{"gene":"PRICKLE3","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2020,"finding":"PRICKLE3 physically interacts with ATP synthase via ATP8 subunit (co-immunoprecipitation), and the p.Arg53Trp mutation causes defective assembly, stability, and function of ATP synthase in mitochondria; PRICKLE3 knockdown recapitulates these defects, and Prickle3-knockout mice exhibit pronounced ATPase deficiencies and LHON-like retinal phenotypes.","method":"Co-immunoprecipitation, PRICKLE3 knockdown/knockout cells and mice, functional ATP synthase assembly assays, retinal ganglion cell degeneration phenotyping","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, knockdown, knockout mouse model with defined cellular phenotype, replicated in multiple family cohorts","pmids":["32516135"],"is_preprint":false},{"year":2016,"finding":"In Xenopus gastrocoel roof plate (GRP), Prickle3 is enriched at the basal body of GRP cells but is recruited by Vangl2 to anterior cell borders; Prickle3 loss-of-function disrupts anterior polarization of Vangl2, posterior cilia localization, and cilia growth, with γ-tubulin and Nedd1 no longer associating with the basal body; Prickle3 physically associates with Wtip (Wilms tumor protein 1-interacting protein), which cooperates with Pk3 to regulate ciliogenesis.","method":"Loss-of-function (morpholino knockdown), immunofluorescence imaging, co-immunoprecipitation (Pk3–Wtip interaction), live imaging","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP for binding partner, clean KD with defined cellular phenotypes (cilia, basal body, PCP), multiple orthogonal methods","pmids":["27062996"],"is_preprint":false},{"year":2016,"finding":"In Xenopus ectoderm, the Prickle3/Vangl2 complex is polarized to anterior cell edges; this polarity is disrupted by Wnt antagonists and redirected by ectopic Wnt5a, Wnt11, or Wnt11b sources, demonstrating that Wnt ligands provide instructive cues for Prickle3/Vangl2 complex orientation.","method":"Live imaging of fluorescent PCP protein fusions in Xenopus embryos, Wnt antagonist treatment, ectopic Wnt source transplantation, Wnt11b depletion","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple Wnt perturbations (gain and loss of function) with direct imaging of Prickle3/Vangl2 polarity readout","pmids":["27658614"],"is_preprint":false},{"year":2015,"finding":"Vangl2/Prickle3 protein complexes are enriched at the apical domain of intercalating multiciliated cells (MCCs) in Xenopus ectoderm and are essential for MCC intercalatory behavior; Vangl2 or Dishevelled loss-of-function caused tissues to contain more cell layers than normal, indicating a role for this complex in radial cell intercalation.","method":"Loss-of-function (morpholino), immunofluorescence, live imaging, genetic epistasis with KIF13B","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with defined intercalation phenotype, epistasis with KIF13B, replicated across multiple PCP components","pmids":["26079437"],"is_preprint":false},{"year":2018,"finding":"Par3 physically associates with Prickle3, promotes its apical localization in the Xenopus neural plate, and enhances formation of the anterior apical PCP complex (Vangl2/Prickle3); overexpression of a Prickle3-binding Par3 fragment disrupts PCP, and Par3 interference inhibits asymmetric PCP protein distribution and causes neural tube defects.","method":"Co-immunoprecipitation (Par3–Prickle3), proximity biotinylation assay in Xenopus embryos, dominant-negative overexpression, live imaging","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, proximity biotinylation, dominant-negative phenotype, multiple orthogonal methods in a single study","pmids":["30256191"],"is_preprint":false},{"year":2021,"finding":"Frizzled3 (Fz3) inhibits Vangl2–Prickle3 association in vivo through Fz3-dependent Vangl2 phosphorylation; a nonphosphorylatable Vangl2 mutant forms a complex with Prickle3 that fails to polarize in the neural plate, establishing that Frizzled3-mediated phosphorylation of Vangl2 regulates Vangl2–Prickle3 complex formation and localization.","method":"Proximity biotinylation, chemical crosslinking, phospho-mutant Vangl2 analysis, loss-of-function in Xenopus neural plate","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — proximity biotinylation + crosslinking + phospho-mutant epistasis, multiple orthogonal approaches in one study","pmids":["34806749"],"is_preprint":false},{"year":2021,"finding":"PCP is progressively acquired in the Xenopus neural plate and requires a planar cue from the dorsal blastopore lip, as demonstrated by imaging of Vangl2 and Prickle3 polarity following tissue transplantations; PCP is not instructed by a preexisting egg polarity gradient.","method":"Tissue transplantation, live imaging of Vangl2/Prickle3 fluorescent fusions in Xenopus embryos","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 — tissue transplantation epistasis with direct PCP