{"gene":"PRICKLE1","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2008,"finding":"A missense mutation in PRICKLE1 (R104Q) blocks the PRICKLE1–REST interaction in vitro, identifying REST as a direct binding partner of PRICKLE1 and placing PRICKLE1 in the noncanonical WNT signaling pathway as the first member directly implicated in human epilepsy.","method":"In vitro protein interaction assay (blocking of PRICKLE1–REST interaction); zebrafish overexpression functional assay","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro interaction assay plus in vivo zebrafish functional validation, single lab","pmids":["18976727"],"is_preprint":false},{"year":2006,"finding":"PRICKLE1 binds Dishevelled3 (DVL3) and promotes its ubiquitination and proteasomal degradation through destruction-box (D-box) motifs on PRICKLE1, thereby negatively regulating the WNT/β-catenin pathway in hepatocellular carcinoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, enforced expression/knockdown with β-catenin reporter assay, D-box motif mutagenesis","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reciprocal Co-IP, ubiquitination assay, mutagenesis of D-box, functional reporter assay, single lab with multiple orthogonal methods","pmids":["17030191"],"is_preprint":false},{"year":2009,"finding":"Mouse Prickle1 (mpk1) is essential for apical-basal polarity of the epiblast; loss of mpk1 causes abnormal cell shapes, mislocalized ECM proteins, and disrupted mitotic spindle orientation. Genetic interaction with Vangl2 (another core PCP gene) was demonstrated, placing Prickle1 downstream in the PCP pathway for epiblast polarity. Dominant-negative ΔPK/LIM construct in Xenopus disrupted apical marker PKCζ localization, confirming a direct role in cortical polarity.","method":"Conditional knockout mice, genetic epistasis with Vangl2, Xenopus dominant-negative overexpression with apical marker (PKCζ) imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function knockout with cellular phenotype, genetic epistasis, and cross-species dominant-negative validation","pmids":["19706528"],"is_preprint":false},{"year":2016,"finding":"PRICKLE1 forms a complex with MINK1 (serine/threonine kinase) and RICTOR (an mTORC2 component); integrity of this PRICKLE1–MINK1–RICTOR complex is required for AKT activation, focal adhesion regulation, and cancer cell migration/dissemination. Disruption of the PRICKLE1–RICTOR interaction strongly impairs breast cancer cell dissemination in xenograft assays.","method":"Co-immunoprecipitation, proximity ligation, xenograft in vivo dissemination assay, focal adhesion imaging","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vivo xenograft functional validation, focal adhesion readout; single lab with multiple orthogonal methods","pmids":["27184734"],"is_preprint":false},{"year":2016,"finding":"PRICKLE1 accumulates at cell retraction sites near focal adhesions, where it promotes focal adhesion disassembly by associating with CLASP1/2 and LL5β (PHLDB2) and enabling LL5β-dependent accumulation of CLASPs at the cell edge to drive microtubule targeting of focal adhesions. Membrane localization via a farnesyl moiety is required for these functions.","method":"Live-cell imaging (TIRF/FRAP), co-immunoprecipitation, siRNA knockdown with focal adhesion turnover assay, farnesylation mutant analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, live imaging correlating dynamics, loss-of-function KD, farnesylation mutant; single lab with multiple orthogonal methods","pmids":["27378169"],"is_preprint":false},{"year":2013,"finding":"PRICKLE1 physically interacts with SYNAPSIN I (SYN1) in neurons, co-localizing with endogenous Syn1. The interaction is through the SYN1 region mutated in ASD and epilepsy. A PRICKLE1 mutation disrupts its ability to increase the size of dense-core vesicles in PC12 cells, implicating PRICKLE1 in synaptic vesicle regulation.","method":"Yeast two-hybrid screen (human brain cDNA library), co-immunoprecipitation/co-localization in neurons, dense-core vesicle size assay in PC12 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — yeast two-hybrid plus neuronal co-localization plus functional vesicle assay; single lab","pmids":["24312498"],"is_preprint":false},{"year":2014,"finding":"Prickle1 is a proteasomal target of WNT5A signaling in mice; complete Prickle1 loss leads to misregulation of DVL2 (a WNT5A target), and Prickle1 mutants phenocopy Wnt5a and Ror2 mutants, placing Prickle1 downstream of WNT5A-ROR2 in the noncanonical WNT pathway.","method":"Multiple Prickle1 mutant alleles in mice, epistasis with Wnt5a/Ror2 mutants, proteasome inhibitor experiments to assess Prickle1 degradation, immunostaining of DVL2","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis across multiple alleles, proteasome assay, DVL2 misregulation; single lab","pmids":["25190059"],"is_preprint":false},{"year":2012,"finding":"Prickle1 associates with Dishevelled1 (DVL1), and overexpression of Prickle1 reduces DVL1 protein levels; overexpression of DVL1 blocks Prickle1-induced neurite-like process formation, demonstrating that Prickle1 promotes neurite outgrowth via a DVL1-dependent mechanism.","method":"Co-immunoprecipitation, overexpression and knockdown in C1300 neuroblastoma cells, neurite outgrowth assay","journal":"Methods in molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and epistasis in cell line with functional readout; single lab","pmids":["22218901"],"is_preprint":false},{"year":2022,"finding":"In Xenopus prechordal mesoderm, cytoplasmic (diffuse) Prickle1 upregulates cortical F-actin content, antagonizing DVL2-mediated cortex downregulation; both factors act upstream of casein kinase II to modulate cortical tension, affecting cell migration and rearrangement during radial intercalation. Punctate/plaque forms of Pk1 are associated with localized depletion of cortical F-actin, suggesting opposite roles for diffuse versus punctate Pk1.","method":"Xenopus live imaging, F-actin quantification, cortical tension measurements, dominant-negative and overexpression constructs, epistasis with casein kinase II","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — quantitative live imaging, multiple constructs, cortical tension measurement, epistasis; single lab with multiple orthogonal methods","pmids":["35512799"],"is_preprint":false},{"year":2021,"finding":"The Prickle1 LIM1 domain mediates protein–protein interactions with DVL2 and DVL3 in chondrocytes; a missense mutation in the LIM1 domain (Prickle1Bj) reduces these interactions, causing randomized chondrocyte polarity (assessed by primary cilia and PRICKLE1/DVL localization) and precocious maturation with stalled terminal differentiation.","method":"In vivo co-immunoprecipitation, proximity ligation assay, immunofluorescence of primary cilia/polarity markers in growth plates","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Co-IP and proximity ligation assay with cellular polarity readout; single lab","pmids":["34423861"],"is_preprint":false},{"year":2019,"finding":"In zebrafish, Prickle1a and Prickle1b are required for epithelial-to-mesenchymal transition (EMT) and collective migration of cranial neural crest cells; loss of Pk1b elevates E-Cadherin and reduces N-Cadherin levels, indicating Prickle1 regulates cadherin switching during EMT.","method":"pk1a/pk1b mutant zebrafish analysis, live-cell time-lapse imaging, immunofluorescence for E-Cadherin and N-Cadherin","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in zebrafish with live imaging and molecular marker readout; single lab","pmids":["30721665"],"is_preprint":false},{"year":2021,"finding":"USP7 (ubiquitin-specific protease 7) deubiquitinates and stabilizes PRICKLE1 protein; morin inhibits USP7, leading to increased PRICKLE1 ubiquitination and proteasomal degradation (blocked by MG132 but not the lysosomal inhibitor BafA1), which in turn disrupts the PRICKLE1–mTORC2 complex and AKT/PKCα activation to impair cell migration.","method":"USP7 overexpression/inhibitor experiments, ubiquitination assay, proteasome/lysosome