{"gene":"PRICKLE2","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2003,"finding":"Human PRICKLE2 (corresponding to DKFZp686D143 cDNA) was identified as a homolog of Drosophila prickle, sharing conserved PET domain, three LIM domains, and a C-terminal Prickle homologous (PKH) domain. The PKH domain distinguishes PRICKLE1/2 from related LIM-domain proteins LMO6 and TESTIN.","method":"Bioinformatics/sequence analysis and domain architecture comparison","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental functional validation","pmids":["12525887"],"is_preprint":false},{"year":2007,"finding":"Mouse Prickle2 is expressed specifically in postmitotic neurons throughout embryonic brain development, and siRNA-mediated depletion of Prickle2 in Neuro2a neuroblastoma cells decreases neurite outgrowth levels.","method":"Immunohistochemistry, in situ hybridization, siRNA knockdown in Neuro2a cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — knockdown with defined cellular phenotype, replicated for both Prickle1 and Prickle2, single lab","pmids":["17868671"],"is_preprint":false},{"year":2011,"finding":"Prickle2 is tightly associated with the postsynaptic density (PSD) fraction and localizes at the PSD of asymmetric synapses in the hippocampal CA1 region. Biochemical assays showed that Pk2 forms a complex with PSD-95 and NMDA receptor subunits via direct binding to the C-terminal guanylate kinase (GK) domain of PSD-95.","method":"Subcellular fractionation, immunoelectron microscopy, co-immunoprecipitation, direct binding assay (GST pulldown)","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, direct binding assay identifying specific domain interaction, immunoelectron microscopy for localization, replicated by independent labs","pmids":["21324980"],"is_preprint":false},{"year":2012,"finding":"Prickle2 associates with Dishevelled1 (Dvl1) and overexpression of Prickle2 reduces Dvl1 protein levels in C1300 neuroblastoma cells. Prickle2-induced neurite-like process formation is blocked by Dvl1 overexpression, placing Prickle2 upstream of Dvl1 in promoting neurite outgrowth.","method":"Co-immunoprecipitation, overexpression and western blot in C1300 cells, epistasis by double overexpression","journal":"Methods in molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus genetic epistasis (double overexpression rescue), single lab","pmids":["22218901"],"is_preprint":false},{"year":2012,"finding":"Prickle2 localizes to the nucleus (not cytoplasm) from the 2-cell to ~16-cell stage in mouse embryos. Farnesylation is required for nuclear localization of Pk2, and nuclear (but not cytoplasmic) Pk2 rescues the apical-basal polarity defect in Pk2-/- embryos. Nuclear Pk2 is required for GTP-bound active RhoA accumulation during compaction and proper apical-basal polarity establishment.","method":"Live imaging, nuclear/cytoplasmic rescue constructs, farnesylation inhibitor treatment, RhoA activity assay, Pk2 knockout mouse embryo analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rescue experiments with defined constructs (nuclear vs cytoplasmic), KO phenotype, farnesylation inhibitor, multiple orthogonal methods in single study","pmids":["22333836"],"is_preprint":false},{"year":2013,"finding":"Disruption of Prickle2 in mice leads to reduced dendrite branching, decreased synapse number, reduced PSD size, and decreased frequency and size of spontaneous miniature synaptic currents in hippocampal neurons. Human ASD-associated PRICKLE2 variants (p.E8Q, p.V153I) show deficits in these morphological and electrophysiological assays compared to wild-type PRICKLE2.","method":"Prickle2 knockout/disrupted mouse model, hippocampal neuron culture morphology analysis, whole-cell patch clamp electrophysiology, human variant functional assays","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined cellular phenotype, electrophysiology, functional testing of human variants, multiple orthogonal methods","pmids":["23711981"],"is_preprint":false},{"year":2014,"finding":"Prickle2-deficient mice display abnormal morphology and motility of ependymal motile cilia and abnormal tracheal motile cilia morphology, demonstrating that Prickle2 is required for normal motile cilia development and function.","method":"Prickle2 knockout mouse analysis, high-speed video microscopy of cilia, electron microscopy of cilia morphology","journal":"Journal of neurogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotype, single lab","pmids":["24708399"],"is_preprint":false},{"year":2014,"finding":"pk2 knockdown in zebrafish disrupts Kupffer's vesicle (a ciliated organ) formation. pk2 knockdown suppresses bbs7-related retrograde intracellular transport delay. pk2 knockdown itself causes a delay in anterograde intracellular transport, revealing a novel role for Pk2 in directional intracellular transport. BBS protein complex formation was preserved in Pk2-/- mice, indicating PCP and BBS pathways function independently.","method":"Morpholino knockdown in zebrafish, melanosome transport assay, Kupffer's vesicle formation assay, genetic epistasis (double knockdown), BBS complex immunoprecipitation in Pk2-/- mouse","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple knockdown experiments with defined phenotypes, genetic epistasis, cross-validated