{"gene":"PORCN","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2012,"finding":"PORCN is a membrane-bound O-acyltransferase required for Wnt palmitoylation; pharmacological inhibition of PORCN with Wnt-C59 (C59) blocks Wnt palmitoylation, Wnt interaction with the carrier protein Wntless/WLS, Wnt secretion, and Wnt activation of β-catenin reporter activity in vitro at nanomolar concentrations.","method":"In vitro PORCN activity assay measuring Wnt palmitoylation, Co-IP of Wnt with WLS, Wnt secretion assay, β-catenin reporter assay; in vivo mouse tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal in vitro assays (palmitoylation, WLS binding, secretion, reporter) plus in vivo validation; replicated across cell and animal systems in one study","pmids":["23188502"],"is_preprint":false},{"year":2015,"finding":"PORCN inhibition (ETC-159) blocks the palmitoleation (Wnt lipid modification) and secretion of all Wnts, demonstrating that PORCN-mediated Wnt palmitoylation is required for Wnt activity; RSPO3-translocated cancers are sensitive to PORCN inhibition, linking receptor abundance regulation to PORCN-dependent Wnt secretion.","method":"PORCN inhibitor treatment in RSPO3-translocated CRC patient-derived xenografts; transcriptome remodeling analysis; Wnt secretion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo xenograft with mechanistic readouts (Wnt secretion, transcriptome), replicated across multiple cancer models","pmids":["26257057"],"is_preprint":false},{"year":2007,"finding":"PORCN encodes a putative O-acyltransferase in the endoplasmic reticulum essential for Wnt protein secretion; loss-of-function mutations in PORCN cause focal dermal hypoplasia (FDH), establishing PORCN as required for Wnt ligand processing and secretion in humans.","method":"Genetic mapping, array CGH, point mutation analysis in FDH patients; identified heterozygous/mosaic PORCN mutations","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent labs simultaneously identified PORCN mutations in FDH by genetic mapping and sequencing, replicated across populations","pmids":["17546031","17546030"],"is_preprint":false},{"year":2011,"finding":"Mouse Porcn-deficient cells exhibit a cell-autonomous defect in Wnt ligand secretion but remain responsive to exogenous Wnts; Porcn hemizygous male embryos fail to generate mesoderm, consistent with loss of Wnt activity; ectodermal Porcn deletion recapitulates FDH skin and limb defects, placing PORCN upstream of Wnt secretion in the ectoderm.","method":"Conditional knockout mouse (Cre-lox), embryo phenotype analysis, exogenous Wnt rescue experiment, tissue-specific Cre deletion (ectoderm, mesenchyme)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with cell-autonomous rescue experiment and tissue-specific epistasis across multiple Cre lines in one rigorous study","pmids":["21768372"],"is_preprint":false},{"year":2012,"finding":"PORCN is required for the proliferation of a subset of transformed epithelial cancer cells in a Wnt-independent manner; re-expression of catalytically inactive PORCN rescues the proliferation defect caused by PORCN knockdown, demonstrating that this function is independent of PORCN's enzymatic activity in Wnt palmitoylation.","method":"siRNA knockdown, inducible shRNA knockdown, orthotopic xenograft, rescue with catalytically inactive PORCN mutant, RNAi of WLS, IWP inhibitor treatment, gene expression profiling","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (siRNA, shRNA, catalytic mutant rescue, WLS KD, inhibitor) in single lab; Wnt-independent function is surprising and warrants replication","pmids":["22509316"],"is_preprint":false},{"year":2012,"finding":"Mesenchyme-specific (Prx-Cre) inactivation of Porcn produces FDH-like limb defects; ectodermal (Krt14-Cre) inactivation produces thin skin, alopecia, and abnormal dentition; cell-based assays confirm that human PORCN mutations reduce WNT3A secretion, placing PORCN as essential for Wnt secretion in both ectodermal and mesodermal contexts.","method":"Conditional knockout mouse (tissue-specific Cre), cell-based Wnt secretion assay with human PORCN mutants","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KOs with distinct phenotypes plus functional cell-based secretion assay validating human mutations","pmids":["22412863"],"is_preprint":false},{"year":2002,"finding":"Human MG61/PORC (PORCN) encodes a multi-pass endoplasmic reticulum protein that can influence Wnt7A activity in a TCF-responsive reporter assay; four protein isoforms (A-D) are generated by alternative splicing in a tissue-specific manner.","method":"cDNA cloning, genomic structure analysis, TCF-responsive reporter assay with WNT7A co-expression","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reporter assay establishes functional connection to Wnt pathway; isoform characterization by molecular cloning; single lab","pmids":["12034504"],"is_preprint":false},{"year":2019,"finding":"PORCN active-site features enforce cis-Δ9 fatty acylation (palmitoleation) of Wnts; supplying a trans-Δ9 fatty acid causes accumulation of WNT-PORCN complexes, indicating that the correct fatty acyl species is required for release of lipidated Wnt from PORCN, revealing a fatty acyl-selective checkpoint in Wnt biosynthesis.","method":"Structurally diverse fatty acyl donor analogs in mouse embryonic fibroblasts expressing PORCN from multiple metazoan phyla; WNT-PORCN complex accumulation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with diverse acyl analogs and cross-phylum PORCN expression, multiple orthogonal lines of evidence establishing catalytic mechanism","pmids":["30737280"],"is_preprint":false},{"year":2021,"finding":"A homology-based structural model of human PORCN reveals 11 membrane domains (9 transmembrane + 2 reentrant loops), an N-terminus oriented to the ER lumen and C-terminus to cytosol; palmitoleoyl-CoA and Wnt hairpin 2 dock into two tunnels in the conserved catalytic core; PORCN adds mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2; clinical inhibitors (ETC-159, IWP-L6, LGK-974) dock in the PORCN catalytic site.","method":"Homology modeling to MBOAT family members, in silico docking of substrates and inhibitors, functional validation of predicted variants","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — structural model with functional validation of variants; no experimental crystal/cryo-EM structure in this paper; single