inhibitor treatment, co-immunoprecipitation","journal":"Molecular nutrition & food research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay, proteasome vs lysosome inhibitor distinction, Co-IP, functional migration assay; single lab","pmids":["34331380"],"is_preprint":false},{"year":2020,"finding":"Prickle1 is required for polarized basement membrane deposition during tear duct elongation; Prickle1 disruption causes loss of basement membrane deposition and aberrant cytoplasmic accumulation of laminin, with associated defects in cell adhesion, cytoskeletal and vesicular transport, and cell axis orientation.","method":"Prickle1 mutant mouse analysis, immunofluorescence for laminin/BM components, cytoskeletal and vesicular transport markers","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined molecular (laminin/BM) and cellular phenotype; single lab","pmids":["33144400"],"is_preprint":false},{"year":2024,"finding":"In iPSC-derived embryoid bodies, Prickle1 directs secretion of basement membrane components through a proper microtubule network and vesicle trafficking in visceral endoderm cells; reintroduction of Prickle1 in mutant EBs rescues BM formation but not apicobasal polarity, demonstrating BM deposition and apicobasal polarity are separable Prickle1 functions.","method":"iPSC-derived embryoid body system, Prickle1 rescue experiments, microtubule network analysis, vesicle trafficking assays, immunofluorescence","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment in iPSC-derived system with mechanistic dissection of BM vs polarity; single lab","pmids":["38185785"],"is_preprint":false},{"year":2021,"finding":"The Prickle1 R104Q mutation impairs the interaction between PK1 and REST, reduces excitatory synapse density in hippocampus, decreases seizure threshold, and impairs social interaction and cognition in mice, linking the PK1–REST interaction to epilepsy/ASD-related synaptic phenotypes.","method":"CRISPR-Cas9 knock-in mouse (R104Q), co-immunoprecipitation for PK1–REST interaction, immunostaining of synaptic markers, behavioral assays","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse with Co-IP, synaptic quantification, and behavioral readout; single lab","pmids":["34597683"],"is_preprint":false},{"year":2024,"finding":"Estrogen receptor alpha (ERα), acting through EZH2-mediated H3K27 methylation at the PRICKLE1 promoter, represses PRICKLE1 expression; reduced PRICKLE1 destabilizes REST protein. Conversely, PRICKLE1 overexpression restores REST in leiomyoma smooth muscle cells, establishing PRICKLE1 as required for REST protein stability in myometrial cells.","method":"Chromatin immunoprecipitation (ChIP) for EZH2 and H3K27me3 at PRICKLE1 promoter, siRNA knockdown of EZH2, overexpression of PRICKLE1, conditional knockout mice (Lhb, Esr1)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for epigenetic mark, siRNA epistasis, genetic mouse models; preprint, single lab","pmids":["39314474"],"is_preprint":true},{"year":2025,"finding":"PRICKLE1 interactome mapping (miniTurboID proximity biotinylation + MS) reveals PRICKLE1 localizes intracellularly and interacts with DVL2/DVL3 as binding partners in the WNT/PCP pathway. Notably, unlike PRICKLE3, PRICKLE1 does not influence levels or phosphorylation status of DVL2 and DVL3 under near-physiological expression conditions, contradicting earlier overexpression-based findings.","method":"miniTurboID proximity biotinylation combined with mass spectrometry, inducible expression system","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proximity biotinylation interactome in single preprint, negative result for DVL regulation needs replication","pmids":["bio_10.1101_2025.03.24.644882"],"is_preprint":true},{"year":2026,"finding":"In quail junctional neural tube, PRICKLE1 is enriched at the apical cortex of medial neuroepithelial cells where it drives actomyosin accumulation and apical constriction to orchestrate mediolateral convergence and EMT-driven cell ingression, independently of classical planar polarity axis establishment.","method":"High-resolution quantitative live imaging in transgenic quail embryos, loss-of-function with actomyosin and polarity marker readout","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative live imaging with genetic loss-of-function and molecular marker validation; single lab, peer-reviewed","pmids":["42045189"],"is_preprint":false}],"current_model":"PRICKLE1 is a core WNT/planar cell polarity (PCP) scaffold protein that acts as a negative regulator of canonical WNT/β-catenin signaling by binding DVL proteins and promoting their ubiquitination/degradation via D-box motifs; it stabilizes the nuclear transcriptional repressor REST (whose protein stability depends on PRICKLE1), interacts with mTORC2 component RICTOR to activate AKT and regulate focal adhesion disassembly (via the CLASP–LL5β complex) during cell migration, binds SYNAPSIN I to regulate synaptic vesicle dynamics, and modulates cortical F-actin and actomyosin tension upstream of casein kinase II to control cell polarity, EMT, and tissue morphogenesis across multiple developmental contexts."},"narrative":{"mechanistic_narrative":"PRICKLE1 is a core WNT/planar cell polarity (PCP) scaffold protein that organizes cortical cytoskeletal architecture and cell polarity across multiple developmental and morphogenetic contexts [PMID:19706528, PMID:35512799]. It acts genetically downstream of the noncanonical WNT5A-ROR2 axis and the core PCP gene Vangl2 to establish apical-basal polarity, orient mitotic spindles, and direct polarized extracellular matrix deposition during epiblast and tissue morphogenesis [PMID:19706528, PMID:25190059]. PRICKLE1 binds Dishevelled proteins through its LIM domain, an interaction that underlies its control of cell polarity, neurite outgrowth, and chondrocyte maturation [PMID:22218901, PMID:34423861, PMID:bio_10.1101_2025.03.24.644882]. Mechanistically, PRICKLE1 regulates the actomyosin cortex: diffuse cytoplasmic PRICKLE1 increases cortical F-actin and tension acting upstream of casein kinase II, while at the apical cortex of neuroepithelial cells it drives actomyosin accumulation and apical constriction to power convergence and EMT-driven cell ingression [PMID:35512799, PMID:42045189]. It also governs migration through a membrane-localized pool that promotes focal adhesion disassembly via CLASP1/2 and LL5β and assembles a complex with MINK1 and the mTORC2 component RICTOR to activate AKT and drive cancer cell dissemination [PMID:27184734, PMID:27378169]. PRICKLE1 controls cadherin switching during epithelial-to-mesenchymal transition and polarized basement membrane secretion via microtubule-dependent vesicle trafficking [PMID:30721665, PMID:33144400, PMID:38185785]. In the nervous system PRICKLE1 binds SYNAPSIN I and stabilizes the transcriptional repressor REST; the epilepsy/ASD-associated R104Q mutation that disrupts the PRICKLE1–REST interaction reduces excitatory synapse density, lowers seizure threshold, and impairs cognition, establishing PRICKLE1 as a human epilepsy gene [PMID:18976727, PMID:24312498, PMID:34597683]. PRICKLE1 protein stability is itself regulated by USP7-mediated deubiquitination and by estrogen-receptor/EZH2-dependent transcriptional repression [PMID:34331380, PMID:39314474].","teleology":[{"year":2006,"claim":"Established that PRICKLE1 negatively regulates canonical WNT/β-catenin signaling by targeting Dishevelled for degradation, defining a molecular mechanism for its pathway role.","evidence":"Co-IP, ubiquitination assay, D-box mutagenesis, and β-catenin reporter in hepatocellular carcinoma cells","pmids":["17030191"],"confidence":"High","gaps":["Based on enforced overexpression; physiological relevance to endogenous DVL3 levels not established","E3 ligase mediating DVL3 ubiquitination not identified"]},{"year":2008,"claim":"Identified REST as a direct PRICKLE1 binding partner and linked PRICKLE1 to human epilepsy via the R104Q mutation that disrupts this interaction.","evidence":"In vitro interaction-blocking assay and zebrafish