protein imaging, single lab","pmids":["34259326"],"is_preprint":false},{"year":2025,"finding":"PRICKLE3 localizes at the plasma membrane and associates with VANGL1 and VANGL2 (core WNT/PCP proteins); it selectively stabilizes VANGL1/2 by protecting them from Casein kinase 1ε (CK1ε)-mediated phosphorylation, and modulates an interaction network involving VANGL1/2, CK1ε, and ubiquitin ligase RNF43 to reduce VANGL ubiquitination and increase VANGL accumulation at the plasma membrane; these effects are specific to PRICKLE3 and not shared by PRICKLE1.","method":"Enhanced proximity biotinylation (miniTurboID) + mass spectrometry, immunoblotting, live imaging, functional stability assays, inducible expression system in human cells and Xenopus/zebrafish embryos","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1–2 — proximity biotinylation + MS interactome + biochemical stability assays + live imaging + in vivo validation, multiple orthogonal methods in one rigorous study","pmids":["41455754"],"is_preprint":false},{"year":2025,"finding":"PRICKLE3 interacts with USP9X and DVL2; PRICKLE3–DVL2 interaction enhances β-catenin phosphorylation at serine 675 for β-catenin nuclear translocation; PRICKLE3 interacts with USP9X to inhibit DVL2 ubiquitination, thereby stabilizing DVL2 and activating canonical WNT signaling to promote NSCLC progression.","method":"Co-immunoprecipitation (PRICKLE3–USP9X–DVL2), PRICKLE3 overexpression/knockout cells, in vivo tumor models, ubiquitination assays, β-catenin reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP of multi-protein complex, KO/OE with defined pathway readout, ubiquitination assay; single lab","pmids":["40973792"],"is_preprint":false},{"year":2023,"finding":"PRICKLE3 p.Arg53Trp mutation, when combined with mitochondrial ND4 11778G>A mutation in patient-derived iPSC-differentiated retinal ganglion cells, causes greater defects in RGC morphology, electrophysiology, ATP content, and apoptosis than either single mutation alone, confirming the synergistic interaction between PRICKLE3 (ATPase biogenesis) and complex I dysfunction.","method":"iPSC differentiation to RGC-like cells, electrophysiology, ATP content measurement, apoptosis assays, morphological quantification","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — patient-derived iPSC model with defined functional readouts; single lab, replicates mechanism from prior study (PMID 32516135)","pmids":["35947995"],"is_preprint":false},{"year":2026,"finding":"SPEM2 interacts with VANGL2, PRICKLE3, and DVL3 (co-immunoprecipitation) to maintain spermiation and cell polarity; the transmembrane region of SPEM2 is the key domain for binding VANGL2, placing PRICKLE3 in a PCP complex required for sperm head morphology and cytoplasmic removal during spermatid release.","method":"Co-immunoprecipitation, domain-deletion analysis (transmembrane region), Spem2-knockout mice with defined spermiation defects","journal":"Biology of reproduction","confidence":"Low","confidence_rationale":"Tier 3 — single Co-IP identifying PRICKLE3 as binding partner; PRICKLE3-specific functional role not directly tested","pmids":["42028965"],"is_preprint":false}],"current_model":"PRICKLE3 is a multifunctional scaffold protein that (1) in mitochondria directly interacts with ATP synthase via the ATP8 subunit to support ATPase assembly and stability (loss of function causing LHON-related mitochondrial dysfunction); (2) in the WNT/PCP pathway localizes to the plasma membrane where it forms complexes with VANGL1/2, protecting them from CK1ε-mediated phosphorylation and RNF43-mediated ubiquitination to stabilize VANGL proteins at the cell surface; (3) partners with Par3 for apical localization of Vangl2/Prickle3 complexes at anterior cell boundaries in the neural plate, with Frizzled3-dependent Vangl2 phosphorylation regulating the Vangl2–Prickle3 interaction; (4) regulates basal body organization and ciliogenesis via physical interaction with Wtip; and (5) in cancer cells interacts with USP9X and DVL2 to promote DVL2 deubiquitination, β-catenin nuclear translocation, and canonical WNT pathway activation."},"narrative":{"teleology":[{"year":2015,"claim":"Establishing that Vangl2/Prickle3 complexes localize apically in intercalating cells and are required for radial intercalation resolved the question of whether Prickle3 plays a functional role in PCP-driven morphogenesis beyond simple polarity readout.","evidence":"Morpholino loss-of-function, immunofluorescence, and live imaging of multiciliated cell intercalation in Xenopus ectoderm","pmids":["26079437"],"confidence":"High","gaps":["Mechanism by which the Vangl2/Prickle3 complex drives intercalation not defined","Direct binding interface between Vangl2 and Prickle3 uncharacterized"]},{"year":2016,"claim":"Demonstrating that Prickle3 localizes to the basal body, interacts with Wtip, and is required for basal body-associated γ-tubulin/Nedd1 