潘偉東 綜 述，王東軍審 校

（廣東醫(yī)學(xué)院，廣東 湛江 524023）

MAPK信號(hào)轉(zhuǎn)導(dǎo)通路是細(xì)胞內(nèi)重要的信號(hào)轉(zhuǎn)導(dǎo)系統(tǒng)。ERK作為MAPKs家族的一個(gè)重要亞族，ERK1和ERK2是其中的兩個(gè)重要成員。ERK可被各種生長(zhǎng)因子等有絲分裂原激活，進(jìn)入細(xì)胞核作用于轉(zhuǎn)錄因子，促進(jìn)某些基因的轉(zhuǎn)錄與表達(dá)，以及促進(jìn)細(xì)胞增殖、分化、遷移、侵襲，抑制細(xì)胞凋亡。ERK的過度表達(dá)在細(xì)胞惡性轉(zhuǎn)化及演進(jìn)中起著重要的作用[1]。

1 ERK1/2的發(fā)現(xiàn)及結(jié)構(gòu)特點(diǎn)

MAPKs家族在調(diào)節(jié)細(xì)胞增殖、分化、凋亡、生存中起著重要作用[2]，其中包括 ERK1/2、p38[MAPK]、JNK[MAPK]、ERK5/BMK1等。ERK1/2是由Boulton等[3-4]于20世紀(jì)90年代初期分離并鑒定出的一種蛋白激酶的C-DNA序列，因多種細(xì)胞外信號(hào)均可激活該蛋白激酶而得名，相對(duì)分子量分別為44 kD和42 kD。ERK定位于染色體1p34～35，全長(zhǎng)3 118 bp，開放閱讀框編碼978個(gè)氨基酸殘基。ERK肽鏈的183位蘇氨酸和185位酪氨酸均發(fā)生磷酸化為該激酶活化所必須[5]，其在MAPK途徑中不僅作為轉(zhuǎn)錄因子，而且是膜蛋白。ERK激酶家族屬于酪氨酸蛋白激酶[6]，此類激酶在磷酸化以后才能發(fā)揮其活性。ERK蛋白具有絲氨酸和酪氨酸的雙重磷酸化能力，是ERK通路中與細(xì)胞轉(zhuǎn)錄水平最為接近的一種蛋白激酶，ERK1和ERK2由激酶結(jié)構(gòu)域組成，高度保守，有90%同源性，并且在體外有相同的作用底物，提示二者有功能上的重疊[5]。ERK1/2為脯氨酸導(dǎo)向的絲氨酸/蘇氨酸激酶，可以使脯氨酸相鄰的絲氨酸/蘇氨酸磷酸化，且ERK1/2蛋白的表達(dá)水平與組織、細(xì)胞類型以及所處的不同階段密切相關(guān)[7]，ERK1/2正常定位于細(xì)胞漿內(nèi)，當(dāng)激活后進(jìn)入細(xì)胞核，作用于多種轉(zhuǎn)錄因子及核蛋白，參與細(xì)胞增殖、分化、遷移、侵襲和凋亡等多種生物學(xué)效應(yīng)。

