{"gene":"WLS","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2006,"finding":"Evi/WLS is a conserved multipass transmembrane protein specifically required for Wg/Wnt secretion in Wnt-producing cells. Epistasis experiments and clonal analysis place Evi in the Wg-producing cell, and evi mutants retain Wg intracellularly, demonstrating its essential role in Wnt release.","method":"RNAi screen in Drosophila, clonal analysis, epistasis experiments, immunostaining for Wg retention","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis, clonal analysis, and multiple RNAi experiments across species (Drosophila and human cells) consistently demonstrate WLS is required in Wnt-producing cells for Wnt secretion","pmids":["16678096"],"is_preprint":false},{"year":2009,"finding":"At the Drosophila NMJ, Evi/WLS is released in exosome-like vesicles to mediate trans-synaptic Wnt (Wingless) transmission. Additionally, Evi acts cell-autonomously in the postsynaptic cell to target dGRIP (a Wg-receptor-interacting protein) to postsynaptic sites, enabling Wnt signal transduction in the receiving cell.","method":"Live imaging, genetic loss-of-function, immunostaining at NMJ, vesicle fractionation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetics, imaging, biochemistry) in a single study demonstrating both pre- and post-synaptic roles of Evi","pmids":["19837038"],"is_preprint":false},{"year":2008,"finding":"Retromer-dependent endosome-to-Golgi recycling of Wntless/Evi is required for efficient Wnt secretion. In the absence of Vps35 (retromer component), Wntless is diverted to a degradative compartment. Biochemical evidence confirms that Wntless engages the retromer complex, and overexpression of Wntless overcomes the Vps35 secretion block.","method":"Drosophila genetics (Vps35 mutant analysis), biochemical co-precipitation, electron microscopy, epistasis (Wls overexpression suppresses Vps35 mutant)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently in two papers (PMID 18193037 and 18160347) using complementary model systems (Drosophila and C. elegans) with biochemical and genetic evidence","pmids":["18193037","18160347"],"is_preprint":false},{"year":2007,"finding":"In C. elegans, retromer-dependent recycling retrieves MIG-14/WLS from the plasma membrane back to the Golgi. Without retromer function, MIG-14/WLS is degraded in lysosomes, becoming limiting for Wnt signaling. AP-2 (DPY-23) mediates endocytosis of MIG-14 from the plasma membrane, and in dpy-23 mutants MIG-14 accumulates at the plasma membrane.","method":"C. elegans genetics, RNAi, subcellular localization by immunofluorescence, lysosomal degradation assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent papers (PMID 18160347 and 18160346) using complementary genetic and cell biological approaches in C. elegans","pmids":["18160347","18160346"],"is_preprint":false},{"year":2010,"finding":"WLS binds WNT3A in an ER-resident complex, and this binding requires PORCN-dependent lipid modification (palmitoylation) of WNT3A at Ser209. Inhibition of vacuolar acidification blocks WNT3A release from the WLS complex and causes accumulation of the WNT3A-WLS complex at the plasma membrane. Structural modeling suggests WLS has a lipocalin-like lipid-binding β-barrel that interacts with the Wnt palmitoyl moiety.","method":"Co-immunoprecipitation of WLS-WNT3A complex, small molecule inhibitor screen, site-directed mutagenesis of WNT3A Ser209, subcellular fractionation, Xenopus embryo functional assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct biochemical interaction, mutagenesis of palmitoylation site, multiple pharmacological tools, and in vivo functional validation in a single study","pmids":["20826466"],"is_preprint":false},{"year":2011,"finding":"Porcupine-mediated lipidation of a conserved serine residue (equivalent to Wg S239) is required for Wnt's physical and functional interaction with Wls in Drosophila. All Drosophila Wnts (except WntD, which lacks this serine) require both Porcupine and Wls for secretion, demonstrating that lipidation at this site is the structural determinant for Wls recognition.","method":"Systematic RNAi-based secretion assays of all Drosophila Wnt family members, site-directed mutagenesis of the conserved serine, co-immunoprecipitation of Wnt-Wls interaction","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — comprehensive mutagenesis combined with physical interaction assays and systematic genetic analysis across all Drosophila Wnts","pmids":["22108505"],"is_preprint":false},{"year":2012,"finding":"Evi/WLS vesicle release at Drosophila synaptic boutons requires Rab11, Syntaxin 1A (Syx1A), and the Rab11 effector Myosin5. Multivesicular bodies (MVBs) containing Evi are present at synaptic boutons and serve as organelles for exosome production. Secreted Evi vesicles have biochemical characteristics conserved with exosomes.","method":"dsRNA screen in cultured cells, motoneuron-specific expression of dominant-negative Rab11 and Syx1A, ultrastructural analysis (electron microscopy), mass spectrometry characterization of exosome fraction","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods including genetics, ultrastructure, and mass spectrometry in both cell culture and in vivo","pmids":["22437826"],"is_preprint":false},{"year":2014,"finding":"Endogenous WLS undergoes a full ER→plasma membrane→Golgi→ER retrograde transport cycle during Wnt secretion. A C-terminal ER-targeting sequence on WLS is critical for ER retrograde recycling and Wnt secretory function. Golgi-to-ER recycling requires ARF (COPI regulator) and ERGIC2, an ER-Golgi intermediate compartment protein also required for efficient Wnt secretion.","method":"Subcellular fractionation, live imaging, mutagenesis of ER-targeting