recruitment and ciliogenesis established a cilia-organizing function for Prickle3 beyond classical PCP.","evidence":"Co-immunoprecipitation (Pk3–Wtip), morpholino knockdown, immunofluorescence, and live imaging in Xenopus GRP cells","pmids":["27062996"],"confidence":"High","gaps":["Whether Wtip is a direct or indirect binding partner is not resolved by reciprocal assay","Mechanism linking Prickle3 to γ-tubulin recruitment unknown"]},{"year":2016,"claim":"Showing that Wnt ligands (Wnt5a, Wnt11, Wnt11b) provide instructive directional cues that orient the Prickle3/Vangl2 complex answered whether Prickle3 polarity is cell-autonomously determined or externally directed.","evidence":"Ectopic Wnt source transplantation, Wnt antagonist treatment, and live imaging of fluorescent PCP fusions in Xenopus ectoderm","pmids":["27658614"],"confidence":"High","gaps":["Receptor-level mechanism transducing the Wnt cue to Prickle3/Vangl2 not identified","Whether the same instructive mechanism operates in mammalian tissues untested"]},{"year":2018,"claim":"Identifying Par3 as a physical partner that promotes apical localization of Prickle3 and thereby the anterior Vangl2/Prickle3 complex linked apical-basal polarity machinery to planar polarity establishment.","evidence":"Reciprocal Co-IP, proximity biotinylation, dominant-negative overexpression, and neural tube phenotyping in Xenopus","pmids":["30256191"],"confidence":"High","gaps":["Structural basis of Par3–Prickle3 interaction unknown","Whether Par3 similarly regulates Prickle1 or Prickle2 localization untested"]},{"year":2020,"claim":"Discovering that PRICKLE3 interacts with ATP synthase via ATP8 and that loss-of-function causes ATPase assembly defects and LHON-like retinal degeneration revealed an unexpected mitochondrial role for a PCP protein and established PRICKLE3 as a modifier gene for Leber hereditary optic neuropathy.","evidence":"Co-immunoprecipitation, PRICKLE3 knockdown/knockout cells and mice, ATP synthase assembly assays, retinal ganglion cell phenotyping across multiple LHON pedigrees","pmids":["32516135"],"confidence":"High","gaps":["How PRICKLE3 accesses mitochondria (import mechanism) not determined","Whether PRICKLE3 affects other OXPHOS complexes not tested","Structural details of PRICKLE3–ATP8 interaction absent"]},{"year":2021,"claim":"Demonstrating that Frizzled3-dependent phosphorylation of Vangl2 inhibits Vangl2–Prickle3 complex formation established a molecular switch controlling PCP complex assembly and explained how Frizzled and Vangl/Prickle complexes are sorted to opposite cell faces.","evidence":"Proximity biotinylation, chemical crosslinking, phospho-mutant Vangl2 analysis in Xenopus neural plate","pmids":["34806749"],"confidence":"High","gaps":["Specific phosphorylation sites on Vangl2 that regulate Prickle3 binding not mapped at residue level","Whether this mechanism is conserved in mammals not directly shown"]},{"year":2023,"claim":"Confirming synergistic pathogenicity of PRICKLE3 p.Arg53Trp with mitochondrial ND4 11778G>A in patient-derived iPSC retinal ganglion cells validated the two-hit model for LHON penetrance involving nuclear PRICKLE3 and mitochondrial complex I mutations.","evidence":"iPSC differentiation to RGC-like cells, electrophysiology, ATP content, and apoptosis assays","pmids":["35947995"],"confidence":"Medium","gaps":["Single lab replication of original finding","Therapeutic rescue of PRICKLE3-related mitochondrial defect not attempted"]},{"year":2025,"claim":"Defining PRICKLE3's mechanism at the plasma membrane — protecting VANGL1/2 from CK1ε phosphorylation and RNF43-mediated ubiquitination — resolved how PRICKLE3 specifically stabilizes VANGL proteins and distinguished its function from PRICKLE1.","evidence":"MiniTurboID proximity biotinylation/mass spectrometry, stability assays, live imaging in human cells, Xenopus and zebrafish embryos","pmids":["41455754"],"confidence":"High","gaps":["Whether PRICKLE3 directly contacts RNF43 or acts indirectly through CK1ε shielding unclear","Stoichiometry of the PRICKLE3–VANGL–CK1ε complex not determined"]},{"year":2025,"claim":"Showing that PRICKLE3 recruits USP9X to deubiquitinate DVL2 and activate canonical WNT/β-catenin signaling in NSCLC revealed an oncogenic function through a non-PCP WNT branch.","evidence":"Co-immunoprecipitation (PRICKLE3–USP9X–DVL2), knockout/overexpression, in vivo tumor models, ubiquitination and β-catenin reporter assays","pmids":["40973792"],"confidence":"Medium","gaps":["Single lab; canonical WNT activation role not independently replicated","Whether this function is cancer-specific or operates in normal tissues unknown","Direct versus bridged interaction between PRICKLE3 and USP9X not resolved"]},{"year":null,"claim":"How PRICKLE3 is dually targeted to mitochondria and the plasma membrane, and whether its PCP and mitochondrial functions are coordinated or