title: EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia.
abstract: The Hedgehog (Hh) pathway depends on primary cilia in vertebrates, but the signaling machinery within cilia remains incompletely defined. We report the identification of a complex between two ciliary proteins, EFCAB7 and IQCE, which positively regulates the Hh pathway. The EFCAB7-IQCE module anchors the EVC-EVC2 complex in a signaling microdomain at the base of cilia. EVC and EVC2 genes are mutated in Ellis van Creveld and Weyers syndromes, characterized by impaired Hh signaling in skeletal, cardiac, and orofacial tissues. EFCAB7 binds to a C-terminal disordered region in EVC2 that is deleted in Weyers patients. EFCAB7 depletion mimics the Weyers cellular phenotype-the mislocalization of EVC-EVC2 within cilia and impaired activation of the transcription factor GLI2. Evolutionary analysis suggests that emergence of these complexes might have been important for adaptation of an ancient organelle, the cilium, for an animal-specific signaling network.
authors.affiliation: Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Pusapati
authors.affiliation: Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Casey E
authors.initials: CE
authors.lastname: Hughes
authors.affiliation: Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Karolin V
authors.initials: KV
authors.lastname: Dorn
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Priscilla
authors.initials: P
authors.lastname: Sugianto
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA. Electronic address: aravind@ncbi.nlm.nih.gov.
authors.forename: L
authors.initials: L
authors.lastname: Aravind
authors.affiliation: Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: rrohatgi@stanford.edu.
authors.forename: Rajat
authors.initials: R
authors.lastname: Rohatgi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002846:Chromatography, Affinity; D002923:Cilia / Q000502:physiology*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D010641:Phenotype; D010802:Phylogeny; D054730:Protein Interaction Domains and Motifs; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000072086:Smoothened Receptor; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000075746:Zinc Finger Protein Gli2
chemical_list: D002135:Calcium-Binding Proteins; C588373:EFCAB7 protein, mouse; C541939:EVC2 protein, mouse; C523527:Evc protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; C588374:IQCE protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000075746:Zinc Finger Protein Gli2