sequence, siRNA knockdown of ARF and ERGIC2, functional Wnt secretion assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (mutagenesis, localization, functional assays, knockdown of specific trafficking factors) in a single study","pmids":["24768165"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure of palmitoleated human WNT8A in complex with WLS at 3.2 Å resolution reveals: (1) the WLS membrane domain has close structural homology to GPCRs; (2) a Wnt hairpin inserts into a conserved hydrophobic cavity in the GPCR-like domain; (3) the palmitoleate of WNT8A protrudes between two WLS helices into the lipid bilayer; (4) a conformational switch of conserved residues on a separate Wnt hairpin may contribute to Wnt transfer to receiving cells.","method":"Cryo-EM structure determination at 3.2 Å, biochemical mutagenesis experiments to validate observed interactions","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure with accompanying biochemical validation provides definitive molecular mechanism of WLS-Wnt interaction","pmids":["33357447"],"is_preprint":false},{"year":2018,"finding":"WLS abundance is regulated by ER-associated degradation (ERAD) via the ubiquitin-proteasome system. In the absence of Wnt ligands, WLS is ubiquitinated and degraded via ERAD in a VCP-dependent manner. The E2-conjugating enzyme UBE2J2 and E3-ligase CGRRF1 mediate WLS ubiquitination. A triaging complex of Porcupine (Porcn) and VCP determines whether WLS enters the secretory pathway or ERAD, thereby adjusting WLS levels to meet Wnt export demand.","method":"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown of ERAD components, functional Wnt secretion assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal biochemical and genetic methods identify specific ERAD machinery and a triaging complex","pmids":["29378775"],"is_preprint":false},{"year":2010,"finding":"WLS/GPR177 physically interacts with the mu-opioid receptor (MOR). This interaction, validated by pulldown, co-immunoprecipitation, and colocalization in mammalian cells and in rodent striatal neurons, is enhanced by morphine treatment, which causes GPR177 to redistribute from cytosol to cell surface. MOR/GPR177 complex formation at the cell periphery inhibits Wnt protein secretion.","method":"Split-ubiquitin yeast two-hybrid screen, co-immunoprecipitation, pulldown assay, colocalization in brain tissue, morphine treatment functional assays","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal co-IP and pulldown in multiple systems, but functional inhibition of Wnt secretion shown only correlatively with MOR/GPR177 complex formation","pmids":["20214800"],"is_preprint":false},{"year":2010,"finding":"Gpr177 (mouse WLS ortholog) is a glycoprotein that primarily accumulates in the Golgi apparatus in Wnt signal-producing cells. Glycosylation of Gpr177 is necessary for proper transportation in the secretory pathway.","method":"Subcellular fractionation, immunofluorescence localization, glycosylation assays (tunicamycin treatment, Western blot mobility shift)","journal":"Developmental dynamics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments with functional link to glycosylation requirement for secretory pathway transport, single lab","pmids":["20549736"],"is_preprint":false},{"year":2020,"finding":"TMEM132A physically interacts with WLS, stabilizes Wnt ligand, enhances the WLS-Wnt ligand interaction, and activates the Wnt signaling pathway.","method":"Co-immunoprecipitation, Wnt ligand stability assays, Wnt signaling reporter assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and functional assays in single lab study establish physical and functional interaction","pmids":["33324648"],"is_preprint":false},{"year":2022,"finding":"GPR177/WLS in A-fiber dorsal root ganglion neurons mediates the secretion of WNT5a into cerebrospinal fluid, which is necessary for maintenance of diabetic neuropathic pain. WNT5a directly activates TRPV1 ion channels by binding residues at the extracellular S5-S6 loop. A peptide disrupting the WNT5a/TRPV1 interaction suppressed neuropathic pain.","method":"Conditional knockout of GPR177 in A-fiber neurons, CSF Wnt5a measurement, electrophysiological patch-clamp recordings of WNT5a-induced TRPV1 currents, computer simulation of WNT5a-TRPV1 binding, peptide inhibitor in rodent behavioral assays","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined mechanistic pathway placement plus electrophysiology and computational docking, single lab","pmids":["35385340"],"is_preprint":false},{"year":2018,"finding":"MIG-14/WLS has a cell-autonomous, Wnt-independent function in dendrite self-avoidance in C. elegans PVD neurons. Functions of dendrite self-avoidance and Wnt secretion map to distinct MIG-14 domains (genetically separable), and MIG-14 engages WASP-dependent actin assembly to regulate dendrite self-avoidance.","method":"C. elegans genetics, domain mapping with deletion constructs, Wnt mutant analysis showing lack of self-avoidance defects, WASP interaction assays","journal":"Neuron","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping separating two distinct functions plus genetic epistasis with WASP pathway; single lab but multiple orthogonal genetic approaches","pmids":["29673481"],"is_preprint":false}],"current_model":"WLS (Wntless/Evi/GPR177) is a conserved multipass transmembrane protein that acts as a dedicated cargo receptor/transporter for Wnt ligands: it binds palmitoleated Wnt proteins in the ER (requiring PORCN-dependent Ser209 lipidation for recognition, as revealed by the 3.2 Å cryo-EM structure showing a GPCR-like membrane domain that accommodates the Wnt palmitoleate), escorts them through the Golgi to the plasma membrane for secretion, and then undergoes retromer-dependent endosome-to-Golgi and COPI/ERGIC2-dependent Golgi-to-ER recycling to sustain Wnt secretion; WLS abundance is further regulated by ERAD via UBE2J2/CGRRF1-mediated ubiquitination and VCP-dependent degradation when Wnt cargo is absent, and at synapses WLS is itself released in MVB-derived exosomes via Rab11/Syntaxin1A/Myosin5-dependent mechanisms to mediate trans-synaptic Wnt transmission."