Affinage

EVC

EvC complex member EVC · UniProt P57679

Length
992 aa
Mass
112.0 kDa
Annotated
2026-04-28
39 papers in source corpus 14 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EVC is a ciliary transmembrane protein that functions as an essential positive transducer of the Hedgehog (Hh) signaling pathway in chondrocytes, osteoblasts, dental epithelia, and other cell types. EVC forms an obligate complex with EVC2, anchored at the base of primary cilia (the EvC zone) by the EFCAB7-IQCE scaffold; upon Hh stimulation, phosphorylation of the Smoothened (Smo) intracellular tail recruits the EVC-EVC2 complex, which acts downstream of Smo and upstream of Sufu to promote Gli3 trafficking to cilia tips, Sufu-Gli3 dissociation, and transcriptional activation of Hh target genes such as Ptch1 and Gli1 (PMID:17660199, PMID:23026747, PMID:22986504, PMID:24582806). Complex stability and EvC-zone localization are regulated by post-translational modifications — monoubiquitination destabilizes the complex while SUMOylation enhances ciliary accumulation through increased EFCAB7 binding — and ciliary entry requires IFT-A (WDR35)-dependent import (PMID:37576597, PMID:25908617). Loss-of-function mutations in EVC cause Ellis-van Creveld syndrome, a chondroectodermal dysplasia, with the severity of the phenotype correlating with the degree of residual EVC-EVC2 complex formation (PMID:32906221).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2007 High

    Establishing that EVC is a ciliary Hedgehog pathway component resolved where it acts: EVC localizes to the basal body of primary cilia in chondrocytes, and its loss reduces Ihh target gene expression at a step downstream of Smo, placing EVC within intracellular Hh signal transduction.

    Evidence Evc-/- mouse knockout with antibody localization, lacZ reporter, Gli3 processing western blot, qRT-PCR in Evc-/- cells

    PMID:17660199

    Open questions at the time
    • Identity of EVC's direct binding partners unknown
    • Whether EVC functions in Hh signaling tissues beyond growth plate chondrocytes not tested
    • Mechanism by which EVC promotes Gli activation undefined
  2. 2009 Medium

    Weyers-type EVC2 missense mutations (but not Ellis-van Creveld truncations) act as dominant-negatives on Hh signaling, revealing that the EVC2 C-terminus has a specific gain-of-function capacity when mutated.

    Evidence Transfection of murine Weyers EVC2 variants into NIH 3T3 cells with Hh reporter assays

    PMID:19810119

    Open questions at the time
    • Mechanism of dominant-negative action not identified at molecular level
    • Only tested in a single cell type
  3. 2011 High

    Identification of EVC-EVC2 as a physical complex whose ciliary localization is mutually co-dependent answered whether EVC acts alone or as part of a heterocomplex, and extended Hh pathway involvement to osteoblasts.

    Evidence Yeast two-hybrid, reciprocal co-IP, immunofluorescence, siRNA knockdown (BMC Biology); Evc-/- mouse histomorphometry with osteoblast ciliary localization (Bone)

    PMID:21356043 PMID:21911092

    Open questions at the time
    • Whether EVC2 nuclear pool has a signaling role unresolved
    • Post-translational regulation of the complex unknown
    • How EVC-EVC2 complex is targeted to cilia not identified
  4. 2012 High

    Two studies demonstrated that Smo phosphorylation-dependent recruitment of EVC-EVC2 is the activation mechanism, and that the complex promotes Gli3 trafficking to cilia tips and Sufu-Gli3 dissociation, defining the step-by-step epistatic position of EVC-EVC2 in Hh transduction.

    Evidence Co-IP with phospho-Smo constructs, Kif3a-/- and Sufu-/- genetic epistasis, Evc2Δ43 knock-in mouse, SAG stimulation (Human Molecular Genetics; Cell Research)

    PMID:22986504 PMID:23026747

    Open questions at the time
    • Whether EVC-EVC2 also functions downstream of Sufu (as suggested in one experiment) versus exclusively upstream remains debated
    • Structural basis of Smo-EVC2 interaction unknown
  5. 2013 Medium

    Extension to dental development revealed that EVC mediates Shh signaling in molar epithelium to establish the buccal-lingual axis, with displaced Wnt activity upon loss, broadening the range of tissues requiring EVC for Hh transduction.

