齊夢迭(綜述)，王學(xué)敏(審校)

(1.蘇州大學(xué)研究生部，江蘇 蘇州 215006； 2.上海交通大學(xué)附屬第六人民醫(yī)院麻醉科/ICU，上海 200233)

YAP調(diào)節(jié)細(xì)胞增殖和凋亡作用機(jī)制的研究進(jìn)展

齊夢迭1△(綜述)，王學(xué)敏2※(審校)

(1.蘇州大學(xué)研究生部，江蘇 蘇州 215006； 2.上海交通大學(xué)附屬第六人民醫(yī)院麻醉科/ICU，上海 200233)

Hippo信號(hào)通路從果蠅屬到哺乳動(dòng)物高度保守，在維持組織器官大小中起著重要作用，并參與多種疾病的發(fā)生和發(fā)展。Hippo信號(hào)通路包含多種癌基因和抑癌基因，該通路的異?？蓪?dǎo)致細(xì)胞增殖和凋亡失衡，組織器官過度增生甚至癌變[1]。Yes相關(guān)蛋白(Yes-associated protein，YAP)作為Hippo信號(hào)通路下游關(guān)鍵的效應(yīng)因子，通過磷酸化形式調(diào)節(jié)細(xì)胞核內(nèi)外的信號(hào)傳遞；作為轉(zhuǎn)錄共激活因子調(diào)節(jié)靶蛋白轉(zhuǎn)錄因子的活性，最終轉(zhuǎn)錄因子對(duì)靶基因的調(diào)控決定YAP的生物學(xué)作用[2]。為了更清楚地了解哺乳動(dòng)物Hippo-YAP信號(hào)通路，現(xiàn)對(duì)該信號(hào)通路作用機(jī)制及涉及的其他信號(hào)通路的相關(guān)研究進(jìn)展予以綜述。

1哺乳動(dòng)物Hippo-YAP信號(hào)通路

哺乳動(dòng)物Hippo信號(hào)通路主要由3部分組成：多重上游信號(hào)分子(包括Fat、Dchs1/2、FRMD6、NF2和KIBRA等)、核心激酶級(jí)聯(lián)反應(yīng)鏈(包括Mstl/2、Sav1/WW45、Latsl/2、Mob1和YAP)和下游調(diào)節(jié)因子(包括TEAD1/4、Wbp-2、p73、RASSF和Ajuba等)[1]。人類YAP基因位于染色體11q22擴(kuò)增區(qū)，編碼65 000蛋白；哺乳動(dòng)物能合成兩種多肽鏈YAP1和YAP2，兩者均參與Hippo信號(hào)通路；YAP1含有1個(gè)WW結(jié)構(gòu)域，YAP2含有2個(gè)WW結(jié)構(gòu)域，特異性地識(shí)別和結(jié)合PPXY基序[3]。YAP通過核心激酶級(jí)聯(lián)反應(yīng)被磷酸化，磷酸化的YAP繼而與14-3-3蛋白偶聯(lián)被阻斷在細(xì)胞質(zhì)中，被泛素依賴的蛋白酶體降解[4]。去磷酸化形式的YAP定位在核內(nèi)，通過WW結(jié)構(gòu)域與轉(zhuǎn)錄因子TEAD家族(TEA domain family)、p73、SMAD家族(BMP通路)、IAP家族(Bric2、Bric5)、ErbB4胞質(zhì)結(jié)合域和PEBP2α等結(jié)合，參與細(xì)胞增殖和凋亡的調(diào)節(jié)[5-6]。

