{"gene":"EVC","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2007,"finding":"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.","method":"Mouse knockout model (Evc-/-), antibody-based localization, in vitro Evc-/- cell studies, lacZ reporter, western blot (Gli3 processing), qRT-PCR","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, direct localization, pathway placement downstream of Smo; foundational paper replicated by subsequent studies","pmids":["17660199"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence, western blot of cytoplasmic/nuclear fractions, siRNA knockdown","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, direct localization, functional rescue; multiple orthogonal methods in one study","pmids":["21356043"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Mouse genetic models (Evc-/-, Evc2-/-, double knockout, Evc2Δ43 knock-in), co-immunoprecipitation, immunofluorescence, SAG (Smo agonist) stimulation assays, western blot","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple genetic models, epistasis in Sufu-/- background; multiple orthogonal methods","pmids":["23026747"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Co-immunoprecipitation, Kif3a-/- and Sufu-/- cell assays, constitutively active Smo constructs, phosphorylation analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — Co-IP with phosphorylation-dependent binding, genetic epistasis in cilium-deficient and Sufu-/- cells; multiple orthogonal approaches","pmids":["22986504"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation/pulldown, immunofluorescence, EFCAB7 siRNA knockdown, Gli2 activation assays, evolutionary analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — direct binding interaction, localization with functional consequence, KD phenotype; multiple orthogonal methods","pmids":["24582806"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Evc-/- mouse model, Ptch1-LacZ reporter, immunofluorescence, histomorphometry, marker expression analysis","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotypes, direct localization in osteoblasts, reporter assays","pmids":["21911092"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Transfection of murine Weyers EVC2 variants in NIH 3T3 cells, Hh reporter assays","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — functional cell-based assay with defined molecular mechanism; single lab, single method","pmids":["19810119"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Evc-/- mouse model, in situ hybridization, reporter assays, histological analysis of molar development","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with specific spatial phenotypic readout; single lab","pmids":["23315474"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Wdr35-/- and Dync2h1-/- mouse fibroblasts, immunofluorescence for EVC/EVC2/SMO ciliary localization, Hh signaling assays, rescue with disease cDNAs","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with clean localization readout, rescue experiments, comparison of two distinct mutant backgrounds","pmids":["25908617"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Proteomic interactome screen (endogenous EVC in control vs Evc-null cells), immunoprecipitation, ubiquitination and SUMOylation assays, immunofluorescence","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — interactome screen with functional PTM validation; single lab, multiple methods","pmids":["37576597"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Patient-derived fibroblasts, Evc-/- MEF complementation, cDNA sequencing, immunoblot, immunofluorescence, co-immunoprecipitation","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay with complex formation readout in patient cells; single lab","pmids":["32906221"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Evc mouse knockout, CRISPR-engineered human NP cells, proteomic profiling, Gli3 processing western blot, extracellular matrix assays, TGF-β treatment","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO and CRISPR KO with defined molecular readouts; single lab","pmids":["41550739"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Loss-of-function (shRNA/CRISPR) in AML cell lines and in vivo mouse models, MYC pathway reporter assays, chromatin interaction analysis, patient sample correlation","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with defined cellular phenotype, pathway placement via MYC; single lab but multiple methods","pmids":["41249566"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Evc-/- mouse model, immunofluorescence, in situ hybridization, histological analysis, Wnt overexpression","journal":"Journal of dental research","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with specific molecular and cellular readouts; single lab","pmids":["41913599"],"is_preprint":false}],"current_model":"EVC is a transmembrane protein that, together with EVC2, forms a complex anchored at the base (EvC zone) of primary cilia by the EFCAB7-IQCE scaffold; upon Hedgehog activation, Smoothened phosphorylation 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 in chondrocytes, osteoblasts, dental epithelia, and other tissues, with complex stability and ciliary targeting further regulated by monoubiquitination (destabilizing) and SUMOylation (stabilizing/localizing)."