},"narrative":{"mechanistic_narrative":"WLS (Wntless/Evi/GPR177) is a conserved multipass transmembrane protein that functions as a dedicated cargo receptor for the secretion of lipid-modified Wnt ligands from Wnt-producing cells, a role first established by genetic epistasis and clonal analysis in Drosophila where evi mutants retain Wg intracellularly [PMID:16678096]. WLS binds Wnt in an ER-resident complex, and this recognition depends strictly on PORCN-dependent palmitoleoylation of a conserved Wnt serine (Ser209/S239), since loss of lipidation abolishes both physical and functional engagement with WLS across the Wnt family [PMID:20826466, PMID:22108505]. The molecular basis of this interaction was resolved by a 3.2 Å cryo-EM structure of WLS bound to palmitoleated WNT8A, which showed a GPCR-like membrane domain accommodating a Wnt hairpin in a hydrophobic cavity with the palmitoleate protruding between two WLS helices into the bilayer [PMID:33357447]. After ER loading, WLS escorts Wnt through the secretory pathway and undergoes an obligatory recycling itinerary to sustain secretion: retromer (Vps35)-dependent retrieval of WLS from endosomes following AP-2-mediated endocytosis prevents its lysosomal degradation [PMID:18193037, PMID:18160347, PMID:18160346], and a C-terminal ER-targeting signal plus ARF/COPI and ERGIC2 drive Golgi-to-ER retrograde transport [PMID:24768165]. When Wnt cargo is absent, WLS levels are tuned down by ERAD through UBE2J2/CGRRF1-mediated ubiquitination and VCP-dependent degradation, with a PORCN–VCP triaging complex deciding between secretion and degradation [PMID:29378775]. Beyond canonical secretion, at synapses WLS is itself released in MVB-derived exosome-like vesicles via Rab11/Syntaxin1A/Myosin5 to mediate trans-synaptic Wnt transmission [PMID:19837038, PMID:22437826].","teleology":[{"year":2006,"claim":"Established that Wnt secretion requires a dedicated factor acting within the producing cell, defining WLS as the founding component of the Wnt export machinery.","evidence":"RNAi screen, clonal analysis and epistasis in Drosophila showing Wg is retained intracellularly in evi mutants","pmids":["16678096"],"confidence":"High","gaps":["Did not define the molecular nature of the WLS-Wnt interaction","Subcellular trafficking route of WLS not yet mapped"]},{"year":2008,"claim":"Answered how WLS is sustained for repeated rounds of secretion by showing retromer retrieves it from endosomes rather than allowing its degradation.","evidence":"Drosophila and C. elegans genetics (Vps35 mutants), co-precipitation, EM, and Wls-overexpression suppression of the Vps35 block","pmids":["18193037","18160347"],"confidence":"High","gaps":["Did not resolve the endocytic step delivering WLS to endosomes","Retromer sorting signal on WLS not defined"]},{"year":2007,"claim":"Showed plasma-membrane WLS is endocytosed and retrieved to the Golgi, explaining why loss of recycling makes WLS limiting for Wnt signaling.","evidence":"C. elegans genetics and immunofluorescence showing AP-2 (DPY-23)-dependent endocytosis and lysosomal degradation of MIG-14/WLS without retromer","pmids":["18160347","18160346"],"confidence":"High","gaps":["Endocytic adaptor recognition motif on WLS not mapped","Did not address Golgi-to-ER segment of the itinerary"]},{"year":2010,"claim":"Defined the biochemical basis of cargo recognition: WLS binds Wnt in the ER and this requires PORCN-dependent lipid modification of Wnt.","evidence":"Co-IP of WLS-WNT3A, Ser209 mutagenesis, vacuolar acidification inhibitors, and Xenopus functional assays","pmids":["20826466"],"confidence":"High","gaps":["Lipocalin-like binding model was inferred from modeling, not structure","Mechanism of pH-dependent Wnt release not molecularly defined"]},{"year":2011,"claim":"Generalized lipidation-dependent recognition across the Wnt family, establishing the conserved serine lipid mark as the structural determinant for WLS binding.","evidence":"Systematic RNAi secretion assays of all Drosophila Wnts, serine mutagenesis, and Wnt-Wls co-IP","pmids":["22108505"],"confidence":"High","gaps":["WntD exception's WLS-independence not mechanistically dissected","Structural geometry of recognition not yet visualized"]},{"year":2012,"claim":"Identified the trafficking machinery for synaptic WLS exosome release, distinguishing it from the canonical secretory route.","evidence":"dsRNA screen, dominant-negative Rab11/Syx1A in motoneurons, EM of MVBs, and mass spectrometry of exosome fractions in Drosophila","pmids":["22437826"],"confidence":"High","gaps":["Conservation of exosomal WLS release in mammals not established","Cargo selectivity for MVB sorting unclear"]},{"year":2014,"claim":"Completed the trafficking cycle by demonstrating Golgi-to-ER retrograde recycling of WLS and identifying its molecular requirements.","evidence":"Subcellular fractionation, live imaging, ER-targeting sequence mutagenesis, and ARF/ERGIC2 knockdown with Wnt secretion assays","pmids":["24768165"],"confidence":"High","gaps":["How the ER-targeting signal is recognized by COPI machinery not defined","Coordination between retromer and COPI arms not resolved"]},{"year":2018,"claim":"Revealed cargo-responsive control of WLS abundance through ERAD, coupling WLS levels to Wnt export demand.","evidence":"Co-IP, ubiquitination assays, and siRNA of ERAD components identifying UBE2J2/CGRRF1 and a PORCN-VCP triaging