2YAP在哺乳動(dòng)物細(xì)胞中的矛盾作用

2.1YAP促進(jìn)細(xì)胞增殖、抑制凋亡研究發(fā)現(xiàn)，YAP在多種實(shí)體腫瘤組織和腫瘤細(xì)胞株中定位于細(xì)胞核并過表達(dá)(如非小細(xì)胞肺癌、肝癌、胃癌、結(jié)直腸癌、卵巢癌、前列腺癌等)，其與腫瘤的臨床分期、轉(zhuǎn)移、放化療敏感性及預(yù)后相關(guān)[7-9]。YAP過表達(dá)促進(jìn)了正常組織的生長，甚至導(dǎo)致癌變[10]，提示YAP可能作為一種重要的癌基因在腫瘤的發(fā)生、發(fā)展中發(fā)揮重要作用。哺乳動(dòng)物TEAD轉(zhuǎn)錄因子普遍表達(dá)，作為YAP在細(xì)胞核內(nèi)的主要目標(biāo)，對(duì)YAP介導(dǎo)的腫瘤細(xì)胞過度增殖和上皮間質(zhì)轉(zhuǎn)化起著關(guān)鍵作用[11]。YAP與TEAD轉(zhuǎn)錄因子結(jié)合后，促進(jìn)下游靶基因如Cyclin E、β聯(lián)蛋白(β-catenin)、AXL (AXL receptor tyrosine kinase)、結(jié)締組織生長因子(Connective tissue growth factor，CTGF)和(Cysteine-rich,angiogenic inducer 61，Cyr61)等的轉(zhuǎn)錄，參與細(xì)胞增殖、黏附和遷移[12-13]。所以，有報(bào)道指出，基因或者藥物干擾YAP-TEAD復(fù)合體的形成，可以中斷YAP介導(dǎo)的細(xì)胞增殖效應(yīng)，YAP-TEAD有望成為抑制腫瘤生長的新靶點(diǎn)[14]。

2.2YAP促進(jìn)細(xì)胞凋亡、抑制增殖乳腺癌組織中YAP陽性率顯著低于正常乳腺組織，剔除YAP乳腺癌細(xì)胞表現(xiàn)出更強(qiáng)浸潤力及轉(zhuǎn)移能力；動(dòng)物模型中，剔除該基因的裸鼠乳腺癌發(fā)生早且生長迅速[15-16]，提示YAP在乳腺癌中可能作為一種抑癌基因。研究發(fā)現(xiàn)，p73作為YAP下游的目標(biāo)轉(zhuǎn)錄因子，基因毒性應(yīng)激DNA損傷時(shí)，活化的YAP入核后，YAP蛋白的WW結(jié)構(gòu)域與p73蛋白的PPXY基序結(jié)合，調(diào)節(jié)p73轉(zhuǎn)錄活性，增加下游促凋亡蛋白(如Bax和Puma)的轉(zhuǎn)錄[17-18]；而且利用干擾小RNA技術(shù)沉默YAP基因的表達(dá)后，降低p73介導(dǎo)的細(xì)胞凋亡[19]。另外，核內(nèi)YAP與ItchE3泛素連接酶競爭結(jié)合到p73的PPXY基序，使p73逃脫ItchE3介導(dǎo)的泛素化降解，增加p73蛋白的穩(wěn)定性[20]?？梢姡琘AP通過增加p73活性和抑制其降解兩條途徑促進(jìn)p73介導(dǎo)的細(xì)胞凋亡。因此，一些學(xué)者提出，YAP作為癌基因或抑癌基因與具體的內(nèi)環(huán)境及腫瘤本身有關(guān)；YAP促增殖和促凋亡的雙重作用可能是對(duì)不同的轉(zhuǎn)錄因子選擇性調(diào)節(jié)的結(jié)果，主要受TEAD和p73的調(diào)節(jié)[21]。YAP是否以及多大程度上與TEAD、p73或者其他轉(zhuǎn)錄因子結(jié)合，似乎與上游信號(hào)及激酶有關(guān)。