},"narrative":{"teleology":[{"year":2007,"claim":"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","pmids":["17660199"],"confidence":"High","gaps":["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"]},{"year":2009,"claim":"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","pmids":["19810119"],"confidence":"Medium","gaps":["Mechanism of dominant-negative action not identified at molecular level","Only tested in a single cell type"]},{"year":2011,"claim":"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)","pmids":["21356043","21911092"],"confidence":"High","gaps":["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"]},{"year":2012,"claim":"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)","pmids":["23026747","22986504"],"confidence":"High","gaps":["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"]},{"year":2013,"claim":"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","pmids":["23315474"],"confidence":"Medium","gaps":["Whether Wnt displacement is a direct or indirect consequence of EVC loss unclear","Mechanism of spatial Shh gradient interpretation by EVC unknown"]},{"year":2014,"claim":"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","pmids":["24582806"],"confidence":"High","gaps":["Full stoichiometry and structure of the EvC-zone complex not determined","How EvC-zone confinement facilitates signal transduction mechanistically unresolved"]},{"year":2015,"claim":"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","pmids":["25908617"],"confidence":"High","gaps":["Whether EVC/EVC2 are direct IFT-A cargo or require an adaptor unknown","Role of retrograde transport in EVC/EVC2 turnover not addressed"]},{"year":2020,"claim":"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","pmids":["32906221"],"confidence":"Medium","gaps":["Whether partial complex formation alters Hh signaling quantitatively or qualitatively not fully resolved","Only two hypomorphic alleles tested"]},{"year":2023,"claim":"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","pmids":["37576597"],"confidence":"Medium","gaps":["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"]},{"year":2025,"claim":"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)","pmids":["41550739","41249566"],"confidence":"Medium","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,2,3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2,4,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,4,5,7,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[5,7,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[12]}],"complexes":["EVC-EVC2 complex","EVC-EVC2-EFCAB7-IQCE (EvC zone complex)"],"partners":["EVC2","SMO","EFCAB7","IQCE","SUFU","GLI3","WDR35"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"P57679","full_name":"EvC complex member EVC","aliases":["DWF-1","Ellis-van Creveld syndrome protein"],"length_aa":992,"mass_kda":112.0,"function":"Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling. Involved in endochondral growth and skeletal development","subcellular_location":"Cell membrane; Cytoplasm, cytoskeleton, cilium basal body; Cell projection, cilium; Cell projection, cilium membrane","url":"https://www.uniprot.org/uniprotkb/P57679/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EVC","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EVC","total_profiled":1310},"omim":[{"mim_id":"619143","title":"CARDIOACROFACIAL DYSPLASIA 2; CAFD2","url":"https://www.omim.org/entry/619143"},{"mim_id":"619142","title":"CARDIOACROFACIAL DYSPLASIA 1; CAFD1","url":"https://www.omim.org/entry/619142"},{"mim_id":"618123","title":"POLYDACTYLY, POSTAXIAL, TYPE A8; PAPA8","url":"https://www.omim.org/entry/618123"},{"mim_id":"617927","title":"OROFACIODIGITAL SYNDROME XVIII; OFD18","url":"https://www.omim.org/entry/617927"},{"mim_id":"617925","title":"SHORT-RIB THORACIC DYSPLASIA 20 WITH POLYDACTYLY; SRTD20","url":"https://www.omim.org/entry/617925"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/EVC"},"hgnc":{"alias_symbol":["DWF-1","EVC1"],"prev_symbol":[]},"alphafold":{"accession":"P57679","domains":[{"cath_id":"-","chopping":"189-685_692-755","consensus_level":"medium","plddt":90.3965,"start":189,"end":755},{"cath_id":"-","chopping":"775-828_864-909","consensus_level":"high","plddt":86.2043,"start":775,"end":909}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P57679","model_url":"https://alphafold.ebi.ac.uk/files/AF-P57679-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P57679-F1-predicted_aligned_error_v6.png","plddt_mean":73.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EVC","jax_strain_url":"https://www.jax.org/strain/search?query=EVC"},"sequence":{"accession":"P57679","fasta_url":"https://rest.uniprot.org/uniprotkb/P57679.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P57679/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P57679"}},"corpus_meta":[{"pmid":"17660199","id":"PMC_17660199","title":"Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia.","date":"2007","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/17660199","citation_count":154,"is_preprint":false},{"pmid":"23026747","id":"PMC_23026747","title":"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.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23026747","citation_count":93,"is_preprint":false},{"pmid":"22986504","id":"PMC_22986504","title":"Smoothened transduces Hedgehog signal by forming a complex with Evc/Evc2.","date":"2012","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/22986504","citation_count":86,"is_preprint":false},{"pmid":"17024374","id":"PMC_17024374","title":"Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients.","date":"2006","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17024374","citation_count":80,"is_preprint":false},{"pmid":"24582806","id":"PMC_24582806","title":"EFCAB7 and IQCE regulate hedgehog signaling by tethering the EVC-EVC2 complex to the base of primary cilia.","date":"2014","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/24582806","citation_count":77,"is_preprint":false},{"pmid":"21356043","id":"PMC_21356043","title":"Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus.","date":"2011","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/21356043","citation_count":75,"is_preprint":false},{"pmid":"23220543","id":"PMC_23220543","title":"Novel and recurrent EVC and EVC2 mutations in Ellis-van Creveld syndrome and Weyers acrofacial dyostosis.","date":"2012","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23220543","citation_count":59,"is_preprint":false},{"pmid":"19810119","id":"PMC_19810119","title":"Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling.","date":"2009","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/19810119","citation_count":52,"is_preprint":false},{"pmid":"23315474","id":"PMC_23315474","title":"Evc regulates a symmetrical response to Shh signaling in molar development.","date":"2013","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/23315474","citation_count":49,"is_preprint":false},{"pmid":"25908617","id":"PMC_25908617","title":"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.