complex","pmids":["29378775"],"confidence":"High","gaps":["Structural basis of the PORCN-VCP triage decision unknown","How Wnt occupancy is sensed to spare WLS from ERAD not defined"]},{"year":2020,"claim":"Provided the definitive molecular mechanism of cargo loading by visualizing how WLS accommodates a palmitoleated Wnt in a GPCR-like fold.","evidence":"3.2 Å cryo-EM structure of WLS-WNT8A complex with biochemical mutagenesis validation","pmids":["33357447"],"confidence":"High","gaps":["Conformational switch hypothesized for Wnt transfer not directly tested in vivo","Structures of recycling/empty WLS states not determined"]},{"year":2020,"claim":"Identified accessory factors and additional binding partners modulating WLS-dependent Wnt secretion in mammalian cells.","evidence":"Co-IP, glycosylation assays, Wnt stability and reporter assays implicating TMEM132A, MOR, and N-glycosylation","pmids":["33324648","20214800","20549736"],"confidence":"Medium","gaps":["MOR/GPR177 inhibition of Wnt secretion shown only correlatively","Single-lab findings without independent replication","Structural basis of TMEM132A and MOR interactions unknown"]},{"year":2022,"claim":"Placed WLS in a physiological signaling context by linking neuronal WLS-mediated WNT5a secretion to TRPV1 activation and neuropathic pain.","evidence":"Conditional GPR177 knockout in A-fiber neurons, CSF Wnt5a measurement, patch-clamp of WNT5a-TRPV1 currents, and peptide inhibitor behavioral assays","pmids":["35385340"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Generality beyond diabetic neuropathic pain not established"]},{"year":2018,"claim":"Uncovered a Wnt-independent, cell-autonomous function of WLS in dendrite morphogenesis, expanding its role beyond ligand secretion.","evidence":"C. elegans domain mapping, Wnt mutant analysis, and WASP interaction assays in PVD neurons","pmids":["29673481"],"confidence":"Medium","gaps":["Molecular mechanism linking WLS to WASP/actin not resolved","Conservation in mammals not tested","Single-lab study"]},{"year":null,"claim":"How the multiple WLS trafficking arms (anterograde loading, endosome retrieval, Golgi-to-ER recycling, ERAD triage) are spatially and temporally coordinated, and whether the structurally inferred Wnt-transfer conformational switch operates at recipient cells, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No integrated structural view of the recycling cycle","Mechanism of Wnt release/handoff to receptors undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,4,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[4,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,7,9]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[7,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,3,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9]}],"complexes":["WLS-Wnt ER complex","retromer (Vps35)","PORCN-VCP triaging complex"],"partners":["WNT3A","WNT8A","PORCN","VPS35","UBE2J2","CGRRF1","TMEM132A","OPRM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T9L3","full_name":"Protein wntless homolog","aliases":["Integral membrane protein GPR177","Protein evenness interrupted homolog","EVI","Putative NF-kappa-B-activating protein 373"],"length_aa":541,"mass_kda":62.3,"function":"Regulates Wnt proteins sorting and secretion in a feedback regulatory mechanism. This reciprocal interaction plays a key role in the regulation of expression, subcellular location, binding and organelle-specific association of Wnt proteins (PubMed:34587386). Plays also an important role in establishment of the anterior-posterior body axis formation during development (By similarity)","subcellular_location":"Golgi apparatus membrane; Cytoplasmic vesicle membrane; Cell membrane; Endoplasmic reticulum membrane; Golgi apparatus membrane; Early endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q5T9L3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WLS","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WLS","total_profiled":1310},"omim":[{"mim_id":"619648","title":"ZAKI SYNDROME; ZKS","url":"https://www.omim.org/entry/619648"},{"mim_id":"615406","title":"GNG12 ANTISENSE RNA 1, NONCODING; GNG12AS1","url":"https://www.omim.org/entry/615406"},{"mim_id":"611514","title":"WNT LIGAND SECRETION MEDIATOR; WLS","url":"https://www.omim.org/entry/611514"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WLS"},"hgnc":{"alias_symbol":["FLJ23091","MRP","EVI","mig-14"],"prev_symbol":["C1orf139","GPR177"]},"alphafold":{"accession":"Q5T9L3","domains":[{"cath_id":"1.20.1070","chopping":"4-38_228-491","consensus_level":"high","plddt":86.615,"start":4,"end":491},{"cath_id":"-","chopping":"42-226","consensus_level":"high","plddt":89.3691,"start":42,"end":226}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T9L3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T9L3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T9L3-F1-predicted_aligned_error_v6.png","plddt_mean":82.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WLS","jax_strain_url":"https://www.jax.org/strain/search?query=WLS"},"sequence":{"accession":"Q5T9L3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T9L3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T9L3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T9L3"}},"corpus_meta":[{"pmid":"16678096","id":"PMC_16678096","title":"Secretion of Wnt ligands requires Evi, a conserved transmembrane protein.