independent, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No mitochondrial targeting sequence or import pathway identified","No structural model for any PRICKLE3 complex exists","Tissue-specific balance between PCP and mitochondrial roles unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,4,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,9]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,5,7,8]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1]}],"complexes":["Vangl2/Prickle3 anterior PCP complex","PRICKLE3–ATP synthase (via ATP8)"],"partners":["VANGL2","VANGL1","ATP8","DVL2","USP9X","PARD3","WTIP","RNF43"],"other_free_text":[]},"mechanistic_narrative":"PRICKLE3 is a planar cell polarity (PCP) scaffold protein that functions in both WNT/PCP signaling and mitochondrial ATP synthase biogenesis. In the WNT/PCP pathway, PRICKLE3 forms asymmetric complexes with VANGL1/2 at anterior cell boundaries, where it stabilizes VANGL proteins at the plasma membrane by shielding them from CK1ε-mediated phosphorylation and RNF43-mediated ubiquitination; this complex formation is regulated by Frizzled3-dependent Vangl2 phosphorylation and requires Par3-mediated apical targeting [PMID:41455754, PMID:34806749, PMID:30256191]. PRICKLE3 also interacts with the ATP8 subunit of mitochondrial ATP synthase, and loss-of-function mutations (notably p.Arg53Trp) cause defective ATPase assembly and stability, leading to Leber hereditary optic neuropathy-like retinal ganglion cell degeneration that is synergistically worsened by mitochondrial complex I mutations [PMID:32516135, PMID:35947995]. Additionally, PRICKLE3 associates with Wtip at the basal body to regulate ciliogenesis and basal body organization, and in cancer cells it recruits USP9X to deubiquitinate DVL2, thereby activating canonical WNT/β-catenin signaling [PMID:27062996, PMID:40973792]."},"prefetch_data":{"uniprot":{"accession":"O43900","full_name":"Prickle planar cell polarity protein 3","aliases":["LIM domain only protein 6","LMO-6","Prickle-like protein 3","Pk3","Triple LIM domain protein 6"],"length_aa":615,"mass_kda":68.6,"function":"Involved in the planar cell polarity (PCP) pathway that is essential for the polarization of epithelial cells during morphogenetic processes, including gastrulation and neurulation (By similarity). PCP is maintained by two molecular modules, the global and the core modules, PRICKLE3 being part of the core module (By similarity). Distinct complexes of the core module segregate to opposite sides of the cell, where they interact with the opposite complex in the neighboring cell at or near the adherents junctions (By similarity). Involved in the organization of the basal body (By similarity). Involved in cilia growth and positioning (By similarity). Required for proper assembly, stability, and function of mitochondrial membrane ATP synthase (mitochondrial complex V) (PubMed:32516135)","subcellular_location":"Cytoplasm; Cell membrane; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/O43900/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRICKLE3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRICKLE3","total_profiled":1310},"omim":[{"mim_id":"535000","title":"LEBER OPTIC ATROPHY","url":"https://www.omim.org/entry/535000"},{"mim_id":"516003","title":"COMPLEX I, SUBUNIT ND4; MTND4","url":"https://www.omim.org/entry/516003"},{"mim_id":"308905","title":"LEBER HEREDITARY OPTIC NEUROPATHY, MODIFIER OF; LOAM","url":"https://www.omim.org/entry/308905"},{"mim_id":"300111","title":"PRICKLE PLANAR CELL POLARITY PROTEIN 3; PRICKLE3","url":"https://www.omim.org/entry/300111"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRICKLE3"},"hgnc":{"alias_symbol":[],"prev_symbol":["LMO6"]},"alphafold":{"accession":"O43900","domains":[{"cath_id":"2.10.110.10","chopping":"93-249","consensus_level":"high","plddt":92.7936,"start":93,"end":249},{"cath_id":"2.10.110.10","chopping":"309-368","consensus_level":"medium","plddt":92.1128,"start":309,"end":368}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43900","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43900-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43900-F1-predicted_aligned_error_v6.png","plddt_mean":67.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRICKLE3","jax_strain_url":"https://www.jax.org/strain/search?query=PRICKLE3"},"sequence":{"accession":"O43900","fasta_url":"https://rest.uniprot.org/uniprotkb/O43900.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43900/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43900"}},"corpus_meta":[{"pmid":"12525887","id":"PMC_12525887","title":"Identification and characterization of human PRICKLE1 and PRICKLE2 genes as well as mouse Prickle1 and Prickle2 genes homologous to Drosophila tissue polarity gene prickle.","date":"2003","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/12525887","citation_count":159,"is_preprint":false},{"pmid":"27658614","id":"PMC_27658614","title":"Wnt proteins can direct planar cell polarity in vertebrate ectoderm.