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25908617","citation_count":48,"is_preprint":false},{"pmid":"21911092","id":"PMC_21911092","title":"Evc works in chondrocytes and osteoblasts to regulate multiple aspects of growth plate development in the appendicular skeleton and cranial base.","date":"2011","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/21911092","citation_count":36,"is_preprint":false},{"pmid":"18947413","id":"PMC_18947413","title":"Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene.","date":"2008","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18947413","citation_count":21,"is_preprint":false},{"pmid":"29321360","id":"PMC_29321360","title":"Ellis-van Creveld syndrome and profound deafness resulted by sequence variants in the EVC/EVC2 and TMC1 genes.","date":"2017","source":"Journal of 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16806023","citation_count":1,"is_preprint":false},{"pmid":"38865824","id":"PMC_38865824","title":"Shugan Tongluo Qiangjing recipe protects against varicocele of EVC rats through modulating sperm DNA damage, telomere expression and oxidative stress.","date":"2024","source":"Tissue & cell","url":"https://pubmed.ncbi.nlm.nih.gov/38865824","citation_count":1,"is_preprint":false},{"pmid":"15884406","id":"PMC_15884406","title":"[From gene to disease; EVC, EVC2, and Ellis-van Creveld syndrome].","date":"2005","source":"Nederlands tijdschrift voor geneeskunde","url":"https://pubmed.ncbi.nlm.nih.gov/15884406","citation_count":0,"is_preprint":false},{"pmid":"26251756","id":"PMC_26251756","title":"EVC gene polymorphisms and risks of isolated hypospadias - a preliminary study.","date":"2015","source":"Central European journal of 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knockout model (Evc-/-), antibody-based localization, in vitro Evc-/- cell studies, lacZ reporter, western blot (Gli3 processing), qRT-PCR\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, direct localization, pathway placement downstream of Smo; foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"17660199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, immunofluorescence, western blot of cytoplasmic/nuclear fractions, siRNA knockdown\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, direct localization, functional rescue; multiple orthogonal methods in one study\",\n      \"pmids\": [\"21356043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse genetic models (Evc-/-, Evc2-/-, double knockout, Evc2Δ43 knock-in), co-immunoprecipitation, immunofluorescence, SAG (Smo agonist) stimulation assays, western blot\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple genetic models, epistasis in Sufu-/- background; multiple orthogonal methods\",\n      \"pmids\": [\"23026747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, Kif3a-/- and Sufu-/- cell assays, constitutively active Smo constructs, phosphorylation analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with phosphorylation-dependent binding, genetic epistasis in cilium-deficient and Sufu-/- cells; multiple orthogonal approaches\",\n      \"pmids\": [\"22986504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation/pulldown, immunofluorescence, EFCAB7 siRNA knockdown, Gli2 activation assays, evolutionary analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding interaction, localization with functional consequence, KD phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"24582806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Evc-/- mouse model, Ptch1-LacZ reporter, immunofluorescence, histomorphometry, marker expression analysis\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotypes, direct localization in osteoblasts, reporter assays\",\n      \"pmids\": [\"21911092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Transfection of murine Weyers EVC2 variants in NIH 3T3 cells, Hh reporter assays\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cell-based assay with defined molecular mechanism; single lab, single method\",\n      \"pmids\": [\"19810119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Evc-/- mouse model, in situ hybridization, reporter assays, histological analysis of molar development\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific spatial phenotypic readout; single lab\",\n      \"pmids\": [\"23315474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Wdr35-/- and Dync2h1-/- mouse fibroblasts, immunofluorescence for EVC/EVC2/SMO ciliary localization, Hh signaling assays, rescue with disease cDNAs\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with clean localization readout, rescue experiments, comparison of two distinct mutant backgrounds\",\n      \"pmids\": [\"25908617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomic interactome screen (endogenous EVC in control vs Evc-null cells), immunoprecipitation, ubiquitination and SUMOylation