3YAP多重作用機(jī)制所涉及的信號(hào)通路

雖然Hippo-YAP途徑中關(guān)鍵成分及作用日趨明確，但是調(diào)節(jié)Hippo途徑的上游信號(hào)及YAP下游的效應(yīng)因子及具體的作用機(jī)制尚不清楚。哺乳動(dòng)物雷帕霉素靶蛋白(the mammalian target of rapamycin，mTOR)、磷脂酰肌醇3-激酶/蛋白激酶B(phosphoinositide 3 kinase / protein kinase B，PI3K/Akt)和Wnt /β聯(lián)蛋白(Wnt/β-catenin)等信號(hào)通路，在調(diào)控細(xì)胞的增殖和凋亡中扮演著重要的角色[22-24]。諸多研究證明Hippo信號(hào)通路與以上通路及蛋白之間存在多重而復(fù)雜的相互作用，共同調(diào)控機(jī)體復(fù)雜的細(xì)胞生物學(xué)行為。

3.1YAP與mTOR信號(hào)通路在哺乳動(dòng)物細(xì)胞mTOR通路可以感受生長因子和營養(yǎng)水平，通過磷酸化兩種效應(yīng)因子調(diào)節(jié)細(xì)胞分裂和增殖，mTOR在很多腫瘤細(xì)胞中表達(dá)上調(diào)[22]。有研究發(fā)現(xiàn)，在果蠅屬生長因子信號(hào)影響Hippo通路，過表達(dá)Yki增加了mTOR底物的磷酸化，表明Hippo通路和mTOR途徑之間存在著潛在的聯(lián)系[25]。在哺乳動(dòng)物細(xì)胞，mTOR和Hippo-YAP是調(diào)節(jié)細(xì)胞生長的兩條關(guān)鍵信號(hào)轉(zhuǎn)導(dǎo)通路，YAP通過miR-29(micro RNA-29)和PTEN(phosphatase and tensin homologue)來調(diào)節(jié)與mTOR通路之間的 “串話”(cross-talk)[26]。剔除Mst1/2-/-或者Lats1/2-/-小鼠，YAP活性增加，從而使PTEN的表達(dá)明顯降低，mTOR底物磷酸化水平增加[27]，更強(qiáng)調(diào)了通過YAP對(duì)PTEN的調(diào)節(jié)在Hippo與mTOR之間交叉的重要性。

3.2YAP與PI3K/Akt、胰島素樣生長因子/蛋白激酶B(insulin-like growth factor/protein kinase B，IGF/Akt)信號(hào)通路PI3K/Akt和IGF/Akt信號(hào)通路在細(xì)胞物質(zhì)代謝、細(xì)胞周期調(diào)控、細(xì)胞增殖和凋亡中發(fā)揮重要作用。以上兩條途中蛋白激酶B(protein kinase B，Akt)都扮演著重要角色，且參與YAP的促凋亡和促增殖作用[19,28]。最初有研究認(rèn)為，DNA損傷時(shí)Akt在Ser127位點(diǎn)磷酸化YAP，從而抑制YAP入核與p73結(jié)合，抑制Aβ25-35誘導(dǎo)的神經(jīng)元凋亡過程[19]。然而，在肝癌細(xì)胞系通過IGF/Akt途徑活化YAP促進(jìn)細(xì)胞增殖，Akt抑制劑也抑制YAP活性及下游靶基因CTGF的表達(dá)，抑制細(xì)胞增殖，誘導(dǎo)細(xì)胞凋亡[25,29]?？赡苁怯捎赮AP對(duì)細(xì)胞增殖和凋亡的雙重影響，所以在不同的細(xì)胞及內(nèi)環(huán)境下，Akt對(duì)YAP的調(diào)節(jié)會(huì)產(chǎn)生不同的結(jié)果。在果蠅屬YAP同源蛋白Yki正向調(diào)節(jié)了Akt的表達(dá)及活性，活化Hippo途徑降低Akt的表達(dá)[23]。另外，在髓母細(xì)胞瘤中發(fā)現(xiàn)癌基因YAP通過誘導(dǎo)IGF的表達(dá)及Akt的活化增加細(xì)胞的放射抵抗，促進(jìn)放療后腫瘤細(xì)胞的生長[28]；增加心肌梗死后心肌細(xì)胞的再生[30]。Akt與YAP之間是否存在一種正反饋機(jī)制，活化的YAP可以通過Akt調(diào)節(jié)細(xì)胞的生長等問題還需進(jìn)一步探討。