lab","pmids":["34817055"],"is_preprint":false},{"year":2021,"finding":"PORCN has 11 membrane domains comprising 9 transmembrane-spanning domains and 2 reentrant domains; N-terminus is oriented toward the ER lumen and C-terminus toward the cytosol; PORCN has a funnel-like structure encapsulated by multiple membrane-spanning helices, consistent with DltB (bacterial MBOAT) topology.","method":"Experimental topology determination combined with homology modeling to DltB crystal structure; functional mapping of FDH-associated residues","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — experimental topology data plus structural modeling, single lab, topology validated functionally","pmids":["34186010"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of human PORCN in complex with inhibitors C59 (2.4 Å) and ETC-159 (2.6 Å) and in ligand-free state (3.3 Å) reveal ordered water molecules forming a hydrogen-bonding network in the active site that mediates inhibitor binding; despite different chemical scaffolds, diverse inhibitors adopt similar conformations within the acyl-CoA binding site and engage a conserved water molecule.","method":"High-resolution cryo-electron microscopy structure determination; docking simulations of diverse PORCN inhibitors","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Strong — experimental cryo-EM structures at 2.4–2.6 Å resolution with multiple inhibitor complexes, providing direct atomic-level mechanism of inhibition","pmids":["bio_10.1101_2025.05.19.654776"],"is_preprint":true},{"year":2013,"finding":"Porcn-dependent Wnt secretion is first required for initiation of gastrulation in mouse; Porcn function is required in the epiblast but not the visceral endoderm for gastrulation; there is no requirement for Porcn-dependent Wnt ligand secretion during preimplantation development.","method":"Conditional knockout using zygotic, oocyte-specific, and visceral endoderm-specific Cre deletions; embryo phenotype analysis at sequential developmental stages","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple tissue-specific conditional knockouts with staged developmental analysis defining precise temporal and spatial requirement","pmids":["23760955"],"is_preprint":false},{"year":2020,"finding":"PORCN negatively regulates AMPAR (GluA1, GluA2, GluA3) trafficking to the plasma membrane and inhibits ligand-gated currents in a subunit-independent manner; this inhibition does not require the amino-terminal domain (ATD) or carboxy-terminal domain (CTD) of GluA subunits; PORCN physically interacts with AMPARs independently of their ATD or CTD.","method":"Co-expression in HEK293T cells, whole-cell patch-clamp recording, surface biotinylation assay, Co-IP/pulldown with domain deletion mutants","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus electrophysiology plus surface expression assay in heterologous system; single lab; no in vivo validation","pmids":["32984326"],"is_preprint":false},{"year":2008,"finding":"Knockdown of PORCN (PPN/MG61) by siRNA in lung cancer cells decreases Wnt pathway activity and induces apoptosis, establishing that PORCN-mediated post-translational processing of Wnt proteins is required for Wnt pathway activity in cancer cells.","method":"siRNA knockdown, Wnt pathway reporter assay, apoptosis assay in lung cancer cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA with functional Wnt pathway readout and apoptosis; single lab, single method per endpoint","pmids":["18193088"],"is_preprint":false},{"year":2022,"finding":"Conditional ubiquitous inactivation of Porcn in mouse around the eye field stage causes optic vesicles to arrest in growth, fail to form an optic cup, and exhibit decreased ventral proliferation with increased apoptotic cell death; Wnt/β-catenin effector LEF1 is downregulated, indicating PORCN-dependent Wnt secretion controls optic cup morphogenesis through regulation of proliferation and survival.","method":"Ubiquitous conditional Porcn knockout (Cre-lox), histology, IHC for transcription factors and LEF1, BrdU proliferation assay, apoptosis assay","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple molecular and cellular readouts (proliferation, apoptosis, transcription factor expression, Wnt effector) in defined developmental window","pmids":["36393832"],"is_preprint":false},{"year":2023,"finding":"PORCN overexpression promotes HCC cell proliferation and migration by inducing nuclear translocation of β-catenin (EMT), demonstrating that PORCN-mediated Wnt palmitoylation drives Wnt/β-catenin pathway activation and downstream EMT in hepatocellular carcinoma.","method":"PORCN overexpression in HCC cells, CCK-8, wound-healing, Transwell assay, xenograft model, immunofluorescence and subcellular fractionation for β-catenin localization","journal":"Translational cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with multiple functional assays and subcellular localization readout; single lab, no catalytic mutant control","pmids":["37588740"],"is_preprint":false},{"year":2022,"finding":"Fibroblasts from a patient with a PORCN missense mutation (p.Asp283His) showed altered PORCN protein abundance and distribution, increased vulnerability to ER stress, and impaired protein secretion, indicating that PORCN mutations can disrupt ER function and protein secretion beyond simple loss of Wnt palmitoylation activity.","method":"Patient-derived fibroblast analysis: PORCN protein localization, ER stress challenge assay, protein secretion assay","journal":"Orphanet journal of rare diseases","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — patient fibroblast functional studies with multiple readouts; single case, single lab","pmids":["35101074"],"is_preprint":false}],"current_model":"PORCN is an endoplasmic reticulum-resident, membrane-bound O-acyltransferase (MBOAT) with 11 membrane domains that catalyzes the addition of cis-Δ9 mono-unsaturated palmitoleic acid to a conserved serine on Wnt hairpin 2; this lipid modification is stereoselectively enforced by the PORCN active site, is essential for Wnt-Wntless (WLS) interaction, Wnt secretion, and all downstream Wnt signaling, and loss-of-function mutations in PORCN cause focal dermal hypoplasia by blocking Wnt ligand secretion in a cell-autonomous manner."