Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2  

作　　者：Cuiping Yang Wenlin Chen Yongbin Chen Jin Jiang 

机构地区：[1]Key Laboratory of Animal Models' and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kun-ming Institute of Zoology, Chinese Academy of Sciences, 32 Jiaochang Donglu, Kunming, Yunnan 650223, China [2]The Depart-ment of Breast Tumor of the 3rd Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650118, China [3]Departmentof Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA

出　　处：《Cell Research》2012年第11期1593-1604,共12页细胞研究（英文版）

摘　　要：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 Droso- phila 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-termi- nal 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.

关 键 词：EVC Evc2 HEDGEHOG SMO GLI 

分 类 号：Q257[生物学—细胞生物学] TP335[自动化与计算机技术—计算机系统结构]