overexpression functional assay","pmids":["18976727"],"confidence":"Medium","gaps":["Interaction shown in vitro; functional consequence of REST binding not yet mechanistically resolved","Did not establish whether epilepsy arises from REST destabilization or noncanonical WNT defects"]},{"year":2009,"claim":"Defined PRICKLE1 as essential for apical-basal epiblast polarity acting downstream of Vangl2 in the PCP pathway, establishing its in vivo developmental role.","evidence":"Conditional knockout mice, genetic epistasis with Vangl2, and Xenopus dominant-negative ΔPK/LIM with PKCζ imaging","pmids":["19706528"],"confidence":"High","gaps":["Molecular effectors linking PRICKLE1 to spindle orientation not defined","How PRICKLE1 couples to Vangl2 mechanistically not resolved"]},{"year":2012,"claim":"Showed PRICKLE1 promotes neurite outgrowth through a DVL1-dependent mechanism, extending its DVL antagonism to neuronal morphogenesis.","evidence":"Co-IP, overexpression/knockdown, and neurite outgrowth assays in C1300 neuroblastoma cells","pmids":["22218901"],"confidence":"Medium","gaps":["Cell-line-based; in vivo relevance not tested","Downstream cytoskeletal effectors not identified"]},{"year":2013,"claim":"Connected PRICKLE1 to synaptic vesicle biology by identifying SYNAPSIN I as a binding partner through the SYN1 region mutated in ASD/epilepsy.","evidence":"Yeast two-hybrid screen, neuronal co-IP/co-localization, and dense-core vesicle size assay in PC12 cells","pmids":["24312498"],"confidence":"Medium","gaps":["Mechanism by which PRICKLE1 controls vesicle size unresolved","Reciprocal validation of the interaction in native neurons limited"]},{"year":2014,"claim":"Placed Prickle1 genetically downstream of WNT5A-ROR2 noncanonical signaling and showed it is a proteasomal target of WNT5A, integrating its degradation into pathway regulation.","evidence":"Multiple mouse mutant alleles, epistasis with Wnt5a/Ror2, proteasome inhibitor assays, and DVL2 immunostaining","pmids":["25190059"],"confidence":"Medium","gaps":["E3 ligase and signal transducing WNT5A degradation not identified","Direct versus indirect DVL2 misregulation not distinguished"]},{"year":2016,"claim":"Revealed a PRICKLE1–MINK1–RICTOR complex driving AKT activation and cancer cell dissemination, defining a noncanonical signaling output coupled to mTORC2.","evidence":"Reciprocal Co-IP, proximity ligation, focal adhesion imaging, and xenograft dissemination assays","pmids":["27184734"],"confidence":"High","gaps":["Whether PRICKLE1 directly activates mTORC2 kinase activity not resolved","Structural basis of the complex not defined"]},{"year":2016,"claim":"Demonstrated a membrane-localized, farnesylation-dependent pool of PRICKLE1 that promotes focal adhesion disassembly via CLASP1/2 and LL5β, linking it to microtubule-targeted adhesion turnover.","evidence":"TIRF/FRAP live imaging, Co-IP, siRNA with focal adhesion turnover assay, and farnesylation mutant analysis","pmids":["27378169"],"confidence":"High","gaps":["How PRICKLE1 recruits CLASPs mechanistically not defined","Relationship between this membrane pool and the RICTOR complex unclear"]},{"year":2019,"claim":"Established PRICKLE1 as a regulator of cadherin switching during EMT and collective neural crest migration in vivo.","evidence":"pk1a/pk1b mutant zebrafish, live time-lapse imaging, and E-/N-Cadherin immunofluorescence","pmids":["30721665"],"confidence":"Medium","gaps":["Molecular link between PRICKLE1 and cadherin transcription/turnover not defined","Whether effect is cell-autonomous not fully resolved"]},{"year":2020,"claim":"Showed PRICKLE1 is required for polarized basement membrane deposition during tear duct elongation, tying it to vesicular and cytoskeletal trafficking of ECM.","evidence":"Prickle1 mutant mouse analysis with laminin/BM, cytoskeletal, and vesicular transport markers","pmids":["33144400"],"confidence":"Medium","gaps":["Trafficking machinery directly controlled by PRICKLE1 not identified","Cause of cytoplasmic laminin accumulation mechanistically unresolved"]},{"year":2021,"claim":"Dissected PRICKLE1 LIM1-domain-mediated DVL2/DVL3 binding as the basis for chondrocyte polarity and maturation, with a disease-associated missense mutation reducing the interaction.","evidence":"In vivo Co-IP, proximity ligation, and primary cilia/polarity immunofluorescence in growth plates","pmids":["34423861"],"confidence":"Medium","gaps":["How reduced DVL binding randomizes polarity mechanistically not resolved","Downstream chondrocyte maturation effectors not defined"]},{"year":2021,"claim":"Identified USP7 as a deubiquitinase that stabilizes PRICKLE1, coupling PRICKLE1 abundance to mTORC2 complex integrity and AKT/PKCα signaling in migration.","evidence":"USP7 overexpression/inhibitor, ubiquitination assays, proteasome vs lysosome inhibitor discrimination, and Co-IP","pmids":["34331380"],"confidence":"Medium","gaps":["E3 ligase opposing USP7 not identified","Direct versus indirect USP7–PRICKLE1 interaction not fully resolved"]},{"year":2021,"claim":"Provided in vivo causal evidence that the PRICKLE1–REST interaction underlies synaptic and behavioral phenotypes relevant to epilepsy and ASD.","evidence":"CRISPR R104Q knock-in mice with Co-IP, synaptic marker quantification, and behavioral/seizure-threshold assays","pmids":["34597683"],"confidence":"Medium","gaps":["How REST destabilization reduces excitatory synapse density mechanistically not defined","Whether noncanonical WNT functions also contribute not separated"]},{"year":2024,"claim":"Separated PRICKLE1's basement-membrane secretion function from its apicobasal polarity function using rescue experiments, showing BM deposition depends on microtubule-based vesicle trafficking.","evidence":"iPSC-derived embryoid body rescue, microtubule network analysis, and vesicle trafficking assays","pmids":["38185785"],"confidence":"Medium","gaps":["Molecular cargo adaptors used by PRICKLE1 for BM secretion not identified","Why polarity is not rescued by PRICKLE1 reintroduction unexplained"]},{"year":2024,"claim":"Placed PRICKLE1 in an estrogen-receptor/EZH2 transcriptional circuit and established it as required for REST protein stability in myometrial cells.","evidence":"ChIP for EZH2/H3K27me3 at the PRICKLE1 promoter, EZH2 siRNA, PRICKLE1 overexpression, and conditional knockout mice (preprint)","pmids":["39314474"],"confidence":"Medium","gaps":["Mechanism by which PRICKLE1 stabilizes REST protein not defined","Preprint status; requires peer-reviewed confirmation"]},{"year":2025,"claim":"Mapped the PRICKLE1 proximity interactome and challenged the model that PRICKLE1 regulates DVL2/DVL3 levels or phosphorylation under near-physiological expression.","evidence":"miniTurboID proximity biotinylation with mass spectrometry in an inducible expression system (preprint)","pmids":["bio_10.1101_2025.03.24.644882"],"confidence":"Low","gaps":["Negative result for DVL regulation awaits independent replication","Single preprint; physiological expression levels need validation against earlier overexpression studies"]},{"year":2026,"claim":"Defined an apical-cortex pool of PRICKLE1 that drives actomyosin accumulation and apical constriction to power convergence and EMT-driven ingression independently of classical planar polarity.","evidence":"Quantitative live imaging in transgenic quail embryos with loss-of-function and actomyosin/polarity marker readouts","pmids":["42045189"],"confidence":"Medium","gaps":["Molecular link between cortical PRICKLE1 and actomyosin recruitment not defined","Relationship to casein-kinase-II-dependent cortical regulation not integrated"]},{"year":null,"claim":"Whether PRICKLE1's distinct outputs — DVL antagonism, mTORC2/AKT signaling, REST stabilization, cortical actomyosin control, and ECM secretion — reflect a single unifying biochemical activity or separable context-specific modules remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model unifies the LIM/farnesyl-dependent interactions","Mechanism by which PRICKLE1 stabilizes REST protein remains unknown","The reported negative