},"narrative":{"mechanistic_narrative":"PORCN is an endoplasmic reticulum-resident membrane-bound O-acyltransferase (MBOAT) that lipid-modifies Wnt ligands and thereby gates all Wnt secretion and downstream β-catenin signaling [PMID:23188502, PMID:17546031, PMID:17546030]. It catalyzes addition of cis-Δ9 mono-unsaturated palmitoleic acid to a conserved serine at the tip of Wnt hairpin 2, and its active site stereoselectively enforces the correct acyl species: supplying a trans-Δ9 fatty acid traps Wnt–PORCN complexes, defining a fatty-acyl-selective release checkpoint in Wnt biosynthesis [PMID:30737280, PMID:34817055]. This palmitoleation is required for Wnt to engage the carrier protein WLS, for Wnt secretion, and for activation of β-catenin reporters, and pharmacological PORCN inhibitors (Wnt-C59, ETC-159, LGK-974) block the modification by occupying the acyl-CoA binding site of the catalytic core [PMID:23188502, PMID:bio_10.1101_2025.05.19.654776]. Structurally, PORCN spans the ER membrane with 11 membrane domains (9 transmembrane helices plus 2 reentrant loops), a luminal N-terminus and cytosolic C-terminus, and an ordered water network in the active site that mediates inhibitor binding [PMID:34186010, PMID:bio_10.1101_2025.05.19.654776]. Through this single biochemical activity PORCN acts cell-autonomously upstream of Wnt: Porcn-deficient cells fail to secrete Wnt yet remain responsive to exogenous Wnt, and PORCN-dependent Wnt secretion is required for gastrulation initiation in the epiblast, mesoderm formation, optic cup morphogenesis, and ectodermal/mesenchymal patterning [PMID:21768372, PMID:23760955, PMID:36393832]. Loss-of-function PORCN mutations cause focal dermal hypoplasia by blocking Wnt ligand secretion [PMID:17546031, PMID:17546030, PMID:22412863]. In cancer, PORCN inhibition suppresses Wnt-driven and RSPO3-translocated tumors, while PORCN overexpression promotes β-catenin nuclear translocation and EMT in hepatocellular carcinoma [PMID:26257057, PMID:37588740]. Beyond canonical Wnt processing, PORCN has been linked to enzyme-independent control of cancer-cell proliferation and to negative regulation of AMPAR surface trafficking, indicating activities not fully explained by Wnt palmitoylation [PMID:22509316, PMID:32984326].","teleology":[{"year":2002,"claim":"Established that human PORCN is a multi-pass ER protein functionally connected to Wnt signaling, framing it as a candidate Wnt-processing enzyme rather than a generic ER protein.","evidence":"cDNA cloning, genomic/isoform analysis, and TCF-responsive reporter assay with WNT7A co-expression","pmids":["12034504"],"confidence":"Medium","gaps":["Did not demonstrate enzymatic activity or a direct biochemical modification of Wnt","Functional role of the four tissue-specific isoforms not resolved"]},{"year":2007,"claim":"Linked PORCN to human disease by showing loss-of-function mutations cause focal dermal hypoplasia, establishing an essential in vivo requirement for PORCN in Wnt ligand processing/secretion.","evidence":"Genetic mapping, array CGH, and point-mutation analysis in FDH patients across independent populations","pmids":["17546031","17546030"],"confidence":"High","gaps":["Did not define the biochemical step PORCN catalyzes","Mosaic/heterozygous inheritance left cell-autonomy unresolved"]},{"year":2008,"claim":"Showed PORCN processing of Wnt is required for Wnt pathway activity and cell survival in cancer cells, nominating PORCN as a tractable pathway node.","evidence":"siRNA knockdown with Wnt reporter and apoptosis assays in lung cancer cell lines","pmids":["18193088"],"confidence":"Medium","gaps":["Single method per endpoint","Did not separate Wnt-dependent from Wnt-independent effects on survival"]},{"year":2011,"claim":"Demonstrated PORCN acts cell-autonomously upstream of Wnt secretion in vivo, since Porcn-null cells cannot secrete Wnt but still respond to exogenous Wnt, and tissue-specific deletion recapitulates FDH.","evidence":"Conditional knockout mouse with exogenous Wnt rescue and tissue-specific Cre deletions","pmids":["21768372"],"confidence":"High","gaps":["Did not resolve the specific lipid species added to Wnt","No structural basis for substrate selection"]},{"year":2012,"claim":"Refined the developmental requirement for PORCN to both ectodermal and mesodermal tissues and validated that human FDH mutations directly impair WNT3A secretion.","evidence":"Tissue-specific conditional knockouts (Prx-Cre, Krt14-Cre) plus cell-based Wnt secretion assays of human PORCN mutants","pmids":["22412863"],"confidence":"High","gaps":["Mechanism linking secretion loss to specific limb/skin phenotypes not fully resolved"]},{"year":2012,"claim":"Uncovered a candidate Wnt- and catalysis-independent role for PORCN in cancer-cell proliferation, complicating the view that PORCN acts solely through Wnt palmitoylation.","evidence":"siRNA/shRNA knockdown with rescue by catalytically inactive PORCN, WLS RNAi, and IWP inhibitor controls in xenografts","pmids":["22509316"],"confidence":"Medium","gaps":["Surprising enzyme-independent function awaits independent replication","Molecular basis of the non-catalytic activity unknown"]},{"year":2013,"claim":"Defined the precise temporal window of PORCN-dependent Wnt secretion in development, showing it is dispensable preimplantation but required in the epiblast to initiate gastrulation.","evidence":"Zygotic, oocyte-specific, and visceral-endoderm-specific conditional knockouts with staged embryo analysis","pmids":["23760955"],"confidence":"High","gaps":["Which specific Wnt ligands drive gastrulation initiation not identified"]},{"year":2015,"claim":"Confirmed PORCN inhibition blocks palmitoleation and secretion of all Wnts and identified RSPO3-translocated cancers as a sensitive class, translating the mechanism into a therapeutic stratification.","evidence":"PORCN inhibitor (ETC-159) in RSPO3-translocated CRC patient-derived xenografts with secretion and transcriptome readouts","pmids":["26257057"],"confidence":"High","gaps":["Did not resolve the atomic basis of inhibitor action"]},{"year":2019,"claim":"Established the catalytic selectivity of PORCN, showing its active site enforces the cis-Δ9 acyl species and that an incorrect acyl group traps Wnt–PORCN complexes, defining a release checkpoint.","evidence":"Structurally diverse fatty-acyl donor analogs and cross-phylum PORCN expression in MEFs with complex-accumulation assays","pmids":["30737280"],"confidence":"High","gaps":["No atomic structure of the acyl-binding tunnel at this stage"]},{"year":2020,"claim":"Identified a