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16678096","citation_count":458,"is_preprint":false},{"pmid":"19837038","id":"PMC_19837038","title":"Trans-synaptic transmission of vesicular Wnt signals through Evi/Wntless.","date":"2009","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/19837038","citation_count":366,"is_preprint":false},{"pmid":"8313895","id":"PMC_8313895","title":"Generation of the AML1-EVI-1 fusion gene in the t(3;21)(q26;q22) causes blastic crisis in chronic myelocytic leukemia.","date":"1994","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8313895","citation_count":350,"is_preprint":false},{"pmid":"9665135","id":"PMC_9665135","title":"The oncoprotein Evi-1 represses TGF-beta signalling by inhibiting Smad3.","date":"1998","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9665135","citation_count":302,"is_preprint":false},{"pmid":"18682242","id":"PMC_18682242","title":"Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells.","date":"2008","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/18682242","citation_count":243,"is_preprint":false},{"pmid":"22437826","id":"PMC_22437826","title":"Mechanism of evenness interrupted (Evi)-exosome release at synaptic boutons.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22437826","citation_count":233,"is_preprint":false},{"pmid":"18193037","id":"PMC_18193037","title":"Wingless secretion requires endosome-to-Golgi retrieval of Wntless/Evi/Sprinter by the retromer complex.","date":"2008","source":"Nature cell 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elegans AP-2 and retromer control Wnt signaling by regulating mig-14/Wntless.","date":"2007","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/18160346","citation_count":170,"is_preprint":false},{"pmid":"20826466","id":"PMC_20826466","title":"WLS-dependent secretion of WNT3A requires Ser209 acylation and vacuolar acidification.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/20826466","citation_count":162,"is_preprint":false},{"pmid":"19211673","id":"PMC_19211673","title":"Smed-Evi/Wntless is required for beta-catenin-dependent and -independent processes during planarian regeneration.","date":"2009","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19211673","citation_count":155,"is_preprint":false},{"pmid":"22108505","id":"PMC_22108505","title":"Porcupine-mediated lipidation is required for Wnt recognition by Wls.","date":"2011","source":"Developmental 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Epistasis experiments and clonal analysis place Evi in the Wg-producing cell, and evi mutants retain Wg intracellularly, demonstrating its essential role in Wnt release.\",\n      \"method\": \"RNAi screen in Drosophila, clonal analysis, epistasis experiments, immunostaining for Wg retention\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis, clonal analysis, and multiple RNAi experiments across species (Drosophila and human cells) consistently demonstrate WLS is required in Wnt-producing cells for Wnt secretion\",\n      \"pmids\": [\"16678096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"At the Drosophila NMJ, Evi/WLS is released in exosome-like vesicles to mediate trans-synaptic Wnt (Wingless) transmission. Additionally, Evi acts cell-autonomously in the postsynaptic cell to target dGRIP (a Wg-receptor-interacting protein) to postsynaptic sites, enabling Wnt signal transduction in the receiving cell.\",\n      \"method\": \"Live imaging, genetic loss-of-function, immunostaining at NMJ, vesicle fractionation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetics, imaging, biochemistry) in a single study demonstrating both pre- and post-synaptic roles of Evi\",\n      \"pmids\": [\"19837038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Retromer-dependent endosome-to-Golgi recycling of Wntless/Evi is required for efficient Wnt secretion. In the absence of Vps35 (retromer component), Wntless is diverted to a degradative compartment. Biochemical evidence confirms that Wntless engages the retromer complex, and overexpression of Wntless overcomes the Vps35 secretion block.\",\n      \"method\": \"Drosophila genetics (Vps35 mutant analysis), biochemical co-precipitation, electron microscopy, epistasis (Wls overexpression suppresses Vps35 mutant)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently in two papers (PMID 18193037 and 18160347) using complementary model systems (Drosophila and C. elegans) with biochemical and genetic evidence\",\n      \"pmids\": [\"18193037\", \"18160347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In C. elegans, retromer-dependent recycling retrieves MIG-14/WLS from the plasma membrane back to the Golgi. Without retromer function, MIG-14/WLS is degraded in lysosomes, becoming limiting for Wnt signaling. AP-2 (DPY-23) mediates endocytosis of MIG-14 from the plasma membrane, and in dpy-23 mutants MIG-14 accumulates at the plasma membrane.\",\n      \"method\": \"C. elegans genetics, RNAi, subcellular localization by immunofluorescence, lysosomal degradation assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent papers (PMID 18160347 and 18160346) using complementary genetic and cell biological approaches in C. elegans\",\n      \"pmids\": [\"18160347\", \"18160346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WLS binds WNT3A in an ER-resident complex, and this binding requires PORCN-dependent lipid modification (palmitoylation) of WNT3A at Ser209. Inhibition of vacuolar acidification blocks WNT3A release from the WLS complex and causes accumulation of the WNT3A-WLS complex at the plasma membrane. Structural modeling suggests WLS has a lipocalin-like lipid-binding β-barrel that interacts with the Wnt palmitoyl moiety.