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27658614","citation_count":63,"is_preprint":false},{"pmid":"32516135","id":"PMC_32516135","title":"PRICKLE3 linked to ATPase biogenesis manifested Leber's hereditary optic neuropathy.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/32516135","citation_count":57,"is_preprint":false},{"pmid":"26079437","id":"PMC_26079437","title":"The involvement of PCP proteins in radial cell intercalations during Xenopus embryonic 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with Wtip to regulate basal body organization and cilia growth.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27062996","citation_count":31,"is_preprint":false},{"pmid":"35947995","id":"PMC_35947995","title":"Abnormal morphology and function in retinal ganglion cells derived from patients-specific iPSCs generated from individuals with Leber's hereditary optic neuropathy.","date":"2023","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35947995","citation_count":15,"is_preprint":false},{"pmid":"34806749","id":"PMC_34806749","title":"Frizzled3 inhibits Vangl2-Prickle3 association to establish planar cell polarity in the vertebrate neural plate.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34806749","citation_count":13,"is_preprint":false},{"pmid":"32019073","id":"PMC_32019073","title":"Diversity and Host Interactions Among Virulent and Temperate Baltic Sea Flavobacterium 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CK1-mediated phosphorylation and RNF43-mediated degradation.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41455754","citation_count":0,"is_preprint":false},{"pmid":"42028965","id":"PMC_42028965","title":"SPEM2 deficiency disrupts spermiation leading to oligoasthenoteratozoospermia and male infertility†.","date":"2026","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/42028965","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.24.644882","title":"Armed with PRICKLE(3)s: Stabilizing WNT/PCP complexes against RNF43-mediated ubiquitination","date":"2025-03-25","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.24.644882","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12269,"output_tokens":3116,"usd":0.041773},"stage2":{"model":"claude-opus-4-6","input_tokens":6502,"output_tokens":2771,"usd":0.152677},"total_usd":0.19445,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"PRICKLE3 physically interacts with ATP synthase via ATP8 subunit (co-immunoprecipitation), and the p.Arg53Trp mutation causes defective assembly, stability, and function of ATP synthase in mitochondria; PRICKLE3 knockdown recapitulates these defects, and Prickle3-knockout mice exhibit pronounced ATPase deficiencies and LHON-like retinal phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, PRICKLE3 knockdown/knockout cells and mice, functional ATP synthase assembly assays, retinal ganglion cell degeneration phenotyping\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, knockdown, knockout mouse model with defined cellular phenotype, replicated in multiple family cohorts\",\n      \"pmids\": [\"32516135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Xenopus gastrocoel roof plate (GRP), Prickle3 is enriched at the basal body of GRP cells but is recruited by Vangl2 to anterior cell borders; Prickle3 loss-of-function disrupts anterior polarization of Vangl2, posterior cilia localization, and cilia growth, with γ-tubulin and Nedd1 no longer associating with the basal body; Prickle3 physically associates with Wtip (Wilms tumor protein 1-interacting protein), which cooperates with Pk3 to regulate ciliogenesis.\",\n      \"method\": \"Loss-of-function (morpholino knockdown), immunofluorescence imaging, co-immunoprecipitation (Pk3–Wtip interaction), live imaging\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for binding partner, clean KD with defined cellular phenotypes (cilia, basal body, PCP), multiple orthogonal methods\",\n      \"pmids\": [\"27062996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Xenopus ectoderm, the Prickle3/Vangl2 complex is polarized to anterior cell edges; this polarity is disrupted by Wnt antagonists and redirected by ectopic Wnt5a, Wnt11, or Wnt11b sources, demonstrating that Wnt ligands provide instructive cues for Prickle3/Vangl2 complex orientation.\",\n      \"method\": \"Live imaging of fluorescent PCP protein fusions in Xenopus embryos, Wnt antagonist treatment, ectopic Wnt source transplantation, Wnt11b depletion\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple Wnt perturbations (gain and loss of function) with direct imaging of Prickle3/Vangl2 polarity readout\",\n      \"pmids\": [\"27658614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Vangl2/Prickle3 protein complexes are enriched at the apical domain of intercalating multiciliated cells (MCCs) in Xenopus ectoderm and are essential for MCC intercalatory behavior; Vangl2 or Dishevelled loss-of-function caused tissues to contain more cell layers than normal, indicating a role for this complex in radial cell intercalation.