non-Wnt activity in which PORCN physically interacts with AMPAR subunits and negatively regulates their surface trafficking and currents, broadening PORCN's functional scope.","evidence":"Co-expression, Co-IP with domain-deletion mutants, surface biotinylation, and whole-cell patch-clamp in HEK293T","pmids":["32984326"],"confidence":"Medium","gaps":["Heterologous system only, no in vivo validation","Whether the interaction requires PORCN catalytic activity not tested"]},{"year":2021,"claim":"Resolved PORCN membrane architecture and a docking model for substrates and inhibitors, providing the first structure-based mechanism for palmitoleation and inhibition.","evidence":"Experimental topology determination plus homology modeling to DltB/MBOAT family with functional mapping of FDH variants and in silico docking","pmids":["34186010","34817055"],"confidence":"Medium","gaps":["No experimental high-resolution structure in these studies","Catalytic chemistry inferred from models rather than observed"]},{"year":2022,"claim":"Extended PORCN's developmental roles to eye morphogenesis and revealed an ER-stress/secretion phenotype in patient cells beyond simple loss of Wnt palmitoylation.","evidence":"Ubiquitous conditional Porcn knockout with proliferation/apoptosis/LEF1 readouts; patient-derived fibroblast ER-stress and secretion assays of the p.Asp283His mutant","pmids":["36393832","35101074"],"confidence":"High","gaps":["Mechanism connecting PORCN mutation to general ER dysfunction (vs Wnt loss) not dissected","Single-patient fibroblast observation"]},{"year":2023,"claim":"Showed PORCN overexpression activates Wnt/β-catenin signaling and EMT in hepatocellular carcinoma, implicating PORCN gain-of-function in tumor progression.","evidence":"PORCN overexpression in HCC cells with proliferation/migration assays, xenografts, and β-catenin subcellular fractionation","pmids":["37588740"],"confidence":"Medium","gaps":["No catalytic-mutant control to confirm dependence on palmitoyltransferase activity"]},{"year":2025,"claim":"Provided direct atomic-level mechanism of PORCN inhibition, showing diverse inhibitor scaffolds converge on the acyl-CoA binding site via a conserved active-site water network.","evidence":"High-resolution cryo-EM of human PORCN with C59 and ETC-159 and in ligand-free state, with docking simulations (preprint)","pmids":["bio_10.1101_2025.05.19.654776"],"confidence":"High","gaps":["Structure of the catalytically engaged Wnt-substrate complex not captured","Preprint, peer review pending"]},{"year":null,"claim":"The molecular basis of PORCN's apparent Wnt-independent functions (cancer-cell proliferation, AMPAR trafficking regulation, ER-stress vulnerability) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Whether non-Wnt activities depend on PORCN catalytic activity is untested in vivo","No structure of a Wnt-bound PORCN intermediate","AMPAR regulation lacks physiological confirmation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,7,8]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2,6,9,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,11,14]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,3]}],"complexes":[],"partners":["WLS","WNT3A","WNT7A","GRIA1","GRIA2","GRIA3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H237","full_name":"Protein-serine O-palmitoleoyltransferase porcupine","aliases":["Protein MG61"],"length_aa":461,"mass_kda":52.3,"function":"Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins. Serine palmitoleoylation of WNT proteins is required for efficient binding to frizzled receptors","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9H237/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PORCN","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DAD1","stoichiometry":10.0},{"gene":"RPN2","stoichiometry":10.0},{"gene":"SEC61B","stoichiometry":10.0},{"gene":"STT3B","stoichiometry":10.0},{"gene":"DDOST","stoichiometry":4.0},{"gene":"RPN1","stoichiometry":4.0},{"gene":"BCAP31","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"CLASP2","stoichiometry":0.2},{"gene":"EMC4","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PORCN","total_profiled":1310},"omim":[{"mim_id":"305600","title":"FOCAL DERMAL HYPOPLASIA; FDH","url":"https://www.omim.org/entry/305600"},{"mim_id":"300652","title":"ANGIOMA SERPIGINOSUM, X-LINKED","url":"https://www.omim.org/entry/300652"},{"mim_id":"300651","title":"PORCUPINE O-ACYLTRANSFERASE; PORCN","url":"https://www.omim.org/entry/300651"},{"mim_id":"300453","title":"FAMILY WITH SEQUENCE SIMILARITY 50, MEMBER A; FAM50A","url":"https://www.omim.org/entry/300453"},{"mim_id":"300261","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, ARMFIELD TYPE; MRXSA","url":"https://www.omim.org/entry/300261"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adrenal gland","ntpm":30.9}],"url":"https://www.proteinatlas.org/search/PORCN"},"hgnc":{"alias_symbol":["MG61","PORC","PPN","por"],"prev_symbol":["DHOF"]},"alphafold":{"accession":"Q9H237","domains":[{"cath_id":"-","chopping":"18-189","consensus_level":"high","plddt":92.8124,"start":18,"end":189},{"cath_id":"-","chopping":"291-461","consensus_level":"medium","plddt":91.1847,"start":291,"end":461}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H237","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H237-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H237-F1-predicted_aligned_error_v6.png","plddt_mean":90.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PORCN","jax_strain_url":"https://www.jax.org/strain/search?query=PORCN"},"sequence":{"accession":"Q9H237","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H237.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H237/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H237"}},"corpus_meta":[{"pmid":"23188502","id":"PMC_23188502","title":"Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23188502","citation_count":329,"is_preprint":false},{"pmid":"26257057","id":"PMC_26257057","title":"Wnt addiction of genetically defined cancers reversed by PORCN inhibition.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/26257057","citation_count":278,"is_preprint":false},{"pmid":"17546031","id":"PMC_17546031","title":"Deficiency of PORCN, a regulator of Wnt signaling, is associated with focal dermal hypoplasia.