2 ERK1/2的信號(hào)通路

MAPK信號(hào)通路是廣泛存在于各種動(dòng)物細(xì)胞中的一條信號(hào)轉(zhuǎn)導(dǎo)途徑，MAPK信號(hào)途徑可調(diào)節(jié)從基因表達(dá)到細(xì)胞死亡幾乎所有的細(xì)胞過程[8-9]，并在細(xì)胞惡變和腫瘤浸潤(rùn)轉(zhuǎn)移過程中起著重要作用[10]。ERK是MAPKs家族一個(gè)重要亞族（ERK又稱為MAPK），遵循MAPKs三級(jí)酶促級(jí)聯(lián)反應(yīng)[11]，上游激活蛋白—MAPK激酶的激酶（MAPKKK）—MAPK激酶(MAPKK)—MAPK。在ERKs傳遞途徑中，Ras作為上游激活蛋白，Raf作為MAPKKK，MAPK/ERK激酶（MEK）作為MAPKK，而ERK作為MAPK。從細(xì)胞受到刺激至細(xì)胞出現(xiàn)相應(yīng)的生物學(xué)效應(yīng)，其間就是通過上述MAPK信號(hào)轉(zhuǎn)導(dǎo)通路多級(jí)激酶級(jí)聯(lián)反應(yīng)過程。Ras蛋白是最早發(fā)現(xiàn)的小G蛋白，是癌基因ras產(chǎn)物，Ras/Raf/MEK/ERK細(xì)胞信號(hào)傳導(dǎo)通路，活化的中心是使Ras進(jìn)行鳥苷酸交換變成其活化形式Ras-GTP。只有磷酸化的ERKl/2才具有活性。ERK接受上游的級(jí)聯(lián)反應(yīng)信號(hào)，變成磷酸化的EKR(P-ERK)，并轉(zhuǎn)位入細(xì)胞核，調(diào)節(jié)核內(nèi)某些的轉(zhuǎn)錄因子活性，如 c-fos、c-Jun、Elk-1、STATs、c-myc、Max、ATF2和NF-κB等，這些轉(zhuǎn)錄因子進(jìn)一步調(diào)節(jié)它們各自靶基因的轉(zhuǎn)錄，引起特定蛋白的表達(dá)或活性改變，從而參與多種細(xì)胞生物學(xué)效應(yīng)（如增殖、分化、轉(zhuǎn)化和凋亡等）[12-14]。PD98059是MAPK信號(hào)傳導(dǎo)通路的特異性阻斷劑，特異地抑制ERK的上游激酶MEK1（MEK1是ERK1/2主要的活化劑[15]），它通過與非活性形式的MEK1結(jié)合抑制MEK1的激活與磷酸化[16]，因而具有阻斷ERK信號(hào)通路的作用。

3 ERKl/2與細(xì)胞生物學(xué)反應(yīng)的關(guān)系

3.1 ERKl/2參與細(xì)胞增殖和分化 Luo等[17]在探究bFGF刺激胃部上皮細(xì)胞增殖可能的機(jī)制中發(fā)現(xiàn)bFGF首先上調(diào)成纖維細(xì)胞生長(zhǎng)因子受體（FGFR1和FGFR2），繼之激活ERK1/2信號(hào)傳導(dǎo)通路，從而增加COX-2表達(dá)引起RGM-1細(xì)胞增殖，且這個(gè)過程和p38[MAPK]、PI3K信號(hào)通路無關(guān)，同時(shí)觀察到地塞米松能夠抑制bFGF誘導(dǎo)的ERK1/2和COX-2表達(dá)，來阻止RGM-1細(xì)胞增殖。ERK1/2信號(hào)途徑，主要是通過影響細(xì)胞周期機(jī)制來調(diào)節(jié)細(xì)胞增殖[18]。Khan等[19]的研究也證實(shí)了這一點(diǎn)，他們研究DHA（Docosahexaenoic acid，二十二碳六烯酸）在FM3A老鼠乳腺癌細(xì)胞中調(diào)節(jié)細(xì)胞生長(zhǎng)增殖過程中的作用時(shí)發(fā)現(xiàn)ERK1/2活性受抑制和P27Kip1水平上調(diào)，它們通過作用參與細(xì)胞周期G1-to-S轉(zhuǎn)化調(diào)節(jié)的CDK2/cyclin E，起著抑制細(xì)胞周期末期G1向S期轉(zhuǎn)化，阻止細(xì)胞生長(zhǎng)增殖的作用，其中DHA誘導(dǎo)的ERK1/2活性受抑制是上調(diào)P27Kip1水平所必須的。ERK的功能是控制細(xì)胞分化[20]，其在細(xì)胞分化中的作用，國(guó)內(nèi)學(xué)者也做了較多研究。何艷等[21]應(yīng)用Western blot法檢測(cè)到經(jīng)蛇毒神經(jīng)生長(zhǎng)因子（NGF）處理的PC12細(xì)胞，在10 min后ERK1/2明顯磷酸化而活化；且培養(yǎng)液中加入NGF作用96 h，見PC12細(xì)胞，明顯分化，出現(xiàn)多個(gè)突起；而在NGF作用前30 min，使用20 μmol/L，PD98059預(yù)處理PC12細(xì)胞后，觀察到細(xì)胞以圓形或橢圓形居多，無明顯分化。