assays, immunofluorescence\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interactome screen with functional PTM validation; single lab, multiple methods\",\n      \"pmids\": [\"37576597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Patient-derived fibroblasts, Evc-/- MEF complementation, cDNA sequencing, immunoblot, immunofluorescence, co-immunoprecipitation\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay with complex formation readout in patient cells; single lab\",\n      \"pmids\": [\"32906221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Evc mouse knockout, CRISPR-engineered human NP cells, proteomic profiling, Gli3 processing western blot, extracellular matrix assays, TGF-β treatment\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO and CRISPR KO with defined molecular readouts; single lab\",\n      \"pmids\": [\"41550739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Loss-of-function (shRNA/CRISPR) in AML cell lines and in vivo mouse models, MYC pathway reporter assays, chromatin interaction analysis, patient sample correlation\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with defined cellular phenotype, pathway placement via MYC; single lab but multiple methods\",\n      \"pmids\": [\"41249566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Evc-/- mouse model, immunofluorescence, in situ hybridization, histological analysis, Wnt overexpression\",\n      \"journal\": \"Journal of dental research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific molecular and cellular readouts; single lab\",\n      \"pmids\": [\"41913599\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EVC is a transmembrane protein that, together with EVC2, forms a complex anchored at the base (EvC zone) of primary cilia by the EFCAB7-IQCE scaffold; upon Hedgehog activation, Smoothened phosphorylation 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 in chondrocytes, osteoblasts, dental epithelia, and other tissues, with complex stability and ciliary targeting further regulated by monoubiquitination (destabilizing) and SUMOylation (stabilizing/localizing).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Evc-/- mouse knockout with antibody localization, lacZ reporter, Gli3 processing western blot, qRT-PCR in Evc-/- cells\",\n      \"pmids\": [\"17660199\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"evidence\": \"Transfection of murine Weyers EVC2 variants into NIH 3T3 cells with Hh reporter assays\",\n      \"pmids\": [\"19810119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of dominant-negative action not identified at molecular level\", \"Only tested in a single cell type\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-IP, immunofluorescence, siRNA knockdown (BMC Biology); Evc-/- mouse histomorphometry with osteoblast ciliary localization (Bone)\",\n      \"pmids\": [\"21356043\", \"21911092\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP with phospho-Smo constructs, Kif3a-/- and Sufu-/- genetic epistasis, Evc2Δ43 knock-in mouse, SAG stimulation (Human Molecular Genetics; Cell Research)\",\n      \"pmids\": [\"23026747\", \"22986504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Evc-/- mouse model with in situ hybridization and histological analysis of molar development\",\n      \"pmids\": [\"23315474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Wnt displacement is a direct or indirect consequence of EVC loss unclear\", \"Mechanism of spatial Shh gradient interpretation by EVC unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP/pulldown, EFCAB7 siRNA knockdown with immunofluorescence and Gli2 activation assays\",\n      \"pmids\": [\"24582806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full stoichiometry and structure of the EvC-zone complex not determined\", \"How EvC-zone confinement facilitates signal transduction mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Wdr35-/- versus Dync2h1-/- mouse fibroblasts with immunofluorescence and Hh signaling assays\",\n      \"pmids\": [\"25908617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether EVC/EVC2 are direct IFT-A cargo or require an adaptor unknown\", \"Role of retrograde transport in EVC/EVC2 turnover not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Hypomorphic EVC variants that retain partial EVC-EVC2 complex formation produce milder phenotypes, establishing a direct genotype-phenotype correlation based on complex integrity.\",\n      \"evidence\": \"Patient-derived fibroblasts and Evc-/- MEF complementation with co-IP and immunoblot\",\n      \"pmids\": [\"32906221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether partial complex formation alters Hh signaling quantitatively or qualitatively not fully resolved\", \"Only two hypomorphic alleles tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Endogenous EVC interactome screen, ubiquitination and SUMOylation assays, immunofluorescence\",\n      \"pmids\": [\"37576597\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"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)\",\n      \"pmids\": [\"41550739\", \"41249566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of EVC or EVC-EVC2 complex exists\", \"E3 ligase and SUMO ligase identities unknown\", \"Hh-independent MYC activation mechanism undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2, 4, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5, 7, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [5, 7, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\n      \"EVC-EVC2 complex\",\n      \"EVC-EVC2-EFCAB7-IQCE (EvC zone complex)\"\n    ],\n    \"partners\": [\n      \"EVC2\",\n      \"SMO\",\n      \"EFCAB7\",\n      \"IQCE\",\n      \"SUFU\",\n      \"GLI3\",\n      \"WDR35\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}