Hh信号通路在胚胎发育及成体组织器官的功能维持中都起着十分重要的作用，其功能紊乱常常导致各种人类疾病包括各种肿瘤的产生：如基底细胞瘤，髓母细胞瘤，肺癌和肝癌等。Hh信号是通过7次跨膜的G蛋白偶联受体Smoothened (Smo)来传递给下游转录因子Gli的，但是哺乳动物系统中将信号从膜蛋白Smo传递给转录因子Gli的中介蛋白及其分子调控机理并不清楚。
2012年9月18日，Cell Research 发表了中国科学院昆明动物研究所陈勇彬课题组的工作：通过遗传学手段发现与疾病(Ellis-van Creveld syndrome)密切相关的两个Primary Cilia（以微管蛋白为基础的细胞器）聚集表达的分子Evc和Evc2, 可以帮助Smo传递Hh信号并激活下游转录因子Gli，同时促进活化形态的Gli在Primary Cilium中聚集表达。研究发现Evc/Evc2作用于Smo膜蛋白的下游， Sufu（抑制Hh信号通路蛋白分子）和转录因子Gli的上游；还发现Hh信号刺激可以促进Smo与Evc/Evc2蛋白结合，而这种蛋白相互作用依赖于Smo蛋白 C-末端的磷酸化水平以及Primary Cilium这一独特的细胞器。该研究不仅首次填补了哺乳动物Hh信号通路级联反应的空缺，让人们更好地了解疾病相关基因Evc/Evc2的分子学功能，同时为未来Hh信号通路相关肿瘤的治疗提供了新的靶点。该工作由课题组杨翠萍副研究员等人协作完成。
该研究项目得到了中国科学院、国家自然科学基金、国家重大科学研究计划等项目的资助。（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.