\",\n      \"method\": \"Co-immunoprecipitation of WLS-WNT3A complex, small molecule inhibitor screen, site-directed mutagenesis of WNT3A Ser209, subcellular fractionation, Xenopus embryo functional assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct biochemical interaction, mutagenesis of palmitoylation site, multiple pharmacological tools, and in vivo functional validation in a single study\",\n      \"pmids\": [\"20826466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Porcupine-mediated lipidation of a conserved serine residue (equivalent to Wg S239) is required for Wnt's physical and functional interaction with Wls in Drosophila. All Drosophila Wnts (except WntD, which lacks this serine) require both Porcupine and Wls for secretion, demonstrating that lipidation at this site is the structural determinant for Wls recognition.\",\n      \"method\": \"Systematic RNAi-based secretion assays of all Drosophila Wnt family members, site-directed mutagenesis of the conserved serine, co-immunoprecipitation of Wnt-Wls interaction\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — comprehensive mutagenesis combined with physical interaction assays and systematic genetic analysis across all Drosophila Wnts\",\n      \"pmids\": [\"22108505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Evi/WLS vesicle release at Drosophila synaptic boutons requires Rab11, Syntaxin 1A (Syx1A), and the Rab11 effector Myosin5. Multivesicular bodies (MVBs) containing Evi are present at synaptic boutons and serve as organelles for exosome production. Secreted Evi vesicles have biochemical characteristics conserved with exosomes.\",\n      \"method\": \"dsRNA screen in cultured cells, motoneuron-specific expression of dominant-negative Rab11 and Syx1A, ultrastructural analysis (electron microscopy), mass spectrometry characterization of exosome fraction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods including genetics, ultrastructure, and mass spectrometry in both cell culture and in vivo\",\n      \"pmids\": [\"22437826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Endogenous WLS undergoes a full ER→plasma membrane→Golgi→ER retrograde transport cycle during Wnt secretion. A C-terminal ER-targeting sequence on WLS is critical for ER retrograde recycling and Wnt secretory function. Golgi-to-ER recycling requires ARF (COPI regulator) and ERGIC2, an ER-Golgi intermediate compartment protein also required for efficient Wnt secretion.\",\n      \"method\": \"Subcellular fractionation, live imaging, mutagenesis of ER-targeting sequence, siRNA knockdown of ARF and ERGIC2, functional Wnt secretion assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (mutagenesis, localization, functional assays, knockdown of specific trafficking factors) in a single study\",\n      \"pmids\": [\"24768165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of palmitoleated human WNT8A in complex with WLS at 3.2 Å resolution reveals: (1) the WLS membrane domain has close structural homology to GPCRs; (2) a Wnt hairpin inserts into a conserved hydrophobic cavity in the GPCR-like domain; (3) the palmitoleate of WNT8A protrudes between two WLS helices into the lipid bilayer; (4) a conformational switch of conserved residues on a separate Wnt hairpin may contribute to Wnt transfer to receiving cells.\",\n      \"method\": \"Cryo-EM structure determination at 3.2 Å, biochemical mutagenesis experiments to validate observed interactions\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure with accompanying biochemical validation provides definitive molecular mechanism of WLS-Wnt interaction\",\n      \"pmids\": [\"33357447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WLS abundance is regulated by ER-associated degradation (ERAD) via the ubiquitin-proteasome system. In the absence of Wnt ligands, WLS is ubiquitinated and degraded via ERAD in a VCP-dependent manner. The E2-conjugating enzyme UBE2J2 and E3-ligase CGRRF1 mediate WLS ubiquitination. A triaging complex of Porcupine (Porcn) and VCP determines whether WLS enters the secretory pathway or ERAD, thereby adjusting WLS levels to meet Wnt export demand.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, siRNA knockdown of ERAD components, functional Wnt secretion assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal biochemical and genetic methods identify specific ERAD machinery and a triaging complex\",\n      \"pmids\": [\"29378775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WLS/GPR177 physically interacts with the mu-opioid receptor (MOR). This interaction, validated by pulldown, co-immunoprecipitation, and colocalization in mammalian cells and in rodent striatal neurons, is enhanced by morphine treatment, which causes GPR177 to redistribute from cytosol to cell surface. MOR/GPR177 complex formation at the cell periphery inhibits Wnt protein secretion.\",\n      \"method\": \"Split-ubiquitin yeast two-hybrid screen, co-immunoprecipitation, pulldown assay, colocalization in brain tissue, morphine treatment functional assays\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal co-IP and pulldown in multiple systems, but functional inhibition of Wnt secretion shown only correlatively with MOR/GPR177 complex formation\",\n      \"pmids\": [\"20214800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Gpr177 (mouse WLS ortholog) is a glycoprotein that primarily accumulates in the Golgi apparatus in Wnt signal-producing cells. Glycosylation of Gpr177 is necessary for proper transportation in the secretory pathway.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence localization, glycosylation assays (tunicamycin treatment, Western blot mobility shift)\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments with functional link to glycosylation requirement for secretory pathway transport, single lab\",\n      \"pmids\": [\"20549736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TMEM132A physically interacts with WLS, stabilizes Wnt ligand, enhances the WLS-Wnt ligand interaction, and activates the Wnt signaling pathway.