來(lái)自加州大學(xué)圣地亞哥分校,、哈佛大學(xué)的研究人員發(fā)表了題為“YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTEN via miR-29”的文章,，證實(shí)YAP通過(guò)miR-29抑制PTEN介導(dǎo)了Hippo與PI(3)K–TOR信號(hào)通路之間的串?dāng)_。相關(guān)成果發(fā)布在11月11日的《自然細(xì)胞生物學(xué)》（Nature Cell Biology）雜志上,。
文章的通訊作者是早年畢業(yè)于杭州大學(xué)的管坤良教授,，管教授主要從事細(xì)胞生長(zhǎng)調(diào)控、腫瘤生物學(xué)以及神經(jīng)生物學(xué)的信號(hào)轉(zhuǎn)導(dǎo)途徑等方面的研究,，他曾榮獲過(guò)包括美國(guó)“麥克阿瑟天才獎(jiǎng)”在內(nèi)的多項(xiàng)榮譽(yù),，現(xiàn)任加州大學(xué)圣地亞哥分校教授，浙江大學(xué)生命科學(xué)研究院兼職教授,、共同院長(zhǎng)等職務(wù),。
Hippo信號(hào)轉(zhuǎn)導(dǎo)通路是幾年前發(fā)現(xiàn)的一個(gè)信號(hào)轉(zhuǎn)導(dǎo)通路。研究發(fā)現(xiàn)Hippo信號(hào)通路是參與調(diào)控器官大小發(fā)育的關(guān)鍵信號(hào)通路,，這一觀點(diǎn)首先在果蠅中被發(fā)現(xiàn),，后來(lái)的研究發(fā)現(xiàn)在哺乳動(dòng)物的發(fā)育過(guò)程中Hippo有相同的功能。近年來(lái)越來(lái)越多的證據(jù)表明,，這條信號(hào)通路還調(diào)控干細(xì)胞自我更新及組織再生,，特別是與癌癥的發(fā)生密切相關(guān)。因而這一通路的研究不但是發(fā)育生物學(xué)的重要課題,，而且對(duì)人類疾病的治療具有指導(dǎo)意義,。
YAP是Hippo信號(hào)通路下游的效應(yīng)因子,從果蠅到哺乳動(dòng)物高度保守。YAP能夠進(jìn)入細(xì)胞核,與核內(nèi)的轉(zhuǎn)錄因子相互結(jié)合,啟動(dòng)下游靶基因的轉(zhuǎn)錄,，促進(jìn)器官生長(zhǎng),。然而目前對(duì)于這一調(diào)控的分子機(jī)制還不是很清楚。
在這篇文章中,，研究人員證實(shí)YAP激活了細(xì)胞生長(zhǎng)的重要調(diào)控因子哺乳動(dòng)物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR),。在YAP對(duì)mTOR的調(diào)控中，mTOR上游負(fù)調(diào)控子PTEN起關(guān)鍵性作用,。YAP通過(guò)誘導(dǎo)miR-29抑制PTEN轉(zhuǎn)錄下調(diào)PTEN表達(dá),，轉(zhuǎn)而激活了mTOR信號(hào)通路。最后,，研究人員證實(shí)YAP調(diào)控PI(3)K–mTOR信號(hào)控制了細(xì)胞的大小,、組織生長(zhǎng)和增生。
新研究揭示了Hippo與PI(3)K–mTOR信號(hào)之間的功能性相關(guān)性,，為在器官大小調(diào)控中協(xié)調(diào)這兩條信號(hào)提供了分子基礎(chǔ),。
目前，針對(duì)Hippo通路的研究已經(jīng)成為國(guó)際上的熱點(diǎn),。國(guó)外許多著名的實(shí)驗(yàn)室都在從事該領(lǐng)域的研究,，他們通過(guò)大規(guī)模的遺傳學(xué)篩選,，獲得了大量參與該通路調(diào)控的新基因信息。有關(guān)Hippo通路新調(diào)控機(jī)制的文章,，發(fā)表速度之快、質(zhì)量之高,，令人驚嘆,。
管坤良教授課題組與國(guó)內(nèi)外的研究人員展開(kāi)合作，在該領(lǐng)域做出了一系列的突出成績(jī),。不久前其與浙江大學(xué)生命科學(xué)院的研究人員合作獲得了G蛋白偶聯(lián)受體信號(hào)介導(dǎo)的Hippo-YAP途徑新機(jī)制,，這項(xiàng)研究指出了調(diào)控Hippo途徑的外信號(hào)，也證明了Hippo-YAP途徑是GPCR下游關(guān)鍵信號(hào)分支,。相關(guān)成果公布在Cell雜志上,。此外，在近期的一篇JBC文章上,，課題組還揭示了Hippo腫瘤抑制信號(hào)中一個(gè)關(guān)鍵的因子TAZ的調(diào)控新機(jī)制,，表明TAZ也在調(diào)控對(duì)PI3K信號(hào)做出反應(yīng)的組織生長(zhǎng)和腫瘤形成中發(fā)揮了作用。(生物谷Bioon.com)
doi:10.1038/ncb2615
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YAP mediates crosstalk between the Hippo and PI(3)K–TOR pathways by suppressing PTENvia miR-29
Karen Tumaneng Karin Schlegelmilch Ryan C. Russell Dean Yimlamai Harihar Basnet Navin Mahadevan Julien Fitamant Nabeel Bardeesy Fernando D. Camargo Kun-Liang Guan
Organ development is a complex process governed by the interplay of several signalling pathways that have critical functions in the regulation of cell growth and proliferation. Over the past years, the Hippo pathway has emerged as a key regulator of organ size. Perturbation of this pathway has been shown to play important roles in tumorigenesis. YAP, the main downstream target of the mammalian Hippo pathway, promotes organ growth, yet the underlying molecular mechanism of this regulation remains unclear. Here we provide evidence that YAP activates the mammalian target of rapamycin (mTOR), a major regulator of cell growth. We have identified the tumour suppressorPTEN, an upstream negative regulator of mTOR, as a critical mediator of YAP in mTOR regulation. We demonstrate that YAP downregulates PTEN by inducing miR-29 to inhibit PTEN translation. Last, we show that PI(3)K–mTOR is a pathway modulated by YAP to regulate cell size, tissue growth and hyperplasia. Our studies reveal a functional link between Hippo and PI(3)K–mTOR, providing a molecular basis for the coordination of these two pathways in organ size regulation.
