EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia

Ganesh V Pusapati; Casey E Hughes; Karolin V Dorn; Dapeng Zhang; Priscilla Sugianto; L Aravind; Rajat Rohatgi

doi:10.1016/j.devcel.2014.01.021

EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia

Dev Cell. 2014 Mar 10;28(5):483-96. doi: 10.1016/j.devcel.2014.01.021. Epub 2014 Feb 27.

Authors

Ganesh V Pusapati¹, Casey E Hughes¹, Karolin V Dorn¹, Dapeng Zhang², Priscilla Sugianto¹, L Aravind³, Rajat Rohatgi⁴

Affiliations

¹ Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
² National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
³ National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA. Electronic address: aravind@ncbi.nlm.nih.gov.
⁴ Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: rrohatgi@stanford.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Blotting, Western
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism*
Chromatography, Affinity
Cilia / physiology*
Gene Expression Regulation*
HEK293 Cells
Hedgehog Proteins / genetics
Hedgehog Proteins / metabolism*
Humans
Immunoprecipitation
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Molecular Sequence Data
Mutation / genetics
NIH 3T3 Cells
Phenotype
Phylogeny
Protein Interaction Domains and Motifs
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Sequence Homology, Amino Acid
Signal Transduction
Smoothened Receptor
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Zinc Finger Protein Gli2

Substances

Calcium-Binding Proteins
EFCAB7 protein, mouse
EVC2 protein, mouse
Evc protein, mouse
Gli2 protein, mouse
Hedgehog Proteins
IQCE protein, mouse
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
Kruppel-Like Transcription Factors
Membrane Proteins
RNA, Messenger
Receptors, G-Protein-Coupled
Smo protein, mouse
Smoothened Receptor
Zinc Finger Protein Gli2

Abstract

Publication types

MeSH terms

Substances

Grants and funding