\",\n      \"method\": \"Loss-of-function (morpholino), immunofluorescence, live imaging, genetic epistasis with KIF13B\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined intercalation phenotype, epistasis with KIF13B, replicated across multiple PCP components\",\n      \"pmids\": [\"26079437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Par3 physically associates with Prickle3, promotes its apical localization in the Xenopus neural plate, and enhances formation of the anterior apical PCP complex (Vangl2/Prickle3); overexpression of a Prickle3-binding Par3 fragment disrupts PCP, and Par3 interference inhibits asymmetric PCP protein distribution and causes neural tube defects.\",\n      \"method\": \"Co-immunoprecipitation (Par3–Prickle3), proximity biotinylation assay in Xenopus embryos, dominant-negative overexpression, live imaging\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, proximity biotinylation, dominant-negative phenotype, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"30256191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Frizzled3 (Fz3) inhibits Vangl2–Prickle3 association in vivo through Fz3-dependent Vangl2 phosphorylation; a nonphosphorylatable Vangl2 mutant forms a complex with Prickle3 that fails to polarize in the neural plate, establishing that Frizzled3-mediated phosphorylation of Vangl2 regulates Vangl2–Prickle3 complex formation and localization.\",\n      \"method\": \"Proximity biotinylation, chemical crosslinking, phospho-mutant Vangl2 analysis, loss-of-function in Xenopus neural plate\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — proximity biotinylation + crosslinking + phospho-mutant epistasis, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"34806749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PCP is progressively acquired in the Xenopus neural plate and requires a planar cue from the dorsal blastopore lip, as demonstrated by imaging of Vangl2 and Prickle3 polarity following tissue transplantations; PCP is not instructed by a preexisting egg polarity gradient.\",\n      \"method\": \"Tissue transplantation, live imaging of Vangl2/Prickle3 fluorescent fusions in Xenopus embryos\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue transplantation epistasis with direct PCP protein imaging, single lab\",\n      \"pmids\": [\"34259326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRICKLE3 localizes at the plasma membrane and associates with VANGL1 and VANGL2 (core WNT/PCP proteins); it selectively stabilizes VANGL1/2 by protecting them from Casein kinase 1ε (CK1ε)-mediated phosphorylation, and modulates an interaction network involving VANGL1/2, CK1ε, and ubiquitin ligase RNF43 to reduce VANGL ubiquitination and increase VANGL accumulation at the plasma membrane; these effects are specific to PRICKLE3 and not shared by PRICKLE1.\",\n      \"method\": \"Enhanced proximity biotinylation (miniTurboID) + mass spectrometry, immunoblotting, live imaging, functional stability assays, inducible expression system in human cells and Xenopus/zebrafish embryos\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — proximity biotinylation + MS interactome + biochemical stability assays + live imaging + in vivo validation, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"41455754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRICKLE3 interacts with USP9X and DVL2; PRICKLE3–DVL2 interaction enhances β-catenin phosphorylation at serine 675 for β-catenin nuclear translocation; PRICKLE3 interacts with USP9X to inhibit DVL2 ubiquitination, thereby stabilizing DVL2 and activating canonical WNT signaling to promote NSCLC progression.\",\n      \"method\": \"Co-immunoprecipitation (PRICKLE3–USP9X–DVL2), PRICKLE3 overexpression/knockout cells, in vivo tumor models, ubiquitination assays, β-catenin reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP of multi-protein complex, KO/OE with defined pathway readout, ubiquitination assay; single lab\",\n      \"pmids\": [\"40973792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRICKLE3 p.Arg53Trp mutation, when combined with mitochondrial ND4 11778G>A mutation in patient-derived iPSC-differentiated retinal ganglion cells, causes greater defects in RGC morphology, electrophysiology, ATP content, and apoptosis than either single mutation alone, confirming the synergistic interaction between PRICKLE3 (ATPase biogenesis) and complex I dysfunction.