A Smoothened-Evc2 Complex Transduces the Hedgehog Signal at Primary Cilia

被引:142
作者
Dorn, Karolin V. [1 ,2 ]
Hughes, Casey E. [1 ,2 ]
Rohatgi, Rajat [1 ,2 ]
机构
[1] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA
[2] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA
关键词
VAN-CREVELD-SYNDROME; PROTEIN-KINASE-A; TRANSITION ZONE; MEMBRANE; GENE; ACTIVATION; MUTATIONS; EVC2; SUPPRESSOR; DISEASE;
D O I
10.1016/j.devcel.2012.07.004
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Vertebrate Hedgehog (Hh) signaling is initiated at primary cilia by the ligand-triggered accumulation of Smoothened (Smo) in the ciliary membrane. The underlying biochemical mechanisms remain unknown. We find that Hh agonists promote the association between Smo and Evc2, a ciliary protein that is defective in two human ciliopathies. The formation of the Smo-Evc2 complex is under strict spatial control, being restricted to a distinct ciliary compartment, the EvC zone. Mutant Evc2 proteins that localize in cilia but are displaced from the EvC zone are dominant inhibitors of Hh signaling. Disabling Evc2 function blocks Hh signaling at a specific step between Smo and the downstream regulators protein kinase A and Suppressor of Fused, preventing activation of the Gli transcription factors. Our data suggest that the Smo-Evc2 signaling complex at the EvC zone is required for Hh signal transmission and elucidate the molecular basis of two human ciliopathies.
引用
收藏
页码:823 / 835
页数:13
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