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17546031","citation_count":209,"is_preprint":false},{"pmid":"17546030","id":"PMC_17546030","title":"Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17546030","citation_count":206,"is_preprint":false},{"pmid":"21768372","id":"PMC_21768372","title":"Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21768372","citation_count":146,"is_preprint":false},{"pmid":"31391551","id":"PMC_31391551","title":"PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/31391551","citation_count":71,"is_preprint":false},{"pmid":"23760955","id":"PMC_23760955","title":"Porcn-dependent Wnt signaling is not required prior to mouse gastrulation.","date":"2013","source":"Development (Cambridge, 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concentrations.\",\n \"method\": \"In vitro PORCN activity assay measuring Wnt palmitoylation, Co-IP of Wnt with WLS, Wnt secretion assay, β-catenin reporter assay; in vivo mouse tumor model\",\n \"journal\": \"Cancer research\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal in vitro assays (palmitoylation, WLS binding, secretion, reporter) plus in vivo validation; replicated across cell and animal systems in one study\",\n \"pmids\": [\"23188502\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2015,\n \"finding\": \"PORCN inhibition (ETC-159) blocks the palmitoleation (Wnt lipid modification) and secretion of all Wnts, demonstrating that PORCN-mediated Wnt palmitoylation is required for Wnt activity; RSPO3-translocated cancers are sensitive to PORCN inhibition, linking receptor abundance regulation to PORCN-dependent Wnt secretion.\",\n \"method\": \"PORCN inhibitor treatment in RSPO3-translocated CRC patient-derived xenografts; transcriptome remodeling analysis; Wnt secretion assays\",\n \"journal\": \"Oncogene\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — in vivo xenograft with mechanistic readouts (Wnt secretion, transcriptome), replicated across multiple cancer models\",\n \"pmids\": [\"26257057\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2007,\n \"finding\": \"PORCN encodes a putative O-acyltransferase in the endoplasmic reticulum essential for Wnt protein secretion; loss-of-function mutations in PORCN cause focal dermal hypoplasia (FDH), establishing PORCN as required for Wnt ligand processing and secretion in humans.\",\n \"method\": \"Genetic mapping, array CGH, point mutation analysis in FDH patients; identified heterozygous/mosaic PORCN mutations\",\n \"journal\": \"Nature genetics\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — two independent labs simultaneously identified PORCN mutations in FDH by genetic mapping and sequencing, replicated across populations\",\n \"pmids\": [\"17546031\", \"17546030\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2011,\n \"finding\": \"Mouse Porcn-deficient cells exhibit a cell-autonomous defect in Wnt ligand secretion but remain responsive to exogenous Wnts; Porcn hemizygous male embryos fail to generate mesoderm, consistent with loss of Wnt activity; ectodermal Porcn deletion recapitulates FDH skin and limb defects, placing PORCN upstream of Wnt secretion in the ectoderm.\",\n \"method\": \"Conditional knockout mouse (Cre-lox), embryo phenotype analysis, exogenous Wnt rescue experiment, tissue-specific Cre deletion (ectoderm, mesenchyme)\",\n \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with cell-autonomous rescue experiment and tissue-specific epistasis across multiple Cre lines in one rigorous study\",\n \"pmids\": [\"21768372\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2012,\n \"finding\": \"PORCN is required for the proliferation of a subset of transformed epithelial cancer cells in a Wnt-independent manner; re-expression of catalytically inactive PORCN rescues the proliferation defect caused by PORCN knockdown, demonstrating that this function is independent of PORCN's enzymatic activity in Wnt palmitoylation.\",\n \"method\": \"siRNA knockdown, inducible shRNA knockdown, orthotopic xenograft, rescue with catalytically inactive PORCN mutant, RNAi of WLS, IWP inhibitor treatment, gene expression profiling\",\n \"journal\": \"PloS one\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (siRNA, shRNA, catalytic mutant rescue, WLS KD, inhibitor) in single lab; Wnt-independent function is surprising and warrants replication\",\n \"pmids\": [\"22509316\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2012,\n \"finding\": \"Mesenchyme-specific (Prx-Cre) inactivation of Porcn produces FDH-like limb defects; ectodermal (Krt14-Cre) inactivation produces thin skin, alopecia, and abnormal dentition; cell-based assays confirm that human PORCN mutations reduce WNT3A secretion, placing PORCN as essential for Wnt secretion in both ectodermal and mesodermal contexts.\",\n \"method\": \"Conditional knockout mouse (tissue-specific Cre), cell-based Wnt secretion assay with human PORCN mutants\",\n \"journal\": \"PloS one\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KOs with distinct phenotypes plus functional cell-based secretion assay validating human mutations\",\n \"pmids\": [\"22412863\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2002,\n \"finding\": \"Human MG61/PORC (PORCN) encodes a multi-pass endoplasmic reticulum protein that can influence Wnt7A activity in a TCF-responsive reporter assay; four protein isoforms (A-D) are generated by alternative splicing in a tissue-specific manner.\",\n \"method\": \"cDNA cloning, genomic structure analysis, TCF-responsive reporter assay with WNT7A co-expression\",\n \"journal\": \"Gene\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — reporter assay establishes functional connection to Wnt pathway; isoform characterization by molecular cloning; single lab\",\n \"pmids\": [\"12034504\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2019,\n \"finding\": \"PORCN active-site features enforce cis-Δ9 fatty acylation (palmitoleation) of Wnts; supplying a trans-Δ9 fatty acid causes accumulation of WNT-PORCN complexes, indicating that the correct fatty acyl species is required for release of lipidated Wnt from PORCN, revealing a fatty acyl-selective checkpoint in Wnt biosynthesis.