\",\n      \"method\": \"iPSC differentiation to RGC-like cells, electrophysiology, ATP content measurement, apoptosis assays, morphological quantification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived iPSC model with defined functional readouts; single lab, replicates mechanism from prior study (PMID 32516135)\",\n      \"pmids\": [\"35947995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SPEM2 interacts with VANGL2, PRICKLE3, and DVL3 (co-immunoprecipitation) to maintain spermiation and cell polarity; the transmembrane region of SPEM2 is the key domain for binding VANGL2, placing PRICKLE3 in a PCP complex required for sperm head morphology and cytoplasmic removal during spermatid release.\",\n      \"method\": \"Co-immunoprecipitation, domain-deletion analysis (transmembrane region), Spem2-knockout mice with defined spermiation defects\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP identifying PRICKLE3 as binding partner; PRICKLE3-specific functional role not directly tested\",\n      \"pmids\": [\"42028965\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRICKLE3 is a multifunctional scaffold protein that (1) in mitochondria directly interacts with ATP synthase via the ATP8 subunit to support ATPase assembly and stability (loss of function causing LHON-related mitochondrial dysfunction); (2) in the WNT/PCP pathway localizes to the plasma membrane where it forms complexes with VANGL1/2, protecting them from CK1ε-mediated phosphorylation and RNF43-mediated ubiquitination to stabilize VANGL proteins at the cell surface; (3) partners with Par3 for apical localization of Vangl2/Prickle3 complexes at anterior cell boundaries in the neural plate, with Frizzled3-dependent Vangl2 phosphorylation regulating the Vangl2–Prickle3 interaction; (4) regulates basal body organization and ciliogenesis via physical interaction with Wtip; and (5) in cancer cells interacts with USP9X and DVL2 to promote DVL2 deubiquitination, β-catenin nuclear translocation, and canonical WNT pathway activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PRICKLE3 is a planar cell polarity (PCP) scaffold protein that functions in both WNT/PCP signaling and mitochondrial ATP synthase biogenesis. In the WNT/PCP pathway, PRICKLE3 forms asymmetric complexes with VANGL1/2 at anterior cell boundaries, where it stabilizes VANGL proteins at the plasma membrane by shielding them from CK1ε-mediated phosphorylation and RNF43-mediated ubiquitination; this complex formation is regulated by Frizzled3-dependent Vangl2 phosphorylation and requires Par3-mediated apical targeting [PMID:41455754, PMID:34806749, PMID:30256191]. PRICKLE3 also interacts with the ATP8 subunit of mitochondrial ATP synthase, and loss-of-function mutations (notably p.Arg53Trp) cause defective ATPase assembly and stability, leading to Leber hereditary optic neuropathy-like retinal ganglion cell degeneration that is synergistically worsened by mitochondrial complex I mutations [PMID:32516135, PMID:35947995]. Additionally, PRICKLE3 associates with Wtip at the basal body to regulate ciliogenesis and basal body organization, and in cancer cells it recruits USP9X to deubiquitinate DVL2, thereby activating canonical WNT/β-catenin signaling [PMID:27062996, PMID:40973792].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that Vangl2/Prickle3 complexes localize apically in intercalating cells and are required for radial intercalation resolved the question of whether Prickle3 plays a functional role in PCP-driven morphogenesis beyond simple polarity readout.\",\n      \"evidence\": \"Morpholino loss-of-function, immunofluorescence, and live imaging of multiciliated cell intercalation in Xenopus ectoderm\",\n      \"pmids\": [\"26079437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the Vangl2/Prickle3 complex drives intercalation not defined\", \"Direct binding interface between Vangl2 and Prickle3 uncharacterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that Prickle3 localizes to the basal body, interacts with Wtip, and is required for basal body-associated γ-tubulin/Nedd1 recruitment and ciliogenesis established a cilia-organizing function for Prickle3 beyond classical PCP.\",\n      \"evidence\": \"Co-immunoprecipitation (Pk3–Wtip), morpholino knockdown, immunofluorescence, and live imaging in Xenopus GRP cells\",\n      \"pmids\": [\"27062996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Wtip is a direct or indirect binding partner is not resolved by reciprocal assay\", \"Mechanism linking Prickle3 to γ-tubulin recruitment unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing that Wnt ligands (Wnt5a, Wnt11, Wnt11b) provide instructive directional cues that orient the Prickle3/Vangl2 complex answered whether Prickle3 polarity is cell-autonomously determined or externally directed.\",\n      \"evidence\": \"Ectopic Wnt source transplantation, Wnt antagonist treatment, and live imaging of fluorescent PCP fusions in Xenopus ectoderm\",\n      \"pmids\": [\"27658614\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor-level mechanism transducing the Wnt cue to Prickle3/Vangl2 not identified\", \"Whether the same instructive mechanism operates in mammalian tissues untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying Par3 as a physical partner that promotes apical localization of Prickle3 and thereby the anterior Vangl2/Prickle3 complex linked apical-basal polarity machinery to planar polarity establishment.