    Evidence Evc-/- mouse model with in situ hybridization and histological analysis of molar development

    PMID:23315474

    Open questions at the time
    • Whether Wnt displacement is a direct or indirect consequence of EVC loss unclear
    • Mechanism of spatial Shh gradient interpretation by EVC unknown
  6. 2014 High

    Discovery of the EFCAB7-IQCE anchoring complex explained how EVC-EVC2 is confined to a basal ciliary microdomain (the EvC zone) and why Weyers C-terminal deletions cause mislocalization — EFCAB7 binds the EVC2 C-terminal region deleted in Weyers patients.

    Evidence Co-IP/pulldown, EFCAB7 siRNA knockdown with immunofluorescence and Gli2 activation assays

    PMID:24582806

    Open questions at the time
    • Full stoichiometry and structure of the EvC-zone complex not determined
    • How EvC-zone confinement facilitates signal transduction mechanistically unresolved
  7. 2015 High

    Demonstration that IFT-A component WDR35 is specifically required for EVC, EVC2, and Smo ciliary entry established ciliary import as a prerequisite for EVC-EVC2 function.

    Evidence Wdr35-/- versus Dync2h1-/- mouse fibroblasts with immunofluorescence and Hh signaling assays

    PMID:25908617

    Open questions at the time
    • Whether EVC/EVC2 are direct IFT-A cargo or require an adaptor unknown
    • Role of retrograde transport in EVC/EVC2 turnover not addressed
  8. 2020 Medium

    Hypomorphic EVC variants that retain partial EVC-EVC2 complex formation produce milder phenotypes, establishing a direct genotype-phenotype correlation based on complex integrity.

    Evidence Patient-derived fibroblasts and Evc-/- MEF complementation with co-IP and immunoblot

    PMID:32906221

    Open questions at the time
    • Whether partial complex formation alters Hh signaling quantitatively or qualitatively not fully resolved
    • Only two hypomorphic alleles tested
  9. 2023 Medium

    Post-translational regulation of EVC-EVC2 was uncovered: monoubiquitination destabilizes the complex while SUMO3 modification promotes EvC-zone accumulation by enhancing EFCAB7 binding, revealing a PTM-based regulatory layer.

    Evidence Endogenous EVC interactome screen, ubiquitination and SUMOylation assays, immunofluorescence

    PMID:37576597

    Open questions at the time
    • E3 ligase and SUMO ligase responsible for these modifications not identified
    • Physiological stimuli triggering these PTMs unknown
    • USP7 interacts with EVC but is not the relevant deubiquitinase — actual DUB unidentified
  10. 2025 Medium

    Two studies expanded EVC function beyond canonical skeletal Hh signaling: EVC facilitates Shh signaling in intervertebral disc nucleus pulposus cells (with TGF-β suppressing EVC expression), and EVC/EVC2 promote AML leukemogenesis through MYC pathway activation independent of Hedgehog signaling.

    Evidence Evc knockout and CRISPR KO in NP cells with Gli3 processing and TGF-β treatment (iScience); shRNA/CRISPR loss-of-function in AML lines with in vivo mouse models and MYC reporter assays (Leukemia)