3.3YAP與Wnt/β-catenin信號(hào)通路Wnt信號(hào)通路是一個(gè)復(fù)雜的蛋白質(zhì)作用網(wǎng)絡(luò)，該信號(hào)途徑中β-catenin是一種多功能蛋白，定位于胞質(zhì)時(shí)被Axin/APC/ GSK3β復(fù)合物降解，而Dvl則可抑制降解復(fù)合物的活性；β-catenin入核后作為T細(xì)胞因子/淋巴細(xì)胞增強(qiáng)因子(T cell factor/ lymphoid enhancing factor，TCF/LEF)的轉(zhuǎn)錄共刺激因子調(diào)節(jié)靶基因的表達(dá)[24]。研究證明，YAP抑制Wnt/β-catenin通路活性有賴于Hippo信號(hào)通路對(duì)YAP的磷酸化及胞質(zhì)定位[31]。過表達(dá)YAP抑制結(jié)直腸癌細(xì)胞的生長，YAP低表達(dá)的結(jié)直腸癌患者臨床預(yù)后差，主要是因?yàn)楸磉_(dá)在胞質(zhì)中的YAP限制Dvl及β-catenin入核，從而抑制Wnt通路[32-33]。相反，核內(nèi)的YAP通過與β-catenin結(jié)合并活化其下游靶基因的轉(zhuǎn)錄，促進(jìn)心肌細(xì)胞和結(jié)腸癌細(xì)胞的增殖[33-34]。然而，YAP/β-catenin之間似乎也存在一種正反饋機(jī)制。Wnt信號(hào)可以促進(jìn)YAP/TAZ(Transcriptional co-activator with PDZ-binding motif)的表達(dá)；β-catenin/TCF4復(fù)合物在YAP基因的第1個(gè)內(nèi)含子位置與DNA增強(qiáng)子結(jié)合，調(diào)節(jié)YAP的表達(dá)，使用小發(fā)卡RNA降低β-catenin的表達(dá)；同時(shí)也降低YAP 信使RNA及蛋白水平的表達(dá)[35-36]。因此，YAP對(duì)Wnt/β-catenin信號(hào)通路的調(diào)節(jié)具有多樣性，同時(shí)YAP與β-catenin之間存在相互調(diào)節(jié)。

3.4其他信號(hào)通路轉(zhuǎn)化生長因子β(transforming growth factor-β，TGF-β)通過胞內(nèi)信號(hào)分子SMADs蛋白轉(zhuǎn)導(dǎo)信號(hào)，具有抑制生長、促進(jìn)細(xì)胞分化等多種作用。YAP作為轉(zhuǎn)錄共激活因子，參與SMADs蛋白的轉(zhuǎn)錄，從而對(duì)TGF-β參與的信號(hào)通路產(chǎn)生影響[37]。Notch信號(hào)通路通過相鄰細(xì)胞之間的相互作用調(diào)節(jié)細(xì)胞、組織、器官的分化和發(fā)育；Hippo信號(hào)通路抑制Notch 信號(hào)，參與細(xì)胞分化、增殖和卵母細(xì)胞極性的調(diào)節(jié)[38]。YAP通過上調(diào)Jag-1活化Notch信號(hào)，促進(jìn)結(jié)腸癌細(xì)胞的生長且與結(jié)腸癌患者的臨床預(yù)后有關(guān)[39]。c-Jun氨基端激酶信號(hào)轉(zhuǎn)導(dǎo)通路是絲裂原活化蛋白激酶(mitogen-activated protein kinases，MAPK)通路的一重要分支，研究認(rèn)為，c-Jun氨基端激酶1/2作為YAP上游的激酶，在多位點(diǎn)磷酸化內(nèi)源性YAP，促進(jìn)YAP的促凋亡效應(yīng)[40]。所以，YAP促增殖或促凋亡效應(yīng)似乎與上游的激酶及翻譯后修飾有關(guān)。