\",\n \"method\": \"Structurally diverse fatty acyl donor analogs in mouse embryonic fibroblasts expressing PORCN from multiple metazoan phyla; WNT-PORCN complex accumulation assay\",\n \"journal\": \"The Journal of biological chemistry\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with diverse acyl analogs and cross-phylum PORCN expression, multiple orthogonal lines of evidence establishing catalytic mechanism\",\n \"pmids\": [\"30737280\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2021,\n \"finding\": \"A homology-based structural model of human PORCN reveals 11 membrane domains (9 transmembrane + 2 reentrant loops), an N-terminus oriented to the ER lumen and C-terminus to cytosol; palmitoleoyl-CoA and Wnt hairpin 2 dock into two tunnels in the conserved catalytic core; PORCN adds mono-unsaturated palmitoleic acid to a serine on the tip of Wnt hairpin 2; clinical inhibitors (ETC-159, IWP-L6, LGK-974) dock in the PORCN catalytic site.\",\n \"method\": \"Homology modeling to MBOAT family members, in silico docking of substrates and inhibitors, functional validation of predicted variants\",\n \"journal\": \"Journal of cell science\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — structural model with functional validation of variants; no experimental crystal/cryo-EM structure in this paper; single lab\",\n \"pmids\": [\"34817055\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2021,\n \"finding\": \"PORCN has 11 membrane domains comprising 9 transmembrane-spanning domains and 2 reentrant domains; N-terminus is oriented toward the ER lumen and C-terminus toward the cytosol; PORCN has a funnel-like structure encapsulated by multiple membrane-spanning helices, consistent with DltB (bacterial MBOAT) topology.\",\n \"method\": \"Experimental topology determination combined with homology modeling to DltB crystal structure; functional mapping of FDH-associated residues\",\n \"journal\": \"Open biology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — experimental topology data plus structural modeling, single lab, topology validated functionally\",\n \"pmids\": [\"34186010\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2025,\n \"finding\": \"Cryo-EM structures of human PORCN in complex with inhibitors C59 (2.4 Å) and ETC-159 (2.6 Å) and in ligand-free state (3.3 Å) reveal ordered water molecules forming a hydrogen-bonding network in the active site that mediates inhibitor binding; despite different chemical scaffolds, diverse inhibitors adopt similar conformations within the acyl-CoA binding site and engage a conserved water molecule.\",\n \"method\": \"High-resolution cryo-electron microscopy structure determination; docking simulations of diverse PORCN inhibitors\",\n \"journal\": \"bioRxiv\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 1 / Strong — experimental cryo-EM structures at 2.4–2.6 Å resolution with multiple inhibitor complexes, providing direct atomic-level mechanism of inhibition\",\n \"pmids\": [\"bio_10.1101_2025.05.19.654776\"],\n \"is_preprint\": true\n },\n {\n \"year\": 2013,\n \"finding\": \"Porcn-dependent Wnt secretion is first required for initiation of gastrulation in mouse; Porcn function is required in the epiblast but not the visceral endoderm for gastrulation; there is no requirement for Porcn-dependent Wnt ligand secretion during preimplantation development.\",\n \"method\": \"Conditional knockout using zygotic, oocyte-specific, and visceral endoderm-specific Cre deletions; embryo phenotype analysis at sequential developmental stages\",\n \"journal\": \"Development (Cambridge, England)\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — multiple tissue-specific conditional knockouts with staged developmental analysis defining precise temporal and spatial requirement\",\n \"pmids\": [\"23760955\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2020,\n \"finding\": \"PORCN negatively regulates AMPAR (GluA1, GluA2, GluA3) trafficking to the plasma membrane and inhibits ligand-gated currents in a subunit-independent manner; this inhibition does not require the amino-terminal domain (ATD) or carboxy-terminal domain (CTD) of GluA subunits; PORCN physically interacts with AMPARs independently of their ATD or CTD.\",\n \"method\": \"Co-expression in HEK293T cells, whole-cell patch-clamp recording, surface biotinylation assay, Co-IP/pulldown with domain deletion mutants\",\n \"journal\": \"Frontiers in cell and developmental biology\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus electrophysiology plus surface expression assay in heterologous system; single lab; no in vivo validation\",\n \"pmids\": [\"32984326\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2008,\n \"finding\": \"Knockdown of PORCN (PPN/MG61) by siRNA in lung cancer cells decreases Wnt pathway activity and induces apoptosis, establishing that PORCN-mediated post-translational processing of Wnt proteins is required for Wnt pathway activity in cancer cells.\",\n \"method\": \"siRNA knockdown, Wnt pathway reporter assay, apoptosis assay in lung cancer cell lines\",\n \"journal\": \"Oncogene\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — siRNA with functional Wnt pathway readout and apoptosis; single lab, single method per endpoint\",\n \"pmids\": [\"18193088\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2022,\n \"finding\": \"Conditional ubiquitous inactivation of Porcn in mouse around the eye field stage causes optic vesicles to arrest in growth, fail to form an optic cup, and exhibit decreased ventral proliferation with increased apoptotic cell death; Wnt/β-catenin effector LEF1 is downregulated, indicating PORCN-dependent Wnt secretion controls optic cup morphogenesis through regulation of proliferation and survival.\",\n \"method\": \"Ubiquitous conditional Porcn knockout (Cre-lox), histology, IHC for transcription factors and LEF1, BrdU proliferation assay, apoptosis assay\",\n \"journal\": \"Frontiers in cell and developmental biology\",\n \"confidence\": \"High\",\n \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple molecular and cellular readouts (proliferation, apoptosis, transcription factor expression, Wnt effector) in defined developmental window\",\n \"pmids\": [\"36393832\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2023,\n \"finding\": \"PORCN overexpression promotes HCC cell proliferation and migration by inducing nuclear translocation of β-catenin (EMT), demonstrating that PORCN-mediated Wnt palmitoylation drives Wnt/β-catenin pathway activation and downstream EMT in hepatocellular carcinoma.