    PMID:41249566 PMID:41550739

    Open questions at the time
    • Mechanism of Hh-independent MYC activation by EVC/EVC2 in AML not defined at molecular level
    • Whether TGF-β-EVC crosstalk is direct transcriptional regulation or indirect not resolved
    • Relevance of AML findings to other cancer types untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the structural basis of the EVC-EVC2-Smo and EVC2-EFCAB7 interactions, the identity of the E3 ubiquitin ligase and SUMO ligase that regulate EVC-EVC2 stability and localization, and the molecular mechanism by which EVC/EVC2 activate MYC independently of Hedgehog signaling in leukemia.
  • No structural model of EVC or EVC-EVC2 complex exists
  • E3 ligase and SUMO ligase identities unknown
  • Hh-independent MYC activation mechanism undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4
Localization
GO:0005929 cilium 5 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 1
Partners
EFCAB7EVC2GLI3IQCESMOSUFUWDR35
Complex memberships
EVC-EVC2 complexEVC-EVC2-EFCAB7-IQCE (EvC zone complex)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 EVC protein localizes to the base of primary cilia (basal body) in chondrocytes, and Evc knockout mice show decreased expression of Ihh downstream targets Ptch1 and Gli1 with defect lying downstream of Smo, establishing EVC as an intracellular component of the Hedgehog signal transduction pathway required for transcriptional activation of Ihh target genes. Mouse knockout model (Evc-/-), antibody-based localization, in vitro Evc-/- cell studies, lacZ reporter, western blot (Gli3 processing), qRT-PCR Development (Cambridge, England) High 17660199
2011 EVC and EVC2 interact directly (yeast two-hybrid and co-immunoprecipitation), co-localize at the basal body and primary cilia membrane as a complex, and their ciliary localization is mutually co-dependent; EVC2 but not EVC is also found in the nucleus. EVC2 positively regulates Hh pathway activation in response to Smo agonist purmorphamine. Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence, western blot of cytoplasmic/nuclear fractions, siRNA knockdown BMC biology High 21356043
2012 EVC and EVC2 form a complex that interacts with Smoothened (Smo) upon Hh stimulation; Smo co-precipitates with Evc/Evc2. Evc2 deficiency impairs Gli3 recruitment to cilia tips and Sufu/Gli3 dissociation without affecting Smo translocation to cilia. A dominantly acting Evc2 mutation (Evc2Δ43/Weyers) causes mislocalization of the complex within the cilium and reproduces these Gli3 defects. Evc silencing in Sufu-/- cells attenuates Hh output, placing Evc/Evc2 function both upstream and downstream of Sufu. Mouse genetic models (Evc-/-, Evc2-/-, double knockout, Evc2Δ43 knock-in), co-immunoprecipitation, immunofluorescence, SAG (Smo agonist) stimulation assays, western blot Human molecular genetics High 23026747
2012 Hh stimulation induces phosphorylation of the Smo C-terminal intracellular tail, which recruits the Evc/Evc2 complex to Smo in primary cilia; this interaction is abolished in Kif3a-/- cilium-deficient cells. Evc/Evc2 act upstream of Sufu to promote Gli activation; they are dispensable for constitutive Gli activity in Sufu-/- cells. Co-immunoprecipitation, Kif3a-/- and Sufu-/- cell assays, constitutively active Smo constructs, phosphorylation analysis Cell research High 22986504
2014 EFCAB7 and IQCE form a complex that anchors the EVC-EVC2 complex in a signaling microdomain at the base of primary cilia (the EvC zone). EFCAB7 binds directly to a C-terminal disordered region in EVC2 that is deleted in Weyers patients. EFCAB7 depletion causes mislocalization of EVC-EVC2 within cilia and impairs activation of GLI2, mimicking the Weyers cellular phenotype. Co-immunoprecipitation/pulldown, immunofluorescence, EFCAB7 siRNA knockdown, Gli2 activation assays, evolutionary analysis Developmental cell High 24582806
2011 Evc mediates Hedgehog signaling in osteoblasts (localizes to osteoblast primary cilia) and promotes chondrocyte proliferation, chondrocyte hypertrophy, and perichondrial osteoblast differentiation; Evc is required for both Pthrp-dependent and Pthrp-independent Ihh functions in endochondral bone formation. Evc-/- mouse model, Ptch1-LacZ reporter, immunofluorescence, histomorphometry, marker expression analysis Bone High 21911092