\",\n      \"method\": \"Co-immunoprecipitation, Wnt ligand stability assays, Wnt signaling reporter assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and functional assays in single lab study establish physical and functional interaction\",\n      \"pmids\": [\"33324648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GPR177/WLS in A-fiber dorsal root ganglion neurons mediates the secretion of WNT5a into cerebrospinal fluid, which is necessary for maintenance of diabetic neuropathic pain. WNT5a directly activates TRPV1 ion channels by binding residues at the extracellular S5-S6 loop. A peptide disrupting the WNT5a/TRPV1 interaction suppressed neuropathic pain.\",\n      \"method\": \"Conditional knockout of GPR177 in A-fiber neurons, CSF Wnt5a measurement, electrophysiological patch-clamp recordings of WNT5a-induced TRPV1 currents, computer simulation of WNT5a-TRPV1 binding, peptide inhibitor in rodent behavioral assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined mechanistic pathway placement plus electrophysiology and computational docking, single lab\",\n      \"pmids\": [\"35385340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MIG-14/WLS has a cell-autonomous, Wnt-independent function in dendrite self-avoidance in C. elegans PVD neurons. Functions of dendrite self-avoidance and Wnt secretion map to distinct MIG-14 domains (genetically separable), and MIG-14 engages WASP-dependent actin assembly to regulate dendrite self-avoidance.\",\n      \"method\": \"C. elegans genetics, domain mapping with deletion constructs, Wnt mutant analysis showing lack of self-avoidance defects, WASP interaction assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping separating two distinct functions plus genetic epistasis with WASP pathway; single lab but multiple orthogonal genetic approaches\",\n      \"pmids\": [\"29673481\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WLS (Wntless/Evi/GPR177) is a conserved multipass transmembrane protein that acts as a dedicated cargo receptor/transporter for Wnt ligands: it binds palmitoleated Wnt proteins in the ER (requiring PORCN-dependent Ser209 lipidation for recognition, as revealed by the 3.2 Å cryo-EM structure showing a GPCR-like membrane domain that accommodates the Wnt palmitoleate), escorts them through the Golgi to the plasma membrane for secretion, and then undergoes retromer-dependent endosome-to-Golgi and COPI/ERGIC2-dependent Golgi-to-ER recycling to sustain Wnt secretion; WLS abundance is further regulated by ERAD via UBE2J2/CGRRF1-mediated ubiquitination and VCP-dependent degradation when Wnt cargo is absent, and at synapses WLS is itself released in MVB-derived exosomes via Rab11/Syntaxin1A/Myosin5-dependent mechanisms to mediate trans-synaptic Wnt transmission.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WLS (Wntless/Evi/GPR177) is a conserved multipass transmembrane protein that functions as a dedicated cargo receptor for the secretion of lipid-modified Wnt ligands from Wnt-producing cells, a role first established by genetic epistasis and clonal analysis in Drosophila where evi mutants retain Wg intracellularly [#0]. WLS binds Wnt in an ER-resident complex, and this recognition depends strictly on PORCN-dependent palmitoleoylation of a conserved Wnt serine (Ser209/S239), since loss of lipidation abolishes both physical and functional engagement with WLS across the Wnt family [#4, #5]. The molecular basis of this interaction was resolved by a 3.2 Å cryo-EM structure of WLS bound to palmitoleated WNT8A, which showed a GPCR-like membrane domain accommodating a Wnt hairpin in a hydrophobic cavity with the palmitoleate protruding between two WLS helices into the bilayer [#8]. After ER loading, WLS escorts Wnt through the secretory pathway and undergoes an obligatory recycling itinerary to sustain secretion: retromer (Vps35)-dependent retrieval of WLS from endosomes following AP-2-mediated endocytosis prevents its lysosomal degradation [#2, #3], and a C-terminal ER-targeting signal plus ARF/COPI and ERGIC2 drive Golgi-to-ER retrograde transport [#7]. When Wnt cargo is absent, WLS levels are tuned down by ERAD through UBE2J2/CGRRF1-mediated ubiquitination and VCP-dependent degradation, with a PORCN–VCP triaging complex deciding between secretion and degradation [#9]. Beyond canonical secretion, at synapses WLS is itself released in MVB-derived exosome-like vesicles via Rab11/Syntaxin1A/Myosin5 to mediate trans-synaptic Wnt transmission [#1, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that Wnt secretion requires a dedicated factor acting within the producing cell, defining WLS as the founding component of the Wnt export machinery.\",\n      \"evidence\": \"RNAi screen, clonal analysis and epistasis in Drosophila showing Wg is retained intracellularly in evi mutants\",\n      \"pmids\": [\"16678096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular nature of the WLS-Wnt interaction\", \"Subcellular trafficking route of WLS not yet mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Answered how WLS is sustained for repeated rounds of secretion by showing retromer retrieves it from endosomes rather than allowing its degradation.\",\n      \"evidence\": \"Drosophila and C. elegans genetics (Vps35 mutants), co-precipitation, EM, and Wls-overexpression suppression of the Vps35 block\",\n      \"pmids\": [\"18193037\", \"18160347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the endocytic step delivering WLS to endosomes\", \"Retromer sorting signal on WLS not defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed plasma-membrane WLS is endocytosed and retrieved to the Golgi, explaining why loss of recycling makes WLS limiting for Wnt signaling.