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

Abstract

SUMMARY 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.

Insect Stage-Specific Receptor Adenylate Cyclases Are Localized to Distinct Subdomains of the Trypanosoma brucei Flagellar Membrane

“…We did not observe any obvious sequence similarities between the C-terminal sequences of ACs and calpain1.3, nor did we identify similarities to published targeting sequences in flagellar membrane proteins of other organisms (84). Protein localization within specific flagellum subdomains is emerging as an important aspect of flagellum biology (22,(85)(86)(87), but the sequences responsible for directing subflagellar targeting are unknown (88,89). In this regard, ACP1 and ACP2 in T. brucei offer potential insights, because they are ϳ90% identical in amino acid sequence and differences are primarily restricted to the C-terminal region that is required for flagellum localization.…”

Cilia and coordination of signaling networks during heart development

“…4), 21,22,142 and defective ciliary assembly is associated with defective cardiomyogenesis 21 as well as Hh-related heart defects that might be independent of nodal cilia, including ventricular and endocardial cushion-derived defects. 122,142,154 Further, 60% of patients with mutations in genes encoding the EVC proteins, EVC1/EVC2, which interact with Smo at the primary cilium to transduce Hh signaling [155][156][157][158][159] , display CHD, including AVSD and ASD. 47,51 In line with these findings, EVC proteins are coexpressed in the OFT and the mesenchymal structures of the atrial septa and AV cushions during heart development in mice 51 ; areas that are known to be ciliated during cardiogenesis.…”

Regulation of polycystin-1 ciliary trafficking by motifs at its C-terminus and polycystin-2 but not cleavage at GPS site

“…Mounting evidence has indicated that the primary cilium houses a high density of signaling molecules and functions as a center to orchestrate a diverse number of signaling pathways important for development or tissue homeostasis (Dorn et al, 2012;Ezratty et al, 2011;Goetz and Anderson, 2010;Lancaster et al, 2011;Oh and Katsanis, 2012). The primary cilium represents the 'cell antenna', and is sensitive to changes in extracellular cues (Barr and Sternberg, 1999;Nauli et al, 2003;Praetorius and Spring, 2005;Singla and Reiter, 2006;Zhang et al, 2004).…”