\",\n \"method\": \"PORCN overexpression in HCC cells, CCK-8, wound-healing, Transwell assay, xenograft model, immunofluorescence and subcellular fractionation for β-catenin localization\",\n \"journal\": \"Translational cancer research\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with multiple functional assays and subcellular localization readout; single lab, no catalytic mutant control\",\n \"pmids\": [\"37588740\"],\n \"is_preprint\": false\n },\n {\n \"year\": 2022,\n \"finding\": \"Fibroblasts from a patient with a PORCN missense mutation (p.Asp283His) showed altered PORCN protein abundance and distribution, increased vulnerability to ER stress, and impaired protein secretion, indicating that PORCN mutations can disrupt ER function and protein secretion beyond simple loss of Wnt palmitoylation activity.\",\n \"method\": \"Patient-derived fibroblast analysis: PORCN protein localization, ER stress challenge assay, protein secretion assay\",\n \"journal\": \"Orphanet journal of rare diseases\",\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"Tier 3 / Moderate — patient fibroblast functional studies with multiple readouts; single case, single lab\",\n \"pmids\": [\"35101074\"],\n \"is_preprint\": false\n }\n ],\n \"current_model\": \"PORCN is an endoplasmic reticulum-resident, membrane-bound O-acyltransferase (MBOAT) with 11 membrane domains that catalyzes the addition of cis-Δ9 mono-unsaturated palmitoleic acid to a conserved serine on Wnt hairpin 2; this lipid modification is stereoselectively enforced by the PORCN active site, is essential for Wnt-Wntless (WLS) interaction, Wnt secretion, and all downstream Wnt signaling, and loss-of-function mutations in PORCN cause focal dermal hypoplasia by blocking Wnt ligand secretion in a cell-autonomous manner.\"\n}\n```","stage2_raw":"{\n \"mechanistic_narrative\": \"PORCN is an endoplasmic reticulum-resident membrane-bound O-acyltransferase (MBOAT) that lipid-modifies Wnt ligands and thereby gates all Wnt secretion and downstream β-catenin signaling [#0, #2]. It catalyzes addition of cis-Δ9 mono-unsaturated palmitoleic acid to a conserved serine at the tip of Wnt hairpin 2, and its active site stereoselectively enforces the correct acyl species: supplying a trans-Δ9 fatty acid traps Wnt–PORCN complexes, defining a fatty-acyl-selective release checkpoint in Wnt biosynthesis [#7, #8]. This palmitoleation is required for Wnt to engage the carrier protein WLS, for Wnt secretion, and for activation of β-catenin reporters, and pharmacological PORCN inhibitors (Wnt-C59, ETC-159, LGK-974) block the modification by occupying the acyl-CoA binding site of the catalytic core [#0, #10]. Structurally, PORCN spans the ER membrane with 11 membrane domains (9 transmembrane helices plus 2 reentrant loops), a luminal N-terminus and cytosolic C-terminus, and an ordered water network in the active site that mediates inhibitor binding [#9, #10]. Through this single biochemical activity PORCN acts cell-autonomously upstream of Wnt: Porcn-deficient cells fail to secrete Wnt yet remain responsive to exogenous Wnt, and PORCN-dependent Wnt secretion is required for gastrulation initiation in the epiblast, mesoderm formation, optic cup morphogenesis, and ectodermal/mesenchymal patterning [#3, #11, #14]. Loss-of-function PORCN mutations cause focal dermal hypoplasia by blocking Wnt ligand secretion [#2, #5]. In cancer, PORCN inhibition suppresses Wnt-driven and RSPO3-translocated tumors, while PORCN overexpression promotes β-catenin nuclear translocation and EMT in hepatocellular carcinoma [#1, #15]. Beyond canonical Wnt processing, PORCN has been linked to enzyme-independent control of cancer-cell proliferation and to negative regulation of AMPAR surface trafficking, indicating activities not fully explained by Wnt palmitoylation [#4, #12].\",\n \"teleology\": [\n {\n \"year\": 2002,\n \"claim\": \"Established that human PORCN is a multi-pass ER protein functionally connected to Wnt signaling, framing it as a candidate Wnt-processing enzyme rather than a generic ER protein.\",\n \"evidence\": \"cDNA cloning, genomic/isoform analysis, and TCF-responsive reporter assay with WNT7A co-expression\",\n \"pmids\": [\"12034504\"],\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Did not demonstrate enzymatic activity or a direct biochemical modification of Wnt\", \"Functional role of the four tissue-specific isoforms not resolved\"]\n },\n {\n \"year\": 2007,\n \"claim\": \"Linked PORCN to human disease by showing loss-of-function mutations cause focal dermal hypoplasia, establishing an essential in vivo requirement for PORCN in Wnt ligand processing/secretion.\",\n \"evidence\": \"Genetic mapping, array CGH, and point-mutation analysis in FDH patients across independent populations\",\n \"pmids\": [\"17546031\", \"17546030\"],\n \"confidence\": \"High\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Did not define the biochemical step PORCN catalyzes\", \"Mosaic/heterozygous inheritance left cell-autonomy unresolved\"]\n },\n {\n \"year\": 2008,\n \"claim\": \"Showed PORCN processing of Wnt is required for Wnt pathway activity and cell survival in cancer cells, nominating PORCN as a tractable pathway node.\",\n \"evidence\": \"siRNA knockdown with Wnt reporter and apoptosis assays in lung cancer cell lines\",\n \"pmids\": [\"18193088\"],\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Single method per endpoint\", \"Did not separate Wnt-dependent from Wnt-independent effects on survival\"]\n },\n {\n \"year\": 2011,\n \"claim\": \"Demonstrated PORCN acts cell-autonomously upstream of Wnt secretion in vivo, since Porcn-null cells cannot secrete Wnt but still respond to exogenous Wnt, and tissue-specific deletion recapitulates FDH.\",\n \"evidence\": \"Conditional knockout mouse with exogenous Wnt rescue and tissue-specific Cre deletions\",\n \"pmids\": [\"21768372\"],\n \"confidence\": \"High\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Did not resolve the specific lipid species added to Wnt\", \"No structural basis for substrate selection\"]\n },\n {\n \"year\": 2012,\n \"claim\": \"Refined the developmental requirement for PORCN to both ectodermal and mesodermal tissues and validated that human FDH mutations directly impair WNT3A secretion.\",\n \"evidence\": \"Tissue-specific conditional knockouts (Prx-Cre, Krt14-Cre) plus cell-based Wnt secretion assays of human PORCN mutants\",\n \"pmids\": [\"22412863\"],\n \"confidence\": \"High\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Mechanism linking secretion loss to specific limb/skin phenotypes not fully resolved\"]\n },\n {\n \"year\": 2012,\n \"claim\": \"Uncovered a candidate Wnt- and catalysis-independent role for PORCN in cancer-cell proliferation, complicating the view that PORCN acts solely through Wnt palmitoylation.