Hh信號(hào)通路在胚胎發(fā)育及成體組織器官的功能維持中都起著十分重要的作用，其功能紊亂常常導(dǎo)致各種人類疾病包括各種腫瘤的產(chǎn)生：如基底細(xì)胞瘤,，髓母細(xì)胞瘤,，肺癌和肝癌等。Hh信號(hào)是通過7次跨膜的G蛋白偶聯(lián)受體Smoothened (Smo)來傳遞給下游轉(zhuǎn)錄因子Gli的,，但是哺乳動(dòng)物系統(tǒng)中將信號(hào)從膜蛋白Smo傳遞給轉(zhuǎn)錄因子Gli的中介蛋白及其分子調(diào)控機(jī)理并不清楚,。
2012年9月18日，Cell Research 發(fā)表了中國(guó)科學(xué)院昆明動(dòng)物研究所陳勇彬課題組的工作：通過遺傳學(xué)手段發(fā)現(xiàn)與疾病(Ellis-van Creveld syndrome)密切相關(guān)的兩個(gè)Primary Cilia（以微管蛋白為基礎(chǔ)的細(xì)胞器）聚集表達(dá)的分子Evc和Evc2, 可以幫助Smo傳遞Hh信號(hào)并激活下游轉(zhuǎn)錄因子Gli,，同時(shí)促進(jìn)活化形態(tài)的Gli在Primary Cilium中聚集表達(dá),。研究發(fā)現(xiàn)Evc/Evc2作用于Smo膜蛋白的下游， Sufu（抑制Hh信號(hào)通路蛋白分子）和轉(zhuǎn)錄因子Gli的上游,；還發(fā)現(xiàn)Hh信號(hào)刺激可以促進(jìn)Smo與Evc/Evc2蛋白結(jié)合,，而這種蛋白相互作用依賴于Smo蛋白 C-末端的磷酸化水平以及Primary Cilium這一獨(dú)特的細(xì)胞器。該研究不僅首次填補(bǔ)了哺乳動(dòng)物Hh信號(hào)通路級(jí)聯(lián)反應(yīng)的空缺,，讓人們更好地了解疾病相關(guān)基因Evc/Evc2的分子學(xué)功能,，同時(shí)為未來Hh信號(hào)通路相關(guān)腫瘤的治療提供了新的靶點(diǎn)。該工作由課題組楊翠萍副研究員等人協(xié)作完成,。
該研究項(xiàng)目得到了中國(guó)科學(xué)院,、國(guó)家自然科學(xué)基金、國(guó)家重大科學(xué)研究計(jì)劃等項(xiàng)目的資助,。（生物谷Bioon.com）
doi: 10.1038/cr.2012.134
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Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2.
Yang C, Chen W, Chen Y, Jiang J.
Hedgehog (Hh) signaling plays pivotal roles in embryonic development and adult tissue homeostasis in species ranging from Drosophila to mammals. The Hh signal is transduced by Smoothened (Smo), a seven-transmembrane protein related to G protein coupled receptors. Despite a conserved mechanism by which Hh activates Smo in Drosophila and mammals, how mammalian Hh signal is transduced from Smo to the Gli transcription factors is poorly understood. Here, we provide evidence that two ciliary proteins, Evc and Evc2, the products of human disease genes responsible for the Ellis-van Creveld syndrome, act downstream of Smo to transduce the Hh signal. We found that loss of Evc/Evc2 does not affect Sonic Hedgehog-induced Smo phosphorylation and ciliary localization but impedes Hh pathway activation mediated by constitutively active forms of Smo. Evc/Evc2 are dispensable for the constitutive Gli activity in Sufu(-/-) cells, suggesting that Evc/Evc2 act upstream of Sufu to promote Gli activation. Furthermore, we demonstrated that Hh stimulates binding of Evc/Evc2 to Smo depending on phosphorylation of the Smo C-terminal intracellular tail and that the binding is abolished in Kif3a(-/-) cilium-deficient cells. We propose that Hh activates Smo by inducing its phosphorylation, which recruits Evc/Evc2 to activate Gli proteins by antagonizing Sufu in the primary cilia.