DVL-regulation result conflicts with earlier overexpression findings and is unreconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,9]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,17]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,17]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,16]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8,12,13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,10,12,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,11]}],"complexes":["PRICKLE1–MINK1–RICTOR (mTORC2-associated) complex"],"partners":["DVL1","DVL2","DVL3","REST","RICTOR","MINK1","SYN1","USP7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96MT3","full_name":"Prickle-like protein 1","aliases":["REST/NRSF-interacting LIM domain protein 1"],"length_aa":831,"mass_kda":94.3,"function":"Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure. Convergent extension is a complex morphogenetic process during which cells elongate, move mediolaterally, and intercalate between neighboring cells, leading to convergence toward the mediolateral axis and extension along the anteroposterior axis. Necessary for nuclear localization of REST. May serve as nuclear receptor","subcellular_location":"Nucleus membrane; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q96MT3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRICKLE1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRICKLE1","total_profiled":1310},"omim":[{"mim_id":"613004","title":"HUNTINGTIN; HTT","url":"https://www.omim.org/entry/613004"},{"mim_id":"612437","title":"EPILEPSY, PROGRESSIVE MYOCLONIC, 1B; EPM1B","url":"https://www.omim.org/entry/612437"},{"mim_id":"611389","title":"PRICKLE PLANAR CELL POLARITY PROTEIN 4; PRICKLE4","url":"https://www.omim.org/entry/611389"},{"mim_id":"608501","title":"PRICKLE, PLANAR CELL POLARITY PROTEIN 2; PRICKLE2","url":"https://www.omim.org/entry/608501"},{"mim_id":"608500","title":"PRICKLE PLANAR CELL POLARITY PROTEIN 1; PRICKLE1","url":"https://www.omim.org/entry/608500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRICKLE1"},"hgnc":{"alias_symbol":["FLJ31937","EPM1B","RILP"],"prev_symbol":[]},"alphafold":{"accession":"Q96MT3","domains":[{"cath_id":"2.10.110.10","chopping":"41-188","consensus_level":"high","plddt":92.6248,"start":41,"end":188},{"cath_id":"-","chopping":"217-246","consensus_level":"medium","plddt":92.8497,"start":217,"end":246}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MT3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MT3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96MT3-F1-predicted_aligned_error_v6.png","plddt_mean":55.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRICKLE1","jax_strain_url":"https://www.jax.org/strain/search?query=PRICKLE1"},"sequence":{"accession":"Q96MT3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96MT3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96MT3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96MT3"}},"corpus_meta":[{"pmid":"18976727","id":"PMC_18976727","title":"A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18976727","citation_count":170,"is_preprint":false},{"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":"17030191","id":"PMC_17030191","title":"Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer.","date":"2006","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/17030191","citation_count":109,"is_preprint":false},{"pmid":"19706528","id":"PMC_19706528","title":"Mouse prickle1, the homolog of a PCP gene, is essential for epiblast apical-basal polarity.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19706528","citation_count":96,"is_preprint":false},{"pmid":"27184734","id":"PMC_27184734","title":"PRICKLE1 Contributes to Cancer Cell Dissemination through Its Interaction with mTORC2.","date":"2016","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/27184734","citation_count":64,"is_preprint":false},{"pmid":"21901791","id":"PMC_21901791","title":"Identification and characterization of novel rare mutations in the planar cell polarity gene PRICKLE1 in human neural tube defects.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/21901791","citation_count":64,"is_preprint":false},{"pmid":"17868671","id":"PMC_17868671","title":"Mouse Prickle1 and Prickle2 are expressed in postmitotic neurons and promote neurite outgrowth.","date":"2007","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/17868671","citation_count":46,"is_preprint":false},{"pmid":"26883626","id":"PMC_26883626","title":"Prickle1 mutation causes planar cell polarity and directional cell migration defects associated with cardiac outflow tract anomalies and other structural birth defects.","date":"2016","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/26883626","citation_count":43,"is_preprint":false},{"pmid":"25190059","id":"PMC_25190059","title":"Null and hypomorph Prickle1 alleles in mice phenocopy human Robinow syndrome and disrupt signaling downstream of Wnt5a.","date":"2014","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/25190059","citation_count":41,"is_preprint":false},{"pmid":"23420014","id":"PMC_23420014","title":"Prickle1 is expressed in distinct cell populations of the central nervous system and contributes to neuronal morphogenesis.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23420014","citation_count":37,"is_preprint":false},{"pmid":"27378169","id":"PMC_27378169","title":"Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells.","date":"2016","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/27378169","citation_count":35,"is_preprint":false},{"pmid":"24312498","id":"PMC_24312498","title":"PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24312498","citation_count":34,"is_preprint":false},{"pmid":"24689077","id":"PMC_24689077","title":"Analysis of PRICKLE1 in human cleft palate and mouse development demonstrates rare and common variants involved in human malformations.","date":"2013","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24689077","citation_count":29,"is_preprint":false},{"pmid":"28837644","id":"PMC_28837644","title":"Prickle1 regulates neurite outgrowth of apical spiral ganglion neurons but not hair cell polarity in the murine cochlea.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28837644","citation_count":29,"is_preprint":false},{"pmid":"30721665","id":"PMC_30721665","title":"Prickle1 is required for EMT and migration of zebrafish cranial neural crest.","date":"2019","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/30721665","citation_count":22,"is_preprint":false},{"pmid":"30575813","id":"PMC_30575813","title":"Prickle1 regulates differentiation of frontal bone osteoblasts.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30575813","citation_count":21,"is_preprint":false},{"pmid":"24927917","id":"PMC_24927917","title":"Prickle1 is necessary for the caudal migration of murine facial branchiomotor neurons.","date":"2014","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/24927917","citation_count":18,"is_preprint":false},{"pmid":"29790814","id":"PMC_29790814","title":"A de novo mutation in PRICKLE1 associated with myoclonic epilepsy and autism spectrum disorder.","date":"2018","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/29790814","citation_count":16,"is_preprint":false},{"pmid":"30345727","id":"PMC_30345727","title":"PRICKLE1-related early onset epileptic encephalopathy.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/30345727","citation_count":12,"is_preprint":false},{"pmid":"34331380","id":"PMC_34331380","title":"Morin Acts as a USP7 Inhibitor to Hold Back the Migration of Rheumatoid Arthritis Fibroblast-Like Synoviocytes in a \"Prickle1-mTORC2\" Dependent Manner.","date":"2021","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/34331380","citation_count":12,"is_preprint":false},{"pmid":"26727662","id":"PMC_26727662","title":"A de novo mutation in PRICKLE1 in fetal agenesis of the corpus callosum and polymicrogyria.","date":"2016","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/26727662","citation_count":11,"is_preprint":false},{"pmid":"35512799","id":"PMC_35512799","title":"Cell cortex regulation by the planar cell polarity protein Prickle1.