\",\n \"evidence\": \"siRNA/shRNA knockdown with rescue by catalytically inactive PORCN, WLS RNAi, and IWP inhibitor controls in xenografts\",\n \"pmids\": [\"22509316\"],\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Surprising enzyme-independent function awaits independent replication\", \"Molecular basis of the non-catalytic activity unknown\"]\n },\n {\n \"year\": 2013,\n \"claim\": \"Defined the precise temporal window of PORCN-dependent Wnt secretion in development, showing it is dispensable preimplantation but required in the epiblast to initiate gastrulation.\",\n \"evidence\": \"Zygotic, oocyte-specific, and visceral-endoderm-specific conditional knockouts with staged embryo analysis\",\n \"pmids\": [\"23760955\"],\n \"confidence\": \"High\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Which specific Wnt ligands drive gastrulation initiation not identified\"]\n },\n {\n \"year\": 2015,\n \"claim\": \"Confirmed PORCN inhibition blocks palmitoleation and secretion of all Wnts and identified RSPO3-translocated cancers as a sensitive class, translating the mechanism into a therapeutic stratification.\",\n \"evidence\": \"PORCN inhibitor (ETC-159) in RSPO3-translocated CRC patient-derived xenografts with secretion and transcriptome readouts\",\n \"pmids\": [\"26257057\"],\n \"confidence\": \"High\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Did not resolve the atomic basis of inhibitor action\"]\n },\n {\n \"year\": 2019,\n \"claim\": \"Established the catalytic selectivity of PORCN, showing its active site enforces the cis-Δ9 acyl species and that an incorrect acyl group traps Wnt–PORCN complexes, defining a release checkpoint.\",\n \"evidence\": \"Structurally diverse fatty-acyl donor analogs and cross-phylum PORCN expression in MEFs with complex-accumulation assays\",\n \"pmids\": [\"30737280\"],\n \"confidence\": \"High\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"No atomic structure of the acyl-binding tunnel at this stage\"]\n },\n {\n \"year\": 2020,\n \"claim\": \"Identified a non-Wnt activity in which PORCN physically interacts with AMPAR subunits and negatively regulates their surface trafficking and currents, broadening PORCN's functional scope.\",\n \"evidence\": \"Co-expression, Co-IP with domain-deletion mutants, surface biotinylation, and whole-cell patch-clamp in HEK293T\",\n \"pmids\": [\"32984326\"],\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Heterologous system only, no in vivo validation\", \"Whether the interaction requires PORCN catalytic activity not tested\"]\n },\n {\n \"year\": 2021,\n \"claim\": \"Resolved PORCN membrane architecture and a docking model for substrates and inhibitors, providing the first structure-based mechanism for palmitoleation and inhibition.\",\n \"evidence\": \"Experimental topology determination plus homology modeling to DltB/MBOAT family with functional mapping of FDH variants and in silico docking\",\n \"pmids\": [\"34186010\", \"34817055\"],\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"No experimental high-resolution structure in these studies\", \"Catalytic chemistry inferred from models rather than observed\"]\n },\n {\n \"year\": 2022,\n \"claim\": \"Extended PORCN's developmental roles to eye morphogenesis and revealed an ER-stress/secretion phenotype in patient cells beyond simple loss of Wnt palmitoylation.\",\n \"evidence\": \"Ubiquitous conditional Porcn knockout with proliferation/apoptosis/LEF1 readouts; patient-derived fibroblast ER-stress and secretion assays of the p.Asp283His mutant\",\n \"pmids\": [\"36393832\", \"35101074\"],\n \"confidence\": \"High\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Mechanism connecting PORCN mutation to general ER dysfunction (vs Wnt loss) not dissected\", \"Single-patient fibroblast observation\"]\n },\n {\n \"year\": 2023,\n \"claim\": \"Showed PORCN overexpression activates Wnt/β-catenin signaling and EMT in hepatocellular carcinoma, implicating PORCN gain-of-function in tumor progression.\",\n \"evidence\": \"PORCN overexpression in HCC cells with proliferation/migration assays, xenografts, and β-catenin subcellular fractionation\",\n \"pmids\": [\"37588740\"],\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"No catalytic-mutant control to confirm dependence on palmitoyltransferase activity\"]\n },\n {\n \"year\": 2025,\n \"claim\": \"Provided direct atomic-level mechanism of PORCN inhibition, showing diverse inhibitor scaffolds converge on the acyl-CoA binding site via a conserved active-site water network.\",\n \"evidence\": \"High-resolution cryo-EM of human PORCN with C59 and ETC-159 and in ligand-free state, with docking simulations (preprint)\",\n \"pmids\": [\"bio_10.1101_2025.05.19.654776\"],\n \"confidence\": \"High\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Structure of the catalytically engaged Wnt-substrate complex not captured\", \"Preprint, peer review pending\"]\n },\n {\n \"year\": null,\n \"claim\": \"The molecular basis of PORCN's apparent Wnt-independent functions (cancer-cell proliferation, AMPAR trafficking regulation, ER-stress vulnerability) remains unresolved.\",\n \"evidence\": \"\",\n \"pmids\": [],\n \"confidence\": \"Medium\",\n \"confidence_rationale\": \"\",\n \"gaps\": [\"Whether non-Wnt activities depend on PORCN catalytic activity is untested in vivo\", \"No structure of a Wnt-bound PORCN intermediate\", \"AMPAR regulation lacks physiological confirmation\"]\n }\n ],\n \"mechanism_profile\": {\n \"molecular_activity\": [\n {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 7, 8]},\n {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 7]},\n {\"term_id\": \"GO:0016747\", \"supporting_discovery_ids\": [0]}\n ],\n \"localization\": [\n {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2, 6, 9, 16]}\n ],\n \"pathway\": [\n {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3]},\n {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 11, 14]},\n {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 3]}\n ],\n \"complexes\": [],\n \"partners\": [\"WLS\", \"WNT3A\", \"WNT7A\", \"GRIA1\", \"GRIA2\", \"GRIA3\"],\n \"other_free_text\": []\n }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}