\",\n      \"evidence\": \"C. elegans genetics and immunofluorescence showing AP-2 (DPY-23)-dependent endocytosis and lysosomal degradation of MIG-14/WLS without retromer\",\n      \"pmids\": [\"18160347\", \"18160346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endocytic adaptor recognition motif on WLS not mapped\", \"Did not address Golgi-to-ER segment of the itinerary\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the biochemical basis of cargo recognition: WLS binds Wnt in the ER and this requires PORCN-dependent lipid modification of Wnt.\",\n      \"evidence\": \"Co-IP of WLS-WNT3A, Ser209 mutagenesis, vacuolar acidification inhibitors, and Xenopus functional assays\",\n      \"pmids\": [\"20826466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipocalin-like binding model was inferred from modeling, not structure\", \"Mechanism of pH-dependent Wnt release not molecularly defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Generalized lipidation-dependent recognition across the Wnt family, establishing the conserved serine lipid mark as the structural determinant for WLS binding.\",\n      \"evidence\": \"Systematic RNAi secretion assays of all Drosophila Wnts, serine mutagenesis, and Wnt-Wls co-IP\",\n      \"pmids\": [\"22108505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"WntD exception's WLS-independence not mechanistically dissected\", \"Structural geometry of recognition not yet visualized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the trafficking machinery for synaptic WLS exosome release, distinguishing it from the canonical secretory route.\",\n      \"evidence\": \"dsRNA screen, dominant-negative Rab11/Syx1A in motoneurons, EM of MVBs, and mass spectrometry of exosome fractions in Drosophila\",\n      \"pmids\": [\"22437826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of exosomal WLS release in mammals not established\", \"Cargo selectivity for MVB sorting unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Completed the trafficking cycle by demonstrating Golgi-to-ER retrograde recycling of WLS and identifying its molecular requirements.\",\n      \"evidence\": \"Subcellular fractionation, live imaging, ER-targeting sequence mutagenesis, and ARF/ERGIC2 knockdown with Wnt secretion assays\",\n      \"pmids\": [\"24768165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the ER-targeting signal is recognized by COPI machinery not defined\", \"Coordination between retromer and COPI arms not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed cargo-responsive control of WLS abundance through ERAD, coupling WLS levels to Wnt export demand.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and siRNA of ERAD components identifying UBE2J2/CGRRF1 and a PORCN-VCP triaging complex\",\n      \"pmids\": [\"29378775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the PORCN-VCP triage decision unknown\", \"How Wnt occupancy is sensed to spare WLS from ERAD not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the definitive molecular mechanism of cargo loading by visualizing how WLS accommodates a palmitoleated Wnt in a GPCR-like fold.\",\n      \"evidence\": \"3.2 Å cryo-EM structure of WLS-WNT8A complex with biochemical mutagenesis validation\",\n      \"pmids\": [\"33357447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational switch hypothesized for Wnt transfer not directly tested in vivo\", \"Structures of recycling/empty WLS states not determined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified accessory factors and additional binding partners modulating WLS-dependent Wnt secretion in mammalian cells.\",\n      \"evidence\": \"Co-IP, glycosylation assays, Wnt stability and reporter assays implicating TMEM132A, MOR, and N-glycosylation\",\n      \"pmids\": [\"33324648\", \"20214800\", \"20549736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MOR/GPR177 inhibition of Wnt secretion shown only correlatively\", \"Single-lab findings without independent replication\", \"Structural basis of TMEM132A and MOR interactions unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed WLS in a physiological signaling context by linking neuronal WLS-mediated WNT5a secretion to TRPV1 activation and neuropathic pain.\",\n      \"evidence\": \"Conditional GPR177 knockout in A-fiber neurons, CSF Wnt5a measurement, patch-clamp of WNT5a-TRPV1 currents, and peptide inhibitor behavioral assays\",\n      \"pmids\": [\"35385340\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without independent replication\", \"Generality beyond diabetic neuropathic pain not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a Wnt-independent, cell-autonomous function of WLS in dendrite morphogenesis, expanding its role beyond ligand secretion.\",\n      \"evidence\": \"C. elegans domain mapping, Wnt mutant analysis, and WASP interaction assays in PVD neurons\",\n      \"pmids\": [\"29673481\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking WLS to WASP/actin not resolved\", \"Conservation in mammals not tested\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple WLS trafficking arms (anterograde loading, endosome retrieval, Golgi-to-ER recycling, ERAD triage) are spatially and temporally coordinated, and whether the structurally inferred Wnt-transfer conformational switch operates at recipient cells, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No integrated structural view of the recycling cycle\", \"Mechanism of Wnt release/handoff to receptors undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 7, 9]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"WLS-Wnt ER complex\",\n      \"retromer (Vps35)\",\n      \"PORCN-VCP triaging complex\"\n    ],\n    \"partners\": [\n      \"WNT3A\",\n      \"WNT8A\",\n      \"PORCN\",\n      \"VPS35\",\n      \"UBE2J2\",\n      \"CGRRF1\",\n      \"TMEM132A\",\n      \"OPRM1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}