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35512799","citation_count":9,"is_preprint":false},{"pmid":"22218901","id":"PMC_22218901","title":"Role of Prickle1 and Prickle2 in neurite outgrowth in murine neuroblastoma cells.","date":"2012","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/22218901","citation_count":9,"is_preprint":false},{"pmid":"31035234","id":"PMC_31035234","title":"A very rare form of autosomal dominant progressive myoclonus epilepsy caused by a novel variant in the PRICKLE1 gene.","date":"2019","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/31035234","citation_count":9,"is_preprint":false},{"pmid":"28935237","id":"PMC_28935237","title":"Prickle1 as positive regulator of oligodendrocyte differentiation.","date":"2017","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28935237","citation_count":8,"is_preprint":false},{"pmid":"34434215","id":"PMC_34434215","title":"PRICKLE1 × FOCAD Interaction Revealed by Genome-Wide vQTL Analysis of Human Facial Traits.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34434215","citation_count":8,"is_preprint":false},{"pmid":"34423861","id":"PMC_34423861","title":"Chondrocyte Polarity During Endochondral Ossification Requires Protein-Protein Interactions Between Prickle1 and Dishevelled2/3.","date":"2021","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/34423861","citation_count":7,"is_preprint":false},{"pmid":"36176272","id":"PMC_36176272","title":"Distinct overlapping functions for Prickle1 and Prickle2 in the polarization of the airway epithelium.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36176272","citation_count":7,"is_preprint":false},{"pmid":"34597683","id":"PMC_34597683","title":"Mutation of the murine Prickle1 (R104Q) causes phenotypes analogous to human symptoms of epilepsy and autism.","date":"2021","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34597683","citation_count":6,"is_preprint":false},{"pmid":"39314474","id":"PMC_39314474","title":"Estrogen receptor alpha mediated repression of PRICKLE1 destabilizes REST and promotes uterine fibroid pathogenesis.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39314474","citation_count":5,"is_preprint":false},{"pmid":"34150013","id":"PMC_34150013","title":"PRICKLE1 promotes gastric cancer metastasis by activating mTOR signaling.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34150013","citation_count":5,"is_preprint":false},{"pmid":"33144400","id":"PMC_33144400","title":"Ontogenesis of the tear drainage system requires Prickle1-driven polarized basement membrane deposition.","date":"2020","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/33144400","citation_count":4,"is_preprint":false},{"pmid":"30564977","id":"PMC_30564977","title":"Sudden unexpected death with rare compound heterozygous variants in PRICKLE1.","date":"2018","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/30564977","citation_count":4,"is_preprint":false},{"pmid":"39917256","id":"PMC_39917256","title":"Loss of PRICKLE1 leads to abnormal endometrial epithelial architecture, decreased embryo implantation, and reduced fertility in mice.","date":"2025","source":"PNAS nexus","url":"https://pubmed.ncbi.nlm.nih.gov/39917256","citation_count":3,"is_preprint":false},{"pmid":"37742487","id":"PMC_37742487","title":"PRICKLE1 gene methylation and abnormal transcription in Chinese patients with ankylosing spondylitis.","date":"2023","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/37742487","citation_count":2,"is_preprint":false},{"pmid":"38185785","id":"PMC_38185785","title":"Prickle1-driven basement membrane deposition of the iPSC-derived embryoid bodies is separable from the establishment of apicobasal polarity.","date":"2024","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/38185785","citation_count":2,"is_preprint":false},{"pmid":"39679867","id":"PMC_39679867","title":"Loss of PRICKLE1 leads to subfertility, aberrant extracellular matrix and abnormal myometrial architecture in mice.","date":"2025","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/39679867","citation_count":1,"is_preprint":false},{"pmid":"39211179","id":"PMC_39211179","title":"Loss of PRICKLE1 leads to abnormal endometrial epithelial architecture, decreased embryo implantation, and reduced fertility in mice.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39211179","citation_count":0,"is_preprint":false},{"pmid":"42045189","id":"PMC_42045189","title":"Quantitative live imaging reveals PRICKLE1 controls junctional neural tube morphogenesis independent of Planar Cell Polarity.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/42045189","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.29.673140","title":"Regulatory Role for Tumor Suppressor REST on Estrogen Receptor (  <i>ESR1</i>  ) Expression and Leiomyoma Pathophysiology","date":"2025-08-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.29.673140","citation_count":0,"is_preprint":true},{"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},{"pmid":null,"id":"bio_10.1101_2024.09.12.612708","title":"Loss of PRICKLE1 in the myometrium leads to reduced fertility, abnormal myometrial architecture, and aberrant extracellular matrix deposition in mice","date":"2024-09-17","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.12.612708","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.06.24318522","title":"Multi-ancestry Genome Wide Association Study Meta-analysis of Non-syndromic Orofacial Clefts","date":"2024-12-11","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.06.24318522","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.15.633117","title":"Proximity interactomics identifies RAI14, EPHA2 and PHACTR4 as essential components of Wnt/planar cell polarity pathway in vertebrates","date":"2025-01-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.15.633117","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22772,"output_tokens":4692,"usd":0.069348,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12807,"output_tokens":5499,"usd":0.100755,"stage2_stop_reason":"end_turn"},"total_usd":0.170103,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"A missense mutation in PRICKLE1 (R104Q) blocks the PRICKLE1–REST interaction in vitro, identifying REST as a direct binding partner of PRICKLE1 and placing PRICKLE1 in the noncanonical WNT signaling pathway as the first member directly implicated in human epilepsy.\",\n      \"method\": \"In vitro protein interaction assay (blocking of PRICKLE1–REST interaction); zebrafish overexpression functional assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro interaction assay plus in vivo zebrafish functional validation, single lab\",\n      \"pmids\": [\"18976727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PRICKLE1 binds Dishevelled3 (DVL3) and promotes its ubiquitination and proteasomal degradation through destruction-box (D-box) motifs on PRICKLE1, thereby negatively regulating the WNT/β-catenin pathway in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, enforced expression/knockdown with β-catenin reporter assay, D-box motif mutagenesis\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reciprocal Co-IP, ubiquitination assay, mutagenesis of D-box, functional reporter assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17030191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mouse Prickle1 (mpk1) is essential for apical-basal polarity of the epiblast; loss of mpk1 causes abnormal cell shapes, mislocalized ECM proteins, and disrupted mitotic spindle orientation. Genetic interaction with Vangl2 (another core PCP gene) was demonstrated, placing Prickle1 downstream in the PCP pathway for epiblast polarity. Dominant-negative ΔPK/LIM construct in Xenopus disrupted apical marker PKCζ localization, confirming a direct role in cortical polarity.