3.2 ERKl/2參與細(xì)胞遷移過程 以往的研究顯示，在正常組織中檢測(cè)不到ERK的激活，在多種惡性腫瘤中發(fā)生ERK的活化，ERK信號(hào)通路參與細(xì)胞遷移能力的調(diào)節(jié)[22]。Rodriguez等[23]在利用海拉癌細(xì)胞株研究人類癌基因Cot和細(xì)胞遷移關(guān)系時(shí)發(fā)現(xiàn)，人類癌基因Cot能特異性引起ERK1/2磷酸化水平增加，是細(xì)胞發(fā)生遷移的必須因素；并且ERKl/2的特異阻斷劑U0126，能降低Cot誘導(dǎo)的ERK1/2磷酸化引起的細(xì)胞遷移能力。先前Eliopoulos等[24]利用小鼠巨噬細(xì)胞應(yīng)用Western blot法分析Cot和LPS（lipopolysaccharide，脂多糖）誘導(dǎo)的前列腺素合成關(guān)系證實(shí)：Cot通過活化的ERK1/2信號(hào)途徑激活p90RSK和Msk1，后者能依次磷酸化和活化CREB和COX2催化劑，促使COX2蛋白表達(dá)，并進(jìn)一步促進(jìn)細(xì)胞遷移過程發(fā)生[22]。

3.3 ERKl/2參與細(xì)胞侵襲與核轉(zhuǎn)位 Piette等[25]在研究巨噬細(xì)胞移動(dòng)抑制因子（MIF）在腫瘤細(xì)胞生長(zhǎng)、侵襲過程中作用時(shí)觀察到：MIF通過活化ERK1/2信號(hào)傳導(dǎo)途徑來增強(qiáng)神經(jīng)膠質(zhì)瘤U373 MG細(xì)胞的遷移和侵襲能力；而地塞米松阻止神經(jīng)膠質(zhì)瘤U373 MG細(xì)胞遷移、侵襲過程是通過GR受體介導(dǎo)抑制ERK1/2途徑完成的。但是較多的研究表明，不同的趨化因子活化多條相互不重疊的信號(hào)傳導(dǎo)通路參與到神經(jīng)膠質(zhì)瘤侵襲作用中[26]，表皮生長(zhǎng)因子（EGF）引起的神經(jīng)膠質(zhì)瘤細(xì)胞株侵襲能力依賴于ERK1/2和PI3K活性，而趨化因子CXCL12引起的神經(jīng)膠質(zhì)瘤細(xì)胞移動(dòng)侵襲過程中，發(fā)現(xiàn)ERK1/2信號(hào)通路參與其中，而未見PI3K信號(hào)通路。先前研究多致力于特異性激酶如何調(diào)節(jié)ERK1/2活性[27]，近來研究發(fā)現(xiàn)：腫瘤細(xì)胞中ERK1/2信號(hào)傳導(dǎo)通路引起的生物學(xué)效應(yīng)可通過內(nèi)生性ERK1/2“調(diào)制器”的表達(dá)發(fā)生變化，另外抗凋亡因子PEA-15，通過抑制Caspases級(jí)聯(lián)激活發(fā)揮作用[28]，另外，PEA-15對(duì)腫瘤細(xì)胞侵襲能力和發(fā)展演進(jìn)過程影響，是通過PEA-15和ERK1/2結(jié)合，阻止ERK1/2細(xì)胞核轉(zhuǎn)位完成的，預(yù)示著ERK1/2細(xì)胞核轉(zhuǎn)位在腫瘤細(xì)胞侵襲過程中的重要性[29]。

4 ERKl/2和PI3K關(guān)系

ERK1/2和PI3K是細(xì)胞內(nèi)重要信號(hào)傳導(dǎo)途徑[30]，ERK1/2和PI3K的表達(dá)與腫瘤的增殖、癌性轉(zhuǎn)化、腫瘤細(xì)胞耐藥等方面有密切關(guān)系[31]。Failly等[32]在培養(yǎng)神經(jīng)膠質(zhì)瘤細(xì)胞株中應(yīng)用ELISA法和流式細(xì)胞儀分別觀察細(xì)胞增殖、凋亡情況時(shí)發(fā)現(xiàn)：ERK1/2和PI3K在體外膠質(zhì)瘤細(xì)胞存活、抗凋亡過程中起著重要作用；ERK1/2和PI3K抑制劑單一或(和)聯(lián)合處理LN215和LN229細(xì)胞，引起大量（85%～95%）細(xì)胞凋亡；實(shí)驗(yàn)中應(yīng)用Western blot方法還觀察到：經(jīng)過U0126處理的U373和LN229細(xì)胞中AKT磷酸化水平下降，表明了RAS/MEK/ERK和PI3K/AKT信號(hào)途徑間存在某種相互聯(lián)系。