2009 Ectopic expression of Weyers acrodental dysostosis EVC2 exon 22 missense mutations (but not truncating Ellis-van Creveld mutations) impairs Hedgehog signal transduction in NIH 3T3 cells, demonstrating a dominant-negative/gain-of-function mechanism specific to the C-terminal residues encoded by EVC2 exon 22. Transfection of murine Weyers EVC2 variants in NIH 3T3 cells, Hh reporter assays Human mutation Medium 19810119
2013 Evc is required for the Shh signaling response in developing molar tooth epithelium, with loss of Evc causing progressive loss of Shh target gene expression in a buccal-to-lingual spatial pattern and displaced Wnt pathway activity, establishing Evc as essential for establishing the buccal-lingual axis of the first molar via Shh signaling. Evc-/- mouse model, in situ hybridization, reporter assays, histological analysis of molar development Journal of dental research Medium 23315474
2015 IFT-A protein WDR35/IFT121 is specifically required for entry of EVC, EVC2, and Smoothened into primary cilia; in Wdr35-/- cells all three proteins fail to localize to cilia, while they localize normally in retrograde motor mutant Dync2h1-/- cells, indicating that IFT-A-mediated ciliary import is required upstream of EVC-EVC2 function. Wdr35-/- and Dync2h1-/- mouse fibroblasts, immunofluorescence for EVC/EVC2/SMO ciliary localization, Hh signaling assays, rescue with disease cDNAs Human molecular genetics High 25908617
2023 Monoubiquitination of EVC-EVC2 cytosolic tails reduces protein levels, while modification with SUMO3 enhances complex accumulation at the EvC zone (base of cilia) via increased binding to the EFCAB7-IQCE complex. EVC2 contains two separate EFCAB7-binding motifs within its Weyers-deleted peptide, with the second motif newly mapped in this study. The interactome includes USP7 (deubiquitinating enzyme), but EVC-EVC2 ubiquitination is independent of USP7 and USP48. Proteomic interactome screen (endogenous EVC in control vs Evc-null cells), immunoprecipitation, ubiquitination and SUMOylation assays, immunofluorescence Frontiers in cell and developmental biology Medium 37576597
2020 Hypomorphic EVC missense variants (p.Arg663Pro, c.1316-7A>G splice change) produce proteins that retain partial ability to complex with EVC2, as shown in patient-derived fibroblasts and Evc-/- MEFs, correlating with a milder clinical phenotype (common atrium/AVCD with polydactyly), demonstrating genotype-phenotype correlation based on degree of EVC-EVC2 complex preservation. Patient-derived fibroblasts, Evc-/- MEF complementation, cDNA sequencing, immunoblot, immunofluorescence, co-immunoprecipitation Human mutation Medium 32906221
2025 EVC facilitates Shh signaling in nucleus pulposus cells of the intervertebral disc; loss of EVC reduces Gli3 processing and impairs Shh pathway activity, while TGF-β signaling suppresses EVC expression, indicating crosstalk between Shh and TGF-β pathways mediated by EVC. Evc mouse knockout, CRISPR-engineered human NP cells, proteomic profiling, Gli3 processing western blot, extracellular matrix assays, TGF-β treatment iScience Medium 41550739
2025 EVC/EVC2 overexpression in AML cells promotes leukemogenic properties through MYC pathway activation, independent of their canonical role in Hedgehog signaling; loss of EVC/EVC2 impairs leukemia cell proliferation, promotes differentiation, and blocks AML progression in vivo. Loss-of-function (shRNA/CRISPR) in AML cell lines and in vivo mouse models, MYC pathway reporter assays, chromatin interaction analysis, patient sample correlation Leukemia Medium 41249566
2026 In Evc knockout mice, loss of Evc in oral tissues causes both upregulation and downregulation of Gli1 in a time- and tissue-specific manner, suggesting dynamic dysregulation of GLI activator/repressor balance; proliferation defects and downregulation of Gli1 and Sostdc1 underlie shortened vestibular lamina, with ectopic tooth germ formation mimicked by Wnt overexpression. Evc-/- mouse model, immunofluorescence, in situ hybridization, histological analysis, Wnt overexpression Journal of dental research Medium 41913599