\",\n      \"method\": \"Conditional knockout mice, genetic epistasis with Vangl2, Xenopus dominant-negative overexpression with apical marker (PKCζ) imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function knockout with cellular phenotype, genetic epistasis, and cross-species dominant-negative validation\",\n      \"pmids\": [\"19706528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRICKLE1 forms a complex with MINK1 (serine/threonine kinase) and RICTOR (an mTORC2 component); integrity of this PRICKLE1–MINK1–RICTOR complex is required for AKT activation, focal adhesion regulation, and cancer cell migration/dissemination. Disruption of the PRICKLE1–RICTOR interaction strongly impairs breast cancer cell dissemination in xenograft assays.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation, xenograft in vivo dissemination assay, focal adhesion imaging\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vivo xenograft functional validation, focal adhesion readout; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27184734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PRICKLE1 accumulates at cell retraction sites near focal adhesions, where it promotes focal adhesion disassembly by associating with CLASP1/2 and LL5β (PHLDB2) and enabling LL5β-dependent accumulation of CLASPs at the cell edge to drive microtubule targeting of focal adhesions. Membrane localization via a farnesyl moiety is required for these functions.\",\n      \"method\": \"Live-cell imaging (TIRF/FRAP), co-immunoprecipitation, siRNA knockdown with focal adhesion turnover assay, farnesylation mutant analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, live imaging correlating dynamics, loss-of-function KD, farnesylation mutant; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"27378169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRICKLE1 physically interacts with SYNAPSIN I (SYN1) in neurons, co-localizing with endogenous Syn1. The interaction is through the SYN1 region mutated in ASD and epilepsy. A PRICKLE1 mutation disrupts its ability to increase the size of dense-core vesicles in PC12 cells, implicating PRICKLE1 in synaptic vesicle regulation.\",\n      \"method\": \"Yeast two-hybrid screen (human brain cDNA library), co-immunoprecipitation/co-localization in neurons, dense-core vesicle size assay in PC12 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — yeast two-hybrid plus neuronal co-localization plus functional vesicle assay; single lab\",\n      \"pmids\": [\"24312498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Prickle1 is a proteasomal target of WNT5A signaling in mice; complete Prickle1 loss leads to misregulation of DVL2 (a WNT5A target), and Prickle1 mutants phenocopy Wnt5a and Ror2 mutants, placing Prickle1 downstream of WNT5A-ROR2 in the noncanonical WNT pathway.\",\n      \"method\": \"Multiple Prickle1 mutant alleles in mice, epistasis with Wnt5a/Ror2 mutants, proteasome inhibitor experiments to assess Prickle1 degradation, immunostaining of DVL2\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis across multiple alleles, proteasome assay, DVL2 misregulation; single lab\",\n      \"pmids\": [\"25190059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Prickle1 associates with Dishevelled1 (DVL1), and overexpression of Prickle1 reduces DVL1 protein levels; overexpression of DVL1 blocks Prickle1-induced neurite-like process formation, demonstrating that Prickle1 promotes neurite outgrowth via a DVL1-dependent mechanism.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown in C1300 neuroblastoma cells, neurite outgrowth assay\",\n      \"journal\": \"Methods in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and epistasis in cell line with functional readout; single lab\",\n      \"pmids\": [\"22218901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Xenopus prechordal mesoderm, cytoplasmic (diffuse) Prickle1 upregulates cortical F-actin content, antagonizing DVL2-mediated cortex downregulation; both factors act upstream of casein kinase II to modulate cortical tension, affecting cell migration and rearrangement during radial intercalation. Punctate/plaque forms of Pk1 are associated with localized depletion of cortical F-actin, suggesting opposite roles for diffuse versus punctate Pk1.\",\n      \"method\": \"Xenopus live imaging, F-actin quantification, cortical tension measurements, dominant-negative and overexpression constructs, epistasis with casein kinase II\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — quantitative live imaging, multiple constructs, cortical tension measurement, epistasis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35512799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Prickle1 LIM1 domain mediates protein–protein interactions with DVL2 and DVL3 in chondrocytes; a missense mutation in the LIM1 domain (Prickle1Bj) reduces these interactions, causing randomized chondrocyte polarity (assessed by primary cilia and PRICKLE1/DVL localization) and precocious maturation with stalled terminal differentiation.\",\n      \"method\": \"In vivo co-immunoprecipitation, proximity ligation assay, immunofluorescence of primary cilia/polarity markers in growth plates\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Co-IP and proximity ligation assay with cellular polarity readout; single lab\",\n      \"pmids\": [\"34423861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In zebrafish, Prickle1a and Prickle1b are required for epithelial-to-mesenchymal transition (EMT) and collective migration of cranial neural crest cells; loss of Pk1b elevates E-Cadherin and reduces N-Cadherin levels, indicating Prickle1 regulates cadherin switching during EMT.\",\n      \"method\": \"pk1a/pk1b mutant zebrafish analysis, live-cell time-lapse imaging, immunofluorescence for E-Cadherin and N-Cadherin\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in zebrafish with live imaging and molecular marker readout; single lab\",\n      \"pmids\": [\"30721665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP7 (ubiquitin-specific protease 7) deubiquitinates and stabilizes PRICKLE1 protein; morin inhibits USP7, leading to increased PRICKLE1 ubiquitination and proteasomal degradation (blocked by MG132 but not the lysosomal inhibitor BafA1), which in turn disrupts the PRICKLE1–mTORC2 complex and AKT/PKCα activation to impair cell migration.\",\n      \"method\": \"USP7 overexpression/inhibitor experiments, ubiquitination assay, proteasome/lysosome inhibitor treatment, co-immunoprecipitation\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay, proteasome vs lysosome inhibitor distinction, Co-IP, functional migration assay; single lab\",\n      \"pmids\": [\"34331380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Prickle1 is required for polarized basement membrane deposition during tear duct elongation; Prickle1 disruption causes loss of basement membrane deposition and aberrant cytoplasmic accumulation of laminin, with associated defects in cell adhesion, cytoskeletal and vesicular transport, and cell axis orientation.\",\n      \"method\": \"Prickle1 mutant mouse analysis, immunofluorescence for laminin/BM components, cytoskeletal and vesicular transport markers\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined molecular (laminin/BM) and cellular phenotype; single lab\",\n      \"pmids\": [\"33144400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In iPSC-derived embryoid bodies, Prickle1 directs secretion of basement membrane components through a proper microtubule network and vesicle trafficking in visceral endoderm cells; reintroduction of Prickle1 in mutant EBs rescues BM formation but not apicobasal polarity, demonstrating BM deposition and apicobasal polarity are separable Prickle1 functions.\",\n      \"method\": \"iPSC-derived embryoid body system, Prickle1 rescue experiments, microtubule network analysis, vesicle trafficking assays, immunofluorescence\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment in iPSC-derived system with mechanistic dissection of BM vs polarity; single lab\",\n      \"pmids\": [\"38185785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Prickle1 R104Q mutation impairs the interaction between PK1 and REST, reduces excitatory synapse density in hippocampus, decreases seizure threshold, and impairs social interaction and cognition in mice, linking the PK1–REST interaction to epilepsy/ASD-related synaptic phenotypes.