4小結(jié)

Hippo信號(hào)通路是調(diào)控機(jī)體內(nèi)環(huán)境穩(wěn)態(tài)重要的信號(hào)通路，人體多種腫瘤的發(fā)生、發(fā)展都與Hippo信號(hào)通路尤其是YAP的表達(dá)異常有關(guān)。在各種癌細(xì)胞中，YAP扮演著癌基因和抑癌基因的雙重角色，不能僅僅以剔除YAP基因，降低YAP蛋白的表達(dá)作為癌癥治療的靶點(diǎn)。所以深入研究哺乳動(dòng)物Hippo信號(hào)通路及其與其他信號(hào)通路形成的網(wǎng)絡(luò)結(jié)構(gòu)，將為疾病的預(yù)防、診斷和治療提供新的思路和方法。

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摘要：Hippo信號(hào)通路首先在果蠅屬中發(fā)現(xiàn)，在哺乳動(dòng)物高度保守，通過調(diào)節(jié)細(xì)胞增殖和凋亡維持器官大小和機(jī)體內(nèi)環(huán)境的穩(wěn)態(tài)。Yes相關(guān)蛋白(YAP)是Hippo信號(hào)通路的關(guān)鍵效應(yīng)分子，作為轉(zhuǎn)錄共激活因子扮演著癌基因和抑癌基因的矛盾角色。YAP去磷酸化后活化，入核參與細(xì)胞增殖和凋亡的調(diào)節(jié)；其中涉及哺乳動(dòng)物雷帕霉素靶蛋白(mTOR)、磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)、Wnt /β聯(lián)蛋白(Wnt/β-catenin)等信號(hào)通路。該文對(duì)哺乳動(dòng)物Hippo-YAP信號(hào)通路調(diào)節(jié)細(xì)胞增殖和凋亡作用機(jī)制的研究進(jìn)展予以綜述。

關(guān)鍵詞：哺乳動(dòng)物；Hippo-Yes相關(guān)蛋白；增殖；凋亡

Research Progress on YAP in the Regulation of Proliferation and ApoptosisQIMeng-die1,WANGXue-min2.(1.PostgraduateSection,SoochowUniversity,Suzhou215006,China; 2.DepartmentofAnesthesiology/ICU,theSixthPeople′sHospital,ShanghaiJiaotongUniversity,Shanghai200233,China)

Abstract:Hippo signaling pathway was first discovered in Drosophila,and was highly conservative in mammalian.It governs organ sizes and internal environment homeostasis through regulation of cell proliferation and apoptosis.YAP is the key effector in Hippo signaling pathway,as a transcriptional coactivator plays a contradictory role of oncogenes and tumor suppressor genes.YAP is activated by dephosphorylation in the nucleus,then regulates the cell proliferation and apoptosis,which involves mTOR,PI3K-Akt,Wnt/β-catenin signaling pathways.Here is to make a review of the mechanisms of mammalian Hippo-YAP signaling pathway in the proliferation and apoptosis.

Key words:Mammalian; Hippo-Yes-associated protein; Proliferation; Apoptosis

收稿日期：2014-04-02修回日期：2014-07-30編輯：鄭雪

doi：10.3969/j.issn.1006-2084.2015.06.013

中圖分類號(hào)：R730.2； R730.7

文獻(xiàn)標(biāo)識(shí)碼：A

文章編號(hào)：1006-2084(2015)06-0994-03