\",\n      \"evidence\": \"Reciprocal Co-IP, proximity biotinylation, dominant-negative overexpression, and neural tube phenotyping in Xenopus\",\n      \"pmids\": [\"30256191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Par3–Prickle3 interaction unknown\", \"Whether Par3 similarly regulates Prickle1 or Prickle2 localization untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovering that PRICKLE3 interacts with ATP synthase via ATP8 and that loss-of-function causes ATPase assembly defects and LHON-like retinal degeneration revealed an unexpected mitochondrial role for a PCP protein and established PRICKLE3 as a modifier gene for Leber hereditary optic neuropathy.\",\n      \"evidence\": \"Co-immunoprecipitation, PRICKLE3 knockdown/knockout cells and mice, ATP synthase assembly assays, retinal ganglion cell phenotyping across multiple LHON pedigrees\",\n      \"pmids\": [\"32516135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PRICKLE3 accesses mitochondria (import mechanism) not determined\", \"Whether PRICKLE3 affects other OXPHOS complexes not tested\", \"Structural details of PRICKLE3–ATP8 interaction absent\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrating that Frizzled3-dependent phosphorylation of Vangl2 inhibits Vangl2–Prickle3 complex formation established a molecular switch controlling PCP complex assembly and explained how Frizzled and Vangl/Prickle complexes are sorted to opposite cell faces.\",\n      \"evidence\": \"Proximity biotinylation, chemical crosslinking, phospho-mutant Vangl2 analysis in Xenopus neural plate\",\n      \"pmids\": [\"34806749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation sites on Vangl2 that regulate Prickle3 binding not mapped at residue level\", \"Whether this mechanism is conserved in mammals not directly shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirming synergistic pathogenicity of PRICKLE3 p.Arg53Trp with mitochondrial ND4 11778G>A in patient-derived iPSC retinal ganglion cells validated the two-hit model for LHON penetrance involving nuclear PRICKLE3 and mitochondrial complex I mutations.\",\n      \"evidence\": \"iPSC differentiation to RGC-like cells, electrophysiology, ATP content, and apoptosis assays\",\n      \"pmids\": [\"35947995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab replication of original finding\", \"Therapeutic rescue of PRICKLE3-related mitochondrial defect not attempted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining PRICKLE3's mechanism at the plasma membrane — protecting VANGL1/2 from CK1ε phosphorylation and RNF43-mediated ubiquitination — resolved how PRICKLE3 specifically stabilizes VANGL proteins and distinguished its function from PRICKLE1.\",\n      \"evidence\": \"MiniTurboID proximity biotinylation/mass spectrometry, stability assays, live imaging in human cells, Xenopus and zebrafish embryos\",\n      \"pmids\": [\"41455754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRICKLE3 directly contacts RNF43 or acts indirectly through CK1ε shielding unclear\", \"Stoichiometry of the PRICKLE3–VANGL–CK1ε complex not determined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that PRICKLE3 recruits USP9X to deubiquitinate DVL2 and activate canonical WNT/β-catenin signaling in NSCLC revealed an oncogenic function through a non-PCP WNT branch.\",\n      \"evidence\": \"Co-immunoprecipitation (PRICKLE3–USP9X–DVL2), knockout/overexpression, in vivo tumor models, ubiquitination and β-catenin reporter assays\",\n      \"pmids\": [\"40973792\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; canonical WNT activation role not independently replicated\", \"Whether this function is cancer-specific or operates in normal tissues unknown\", \"Direct versus bridged interaction between PRICKLE3 and USP9X not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRICKLE3 is dually targeted to mitochondria and the plasma membrane, and whether its PCP and mitochondrial functions are coordinated or independent, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mitochondrial targeting sequence or import pathway identified\", \"No structural model for any PRICKLE3 complex exists\", \"Tissue-specific balance between PCP and mitochondrial roles unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 4, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\n      \"Vangl2/Prickle3 anterior PCP complex\",\n      \"PRICKLE3–ATP synthase (via ATP8)\"\n    ],\n    \"partners\": [\n      \"VANGL2\",\n      \"VANGL1\",\n      \"ATP8\",\n      \"DVL2\",\n      \"USP9X\",\n      \"PARD3\",\n      \"WTIP\",\n      \"RNF43\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}