\",\n      \"method\": \"CRISPR-Cas9 knock-in mouse (R104Q), co-immunoprecipitation for PK1–REST interaction, immunostaining of synaptic markers, behavioral assays\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse with Co-IP, synaptic quantification, and behavioral readout; single lab\",\n      \"pmids\": [\"34597683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Estrogen receptor alpha (ERα), acting through EZH2-mediated H3K27 methylation at the PRICKLE1 promoter, represses PRICKLE1 expression; reduced PRICKLE1 destabilizes REST protein. Conversely, PRICKLE1 overexpression restores REST in leiomyoma smooth muscle cells, establishing PRICKLE1 as required for REST protein stability in myometrial cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for EZH2 and H3K27me3 at PRICKLE1 promoter, siRNA knockdown of EZH2, overexpression of PRICKLE1, conditional knockout mice (Lhb, Esr1)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for epigenetic mark, siRNA epistasis, genetic mouse models; preprint, single lab\",\n      \"pmids\": [\"39314474\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PRICKLE1 interactome mapping (miniTurboID proximity biotinylation + MS) reveals PRICKLE1 localizes intracellularly and interacts with DVL2/DVL3 as binding partners in the WNT/PCP pathway. Notably, unlike PRICKLE3, PRICKLE1 does not influence levels or phosphorylation status of DVL2 and DVL3 under near-physiological expression conditions, contradicting earlier overexpression-based findings.\",\n      \"method\": \"miniTurboID proximity biotinylation combined with mass spectrometry, inducible expression system\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proximity biotinylation interactome in single preprint, negative result for DVL regulation needs replication\",\n      \"pmids\": [\"bio_10.1101_2025.03.24.644882\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In quail junctional neural tube, PRICKLE1 is enriched at the apical cortex of medial neuroepithelial cells where it drives actomyosin accumulation and apical constriction to orchestrate mediolateral convergence and EMT-driven cell ingression, independently of classical planar polarity axis establishment.\",\n      \"method\": \"High-resolution quantitative live imaging in transgenic quail embryos, loss-of-function with actomyosin and polarity marker readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative live imaging with genetic loss-of-function and molecular marker validation; single lab, peer-reviewed\",\n      \"pmids\": [\"42045189\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRICKLE1 is a core WNT/planar cell polarity (PCP) scaffold protein that acts as a negative regulator of canonical WNT/β-catenin signaling by binding DVL proteins and promoting their ubiquitination/degradation via D-box motifs; it stabilizes the nuclear transcriptional repressor REST (whose protein stability depends on PRICKLE1), interacts with mTORC2 component RICTOR to activate AKT and regulate focal adhesion disassembly (via the CLASP–LL5β complex) during cell migration, binds SYNAPSIN I to regulate synaptic vesicle dynamics, and modulates cortical F-actin and actomyosin tension upstream of casein kinase II to control cell polarity, EMT, and tissue morphogenesis across multiple developmental contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRICKLE1 is a core WNT/planar cell polarity (PCP) scaffold protein that organizes cortical cytoskeletal architecture and cell polarity across multiple developmental and morphogenetic contexts [#2, #8]. It acts genetically downstream of the noncanonical WNT5A-ROR2 axis and the core PCP gene Vangl2 to establish apical-basal polarity, orient mitotic spindles, and direct polarized extracellular matrix deposition during epiblast and tissue morphogenesis [#2, #6]. PRICKLE1 binds Dishevelled proteins through its LIM domain, an interaction that underlies its control of cell polarity, neurite outgrowth, and chondrocyte maturation [#7, #9, #16]. Mechanistically, PRICKLE1 regulates the actomyosin cortex: diffuse cytoplasmic PRICKLE1 increases cortical F-actin and tension acting upstream of casein kinase II, while at the apical cortex of neuroepithelial cells it drives actomyosin accumulation and apical constriction to power convergence and EMT-driven cell ingression [#8, #17]. It also governs migration through a membrane-localized pool that promotes focal adhesion disassembly via CLASP1/2 and LL5\\u03b2 and assembles a complex with MINK1 and the mTORC2 component RICTOR to activate AKT and drive cancer cell dissemination [#3, #4]. PRICKLE1 controls cadherin switching during epithelial-to-mesenchymal transition and polarized basement membrane secretion via microtubule-dependent vesicle trafficking [#10, #12, #13]. In the nervous system PRICKLE1 binds SYNAPSIN I and stabilizes the transcriptional repressor REST; the epilepsy/ASD-associated R104Q mutation that disrupts the PRICKLE1\\u2013REST interaction reduces excitatory synapse density, lowers seizure threshold, and impairs cognition, establishing PRICKLE1 as a human epilepsy gene [#0, #5, #14]. PRICKLE1 protein stability is itself regulated by USP7-mediated deubiquitination and by estrogen-receptor/EZH2-dependent transcriptional repression [#11, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that PRICKLE1 negatively regulates canonical WNT/\\u03b2-catenin signaling by targeting Dishevelled for degradation, defining a molecular mechanism for its pathway role.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, D-box mutagenesis, and \\u03b2-catenin reporter in hepatocellular carcinoma cells\",\n      \"pmids\": [\"17030191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Based on enforced overexpression; physiological relevance to endogenous DVL3 levels not established\", \"E3 ligase mediating DVL3 ubiquitination not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified REST as a direct PRICKLE1 binding partner and linked PRICKLE1 to human epilepsy via the R104Q mutation that disrupts this interaction.\",\n      \"evidence\": \"In vitro interaction-blocking assay and zebrafish overexpression functional assay\",\n      \"pmids\": [\"18976727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction shown in vitro; functional consequence of REST binding not yet mechanistically resolved\", \"Did not establish whether epilepsy arises from REST destabilization or noncanonical WNT defects\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined PRICKLE1 as essential for apical-basal epiblast polarity acting downstream of Vangl2 in the PCP pathway, establishing its in vivo developmental role.\",\n      \"evidence\": \"Conditional knockout mice, genetic epistasis with Vangl2, and Xenopus dominant-negative \\u0394PK/LIM with PKC\\u03b6 imaging\",\n      \"pmids\": [\"19706528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effectors linking PRICKLE1 to spindle orientation not defined\", \"How PRICKLE1 couples to Vangl2 mechanistically not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed PRICKLE1 promotes neurite outgrowth through a DVL1-dependent mechanism, extending its DVL antagonism to neuronal morphogenesis.\",\n      \"evidence\": \"Co-IP, overexpression/knockdown, and neurite outgrowth assays in C1300 neuroblastoma cells\",\n      \"pmids\": [\"22218901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-line-based; in vivo relevance not tested\", \"Downstream cytoskeletal effectors not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected PRICKLE1 to synaptic vesicle biology by identifying SYNAPSIN I as a binding partner through the SYN1 region mutated in ASD/epilepsy.