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia. Development (Cambridge, England) 154 17660199
2012 The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia. Human molecular genetics 93 23026747
2012 Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2. Cell research 86 22986504
2006 Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients. Human genetics 80 17024374
2014 EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia. Developmental cell 77 24582806
2011 Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus. BMC biology 75 21356043
2012 Novel and recurrent EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers acrofacial dyostosis. European journal of medical genetics 59 23220543
2009 Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling. Human mutation 52 19810119
2013 Evc regulates a symmetrical response to Shh signaling in molar development. Journal of dental research 49 23315474
2015 Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium. Human molecular genetics 48 25908617
2011 Evc works in chondrocytes and osteoblasts to regulate multiple aspects of growth plate development in the appendicular skeleton and cranial base. Bone 36 21911092
2008 Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene. BMC medical genetics 21 18947413
2017 Ellis-van Creveld syndrome and profound deafness resulted by sequence variants in the EVC/EVC2 and TMC1 genes. Journal of genetics 19 29321360
2016 Truncation and microdeletion of EVC/EVC2 with missense mutation of EFCAB7 in Ellis-van Creveld syndrome. Congenital anomalies 12 26748586
2020 Common atrium/atrioventricular canal defect and postaxial polydactyly: A mild clinical subtype of Ellis-van Creveld syndrome caused by hypomorphic mutations in the EVC gene. Human mutation 11 32906221
2014 Complete coding regions of the prototypes enterovirus B93 and C95: phylogenetic analyses of the P1 and P3 regions of EV-B and EV-C strains. Journal of medical virology 9 25163640
2023 Establishing an objective clinical spectrum, genotype-phenotype correlations, and CRMP1 as a modifier in the Ellis-van Creveld syndrome: The first systematic review of EVC- and EVC2-associated conditions. Genetics in medicine open 8 39669252
2022 Blocking chondrocyte hypertrophy in conditional Evc knockout mice does not modify cartilage damage in osteoarthritis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 35334131
2016 Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome. Clinical dysmorphology 8 26580685
2009 A novel missense mutation in the EVC gene underlies Ellis-van Creveld syndrome in a Pakistani family. Pediatrics international : official journal of the Japan Pediatric Society 8 19744229
2023 EVC-EVC2 complex stability and ciliary targeting are regulated by modification with ubiquitin and SUMO. Frontiers in cell and developmental biology 7 37576597
2017 Phenotypic Variation in Patients with Homozygous c.1678G>T Mutation in EVC Gene: Report of Two Mexican Families with Ellis-van Creveld Syndrome. The American journal of case reports 7 29229899
2019 Identification of a novel EVC variant in a Han-Chinese family with Ellis-van Creveld syndrome. Molecular genetics & genomic medicine 6 31338997
2001 Automatic analysis of image of surface structure of cell wall-deficient EVC. Bio-medical materials and engineering 6 11564900
2023 A homozygous EVC mutation in a prenatal fetus with Ellis-van Creveld syndrome. Molecular genetics & genomic medicine 5 37157924
2015 Novel mutations in EVC cause aberrant splicing in Ellis-van Creveld syndrome. Molecular genetics and genomics : MGG 3 26621368
2004 Expression of the Ellis-van Creveld (Evc) gene in the rat tibial growth plate. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology 2 15278943
2024 Shugan Tongluo Qiangjing recipe protects against varicocele of EVC rats through modulating sperm DNA damage, telomere expression and oxidative stress. Tissue & cell 1 38865824
2022 Novel large deletion involving EVC and EVC2 in Ellis-van Creveld syndrome. Human genome variation 1 35581188
2006 [Inhibition of rhodiola on the growth of EVC-304 cell line]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 1 16806023
2004 Haplotype and linkage disequilibrium analysis of the CRMP1 and EVC genes. International journal of molecular medicine 1 15492864
2026 Aberrant Proliferation and Cell Fate Underlie Oral Defects in a Mouse Model of EvC Syndrome. Journal of dental research 0 41913599
2025 Oncogenic activation of EVC/EVC2 defines a therapeutically targetable subset of acute myeloid leukemia. Leukemia 0 41249566
2025 Case Report of a Novel EVC Gene Mutation in Ellis-van Creveld Syndrome: Implications for Pediatric Dental Management. Case reports in dentistry 0 41438176
2025 EVC protein regulates Sonic hedgehog signaling during human intervertebral disc development and degeneration. iScience 0 41550739
2025 Mandibular morphogenesis: Genetic insights into malocclusion from EVC perspective. Journal of oral biosciences 0 41714013
2024 Ellis-Van Creveld Syndrome with Severe Mitral Valve Insufficiency Caused by a Homozygous Intragenic Deletion of the EVC Gene. Molecular syndromology 0 40475170
2015 EVC gene polymorphisms and risks of isolated hypospadias - a preliminary study. Central European journal of urology 0 26251756
2005 [From gene to disease; EVC, EVC2, and Ellis-van Creveld syndrome]. Nederlands tijdschrift voor geneeskunde 0 15884406