核固縮。這種“壞死-凋亡”現(xiàn)象不能被caspases抑制劑所阻斷。在這種獨(dú)特的不依賴(lài)與caspases的細(xì)胞死亡中,ERK似乎扮演著關(guān)鍵的角色。此外,在一些不依賴(lài)caspases的促進(jìn)死亡模型中,如 P物質(zhì)和它的受體,IL-1和其他的非凋亡形式的細(xì)胞死亡,也發(fā)現(xiàn)了ERK的激活,一些神經(jīng)營(yíng)養(yǎng)因子誘發(fā)的神經(jīng)細(xì)胞死亡也是由ERK激活介導(dǎo)的[38-39]。這些說(shuō)明了 ERK介導(dǎo)的神經(jīng)細(xì)胞死亡可能不是依賴(lài)于細(xì)胞的類(lèi)型與刺激,而是源于細(xì)胞的死亡模型。Castro-Obregon等同樣發(fā)現(xiàn)定位到細(xì)胞核的 ERK激活促進(jìn)細(xì)胞的死亡,而胞膜上ERK的激活并不能刺激細(xì)胞的死亡[38]。這暗示了定位到核的ERK調(diào)節(jié)了一些促死亡基因的表達(dá),而胞膜上的激活的ERK則調(diào)節(jié)了這些促死亡基因的表達(dá)阻滯。

因此,ERK促進(jìn)神經(jīng)細(xì)胞死亡是一種非凋亡式的細(xì)胞死亡,其機(jī)理可能聯(lián)系著ERK的多個(gè)激活子和效應(yīng)子,它們之間有著復(fù)雜的相互作用和調(diào)節(jié),而ERK的核停留是其關(guān)鍵因素。

5 展望

ERK信號(hào)通路對(duì)神經(jīng)細(xì)胞的存活、增殖、轉(zhuǎn)化和凋亡的重要調(diào)控作用,尤其是對(duì)神經(jīng)細(xì)胞的雙重作用,是影響神經(jīng)系統(tǒng)疾病與神經(jīng)損傷的發(fā)生發(fā)展的重要因素。研究ERK信號(hào)通路與神經(jīng)疾病與神經(jīng)損傷的關(guān)系,對(duì)揭示神經(jīng)疾病與損傷的發(fā)病機(jī)制、發(fā)展與轉(zhuǎn)歸,指導(dǎo)神經(jīng)疾病與損傷的治療有很大的幫助。雖然ERK信號(hào)通路在神經(jīng)細(xì)胞命運(yùn)中扮演的雙重角色的機(jī)理還不甚清楚,但是ERK通路可能是神經(jīng)疾病與損傷的藥物治療的潛在靶點(diǎn)。對(duì)ERK進(jìn)行有選擇性干預(yù),從而影響神經(jīng)細(xì)胞的存活與死亡,達(dá)到治療神經(jīng)疾病和損傷的良好效果。我們相信,隨著研究的不斷深入,神經(jīng)系統(tǒng)復(fù)雜的調(diào)控和修復(fù)機(jī)制的逐漸闡明,一定會(huì)給神經(jīng)疾病與損傷的治療帶來(lái)曙光。

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