\",\n      \"evidence\": \"Yeast two-hybrid screen, neuronal co-IP/co-localization, and dense-core vesicle size assay in PC12 cells\",\n      \"pmids\": [\"24312498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PRICKLE1 controls vesicle size unresolved\", \"Reciprocal validation of the interaction in native neurons limited\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed Prickle1 genetically downstream of WNT5A-ROR2 noncanonical signaling and showed it is a proteasomal target of WNT5A, integrating its degradation into pathway regulation.\",\n      \"evidence\": \"Multiple mouse mutant alleles, epistasis with Wnt5a/Ror2, proteasome inhibitor assays, and DVL2 immunostaining\",\n      \"pmids\": [\"25190059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase and signal transducing WNT5A degradation not identified\", \"Direct versus indirect DVL2 misregulation not distinguished\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a PRICKLE1\\u2013MINK1\\u2013RICTOR complex driving AKT activation and cancer cell dissemination, defining a noncanonical signaling output coupled to mTORC2.\",\n      \"evidence\": \"Reciprocal Co-IP, proximity ligation, focal adhesion imaging, and xenograft dissemination assays\",\n      \"pmids\": [\"27184734\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRICKLE1 directly activates mTORC2 kinase activity not resolved\", \"Structural basis of the complex not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated a membrane-localized, farnesylation-dependent pool of PRICKLE1 that promotes focal adhesion disassembly via CLASP1/2 and LL5\\u03b2, linking it to microtubule-targeted adhesion turnover.\",\n      \"evidence\": \"TIRF/FRAP live imaging, Co-IP, siRNA with focal adhesion turnover assay, and farnesylation mutant analysis\",\n      \"pmids\": [\"27378169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PRICKLE1 recruits CLASPs mechanistically not defined\", \"Relationship between this membrane pool and the RICTOR complex unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established PRICKLE1 as a regulator of cadherin switching during EMT and collective neural crest migration in vivo.\",\n      \"evidence\": \"pk1a/pk1b mutant zebrafish, live time-lapse imaging, and E-/N-Cadherin immunofluorescence\",\n      \"pmids\": [\"30721665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between PRICKLE1 and cadherin transcription/turnover not defined\", \"Whether effect is cell-autonomous not fully resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed PRICKLE1 is required for polarized basement membrane deposition during tear duct elongation, tying it to vesicular and cytoskeletal trafficking of ECM.\",\n      \"evidence\": \"Prickle1 mutant mouse analysis with laminin/BM, cytoskeletal, and vesicular transport markers\",\n      \"pmids\": [\"33144400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking machinery directly controlled by PRICKLE1 not identified\", \"Cause of cytoplasmic laminin accumulation mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Dissected PRICKLE1 LIM1-domain-mediated DVL2/DVL3 binding as the basis for chondrocyte polarity and maturation, with a disease-associated missense mutation reducing the interaction.\",\n      \"evidence\": \"In vivo Co-IP, proximity ligation, and primary cilia/polarity immunofluorescence in growth plates\",\n      \"pmids\": [\"34423861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How reduced DVL binding randomizes polarity mechanistically not resolved\", \"Downstream chondrocyte maturation effectors not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified USP7 as a deubiquitinase that stabilizes PRICKLE1, coupling PRICKLE1 abundance to mTORC2 complex integrity and AKT/PKC\\u03b1 signaling in migration.\",\n      \"evidence\": \"USP7 overexpression/inhibitor, ubiquitination assays, proteasome vs lysosome inhibitor discrimination, and Co-IP\",\n      \"pmids\": [\"34331380\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase opposing USP7 not identified\", \"Direct versus indirect USP7\\u2013PRICKLE1 interaction not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided in vivo causal evidence that the PRICKLE1\\u2013REST interaction underlies synaptic and behavioral phenotypes relevant to epilepsy and ASD.\",\n      \"evidence\": \"CRISPR R104Q knock-in mice with Co-IP, synaptic marker quantification, and behavioral/seizure-threshold assays\",\n      \"pmids\": [\"34597683\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How REST destabilization reduces excitatory synapse density mechanistically not defined\", \"Whether noncanonical WNT functions also contribute not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Separated PRICKLE1's basement-membrane secretion function from its apicobasal polarity function using rescue experiments, showing BM deposition depends on microtubule-based vesicle trafficking.\",\n      \"evidence\": \"iPSC-derived embryoid body rescue, microtubule network analysis, and vesicle trafficking assays\",\n      \"pmids\": [\"38185785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cargo adaptors used by PRICKLE1 for BM secretion not identified\", \"Why polarity is not rescued by PRICKLE1 reintroduction unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed PRICKLE1 in an estrogen-receptor/EZH2 transcriptional circuit and established it as required for REST protein stability in myometrial cells.\",\n      \"evidence\": \"ChIP for EZH2/H3K27me3 at the PRICKLE1 promoter, EZH2 siRNA, PRICKLE1 overexpression, and conditional knockout mice (preprint)\",\n      \"pmids\": [\"39314474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PRICKLE1 stabilizes REST protein not defined\", \"Preprint status; requires peer-reviewed confirmation\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapped the PRICKLE1 proximity interactome and challenged the model that PRICKLE1 regulates DVL2/DVL3 levels or phosphorylation under near-physiological expression.\",\n      \"evidence\": \"miniTurboID proximity biotinylation with mass spectrometry in an inducible expression system (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.24.644882\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Negative result for DVL regulation awaits independent replication\", \"Single preprint; physiological expression levels need validation against earlier overexpression studies\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined an apical-cortex pool of PRICKLE1 that drives actomyosin accumulation and apical constriction to power convergence and EMT-driven ingression independently of classical planar polarity.\",\n      \"evidence\": \"Quantitative live imaging in transgenic quail embryos with loss-of-function and actomyosin/polarity marker readouts\",\n      \"pmids\": [\"42045189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between cortical PRICKLE1 and actomyosin recruitment not defined\", \"Relationship to casein-kinase-II-dependent cortical regulation not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether PRICKLE1's distinct outputs \\u2014 DVL antagonism, mTORC2/AKT signaling, REST stabilization, cortical actomyosin control, and ECM secretion \\u2014 reflect a single unifying biochemical activity or separable context-specific modules remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model unifies the LIM/farnesyl-dependent interactions\", \"Mechanism by which PRICKLE1 stabilizes REST protein remains unknown\", \"The reported negative DVL-regulation result conflicts with earlier overexpression findings and is unreconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 9]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 17]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 16]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8, 12, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 10, 12, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"complexes\": [\n      \"PRICKLE1\\u2013MINK1\\u2013RICTOR (mTORC2-associated) complex\"\n    ],\n    \"partners\": [\n      \"DVL1\",\n      \"DVL2\",\n      \"DVL3\",\n      \"REST\",\n      \"RICTOR\",\n      \"MINK1\",\n      \"SYN1\",\n      \"USP7\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}