Allen等[33]的研究表明，ERK1/2和PI3K兩條信號(hào)途徑之間存在交叉關(guān)系，且兩條信號(hào)途徑間相互作用形式具體表現(xiàn)為協(xié)同或拮抗。May等[34]研究證實(shí)：ATP激活ERK1/2，活化過程依賴于PI3K活性，應(yīng)用PI3K抑制劑（Ly294002）能夠阻止ATP對(duì)ERK1/2磷酸化作用。對(duì)c-myc誘導(dǎo)的細(xì)胞轉(zhuǎn)化和凋亡研究中發(fā)現(xiàn)ERK1/2信號(hào)途徑的成員Raf促進(jìn)凋亡，PI3-K信號(hào)途徑的成員Akt抑制凋亡[35]，而Akt通過磷酸化Raf Ser259，使Raf活性喪失，進(jìn)而Raf與其負(fù)調(diào)控因子14-3-3蛋白結(jié)合，抑制ERK1/2信號(hào)途徑[36]。

5 ERKl/2與神經(jīng)膠質(zhì)瘤細(xì)胞凋亡的關(guān)系

許多癌基因和抑癌基因相關(guān)產(chǎn)物是細(xì)胞生長(zhǎng)、增殖、分化等信號(hào)轉(zhuǎn)導(dǎo)途徑中的因子，如：ERK1/2信號(hào)途徑的Ras、Raf、C-Myc以及PI-3K信號(hào)途徑的Akt等均為原癌基因產(chǎn)物[37]，其中細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)通路的異常是細(xì)胞癌變的主要原因之一。ERK1/2在細(xì)胞轉(zhuǎn)化、存活、抗凋亡過程中起著至關(guān)重要的作用[38]，ERK1/2的激活使轉(zhuǎn)錄因子磷酸化來調(diào)節(jié)基因的表達(dá)，促進(jìn)細(xì)胞增殖，阻止細(xì)胞凋亡。對(duì)神經(jīng)鞘氨醇誘導(dǎo)的神經(jīng)膠質(zhì)瘤C6細(xì)胞凋亡研究發(fā)現(xiàn)ERK1/2信號(hào)途徑介導(dǎo)細(xì)胞凋亡過程，且細(xì)胞的凋亡只發(fā)生于ERK1/2活性降低或消失時(shí)[39]。Tian等[40]研究也證實(shí)：PKCα-ERK1/2信號(hào)途徑在三苯氧胺（TAM）誘導(dǎo)的神經(jīng)膠質(zhì)瘤C6細(xì)胞凋亡中起消極（負(fù)性）作用，使用ERK1/2抑制劑能有效增強(qiáng)TAM抑制腫瘤細(xì)胞生長(zhǎng)、增殖作用。深入研究發(fā)現(xiàn)：ERK1/2在細(xì)胞生存和凋亡過程中的作用，依靠于ERK1/2持續(xù)的激活和亞細(xì)胞定位[41]，且在所有神經(jīng)膠質(zhì)瘤細(xì)胞系細(xì)胞凋亡中發(fā)現(xiàn)ERK1/2和PKB/AKT磷酸化水平下降，但與U373和LN401發(fā)生細(xì)胞凋亡無關(guān)系，提示還有另外促使細(xì)胞凋亡的機(jī)制節(jié)點(diǎn)存在[32]。

6 展 望

神經(jīng)膠質(zhì)瘤是中樞神經(jīng)系統(tǒng)最常見的原發(fā)惡性腫瘤，年發(fā)病率為5/100 000左右[42]，具有侵襲性生長(zhǎng)，惡性程度高、易復(fù)發(fā)、手術(shù)切除率低等特點(diǎn)，放療、傳統(tǒng)細(xì)胞毒性化療藥物缺乏特異性，是預(yù)后最差的惡性腫瘤之一。ERK信號(hào)傳導(dǎo)通路是細(xì)胞存活和抗凋亡信號(hào)途徑，可被多種細(xì)胞外刺激信號(hào)激活,參與調(diào)節(jié)細(xì)胞的增殖、分化、遷移、侵襲和凋亡等細(xì)胞生理活動(dòng)。盡管ERK1/2信號(hào)通路與神經(jīng)膠質(zhì)瘤的發(fā)生密切相關(guān)，但其確切的作用機(jī)制尚不完全清楚。相信隨著基因組學(xué)和生物學(xué)技術(shù)的進(jìn)一步發(fā)展，其在神經(jīng)膠質(zhì)瘤的發(fā)生發(fā)展中的作用機(jī)制將會(huì)越來越清晰，也將會(huì)為臨床上神經(jīng)膠質(zhì)瘤的治療及預(yù)后判斷提供新的思路和方法。

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