in mouse and zebrafish","pmids":["24938409"],"is_preprint":false},{"year":2015,"finding":"The PDZ interaction of Vangl2 enhances protein interactions between PSD-95 and Prickle2 at the postsynaptic density, linking these three proteins into a complex at synapses.","method":"Co-immunoprecipitation in transfected cells and hippocampal neurons, PDZ-binding motif deletion constructs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with deletion mutants, single lab, functional link established through domain analysis","pmids":["26257100"],"is_preprint":false},{"year":2019,"finding":"Vangl2 physically interacts with Prickle2 and promotes its proteasomal degradation. Vangl2 enhances polyubiquitination of Prickle2 in a Cullin-1 E3 ubiquitin ligase-dependent manner via Lys48-linked polyubiquitin chains, establishing a post-translational regulatory mechanism that limits Prickle2 protein levels.","method":"Co-immunoprecipitation, proteasome inhibitor treatment, Cullin-1 dominant-negative and siRNA, ubiquitin Lys48 mutant co-expression, polyubiquitination assay in HEK293T cells","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in-cell ubiquitination assay with mechanistic dissection (specific ubiquitin chain type, specific E3 ligase identified), multiple orthogonal methods, single lab","pmids":["30814664"],"is_preprint":false},{"year":2022,"finding":"Prickle2 colocalizes with AnkG480 (the AIS master organizer) at the axonal initial segment (AIS) and directly binds AnkG480. By regulating AnkG480, Prickle2 modulates its ability to bundle microtubules, which is required for neuronal polarity establishment and AIS formation. Prickle2 depletion alters cytoskeleton organization, reduces axon number, impairs AIS maturation, and decreases action potential firing.","method":"Immunofluorescence colocalization, co-immunoprecipitation (binding assay), siRNA knockdown in neurons, microtubule bundling assay, whole-cell patch clamp electrophysiology","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay identifying specific interaction partner (AnkG480), functional consequence (microtubule bundling, AP firing) via KD with multiple orthogonal methods","pmids":["36083912"],"is_preprint":false},{"year":2022,"finding":"In the mouse airway epithelium, Prickle2 segregates asymmetrically within multiciliated cells (consistent with core PCP protein behavior) but is absent from other airway cell types. Prickle2 mutant mice show modest ciliary polarity defects. Prickle1 and Prickle2 mutants genetically interact, indicating partially overlapping functions in airway epithelial polarization.","method":"Immunofluorescence localization in airway epithelium, Prickle2 mutant mouse phenotyping, genetic interaction analysis (double mutant)","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cellular phenotype, direct localization experiment, genetic epistasis, single lab","pmids":["36176272"],"is_preprint":false},{"year":2025,"finding":"The LIM domain-containing region (LCR) of Prickle2 binds strained/stressed actin filaments in Xenopus mesoderm. In the full-length protein, both the structured PET domain and the unstructured C-terminal region suppress LCR recruitment to strained actin and instead promote recruitment to Pk2-rich nodes. Two human patient-derived epilepsy-associated variants result in loss of Pk2-LCR recruitment to actin filaments.","method":"Live imaging in Xenopus mesoderm, structure-function analysis with domain deletion/fusion constructs, human variant functional assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo actin binding assay with domain dissection and mutagenesis, functional testing of patient variants, multiple orthogonal constructs in single study","pmids":["41160432"],"is_preprint":false},{"year":2025,"finding":"Prickle2 increases tissue fluidity in Xenopus neuroectoderm by promoting remodeling of apical junctions (AJs). This activity requires Rac1 and is mediated by the evolutionarily conserved Ser/Thr-rich region (STR) in the C-terminal half of Pk2. Pk2 depletion leads to accumulation of mediolaterally oriented cells, and overexpression promotes anteroposterior cell elongation.","method":"Xenopus loss-of-function/gain-of-function, live imaging of junction dynamics (C-cadherin dynamics, tricellular junctions), domain mapping (STR constructs), Rac1 inhibition","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain mapping, genetic epistasis with Rac1, live imaging of junction dynamics, KD and OE with defined phenotypes, multiple orthogonal methods","pmids":["39951022"],"is_preprint":false},{"year":2025,"finding":"Prickle2 knockdown in tooth organ cultures alters histogenesis and signaling molecule expression. In a pulp exposure animal model, siRNA-mediated knockdown of Prickle2 facilitated dentinal bridge formation, suggesting Prickle2 regulates dentinogenesis through Wnt/PCP signaling.","method":"In situ hybridization, siRNA knockdown in organ culture, renal capsule transplantation, pulp exposure animal model","journal":"International endodontic journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo knockdown with defined phenotypic readout (dentinal bridge formation), single lab, mechanistic pathway placement inferred","pmids":["40916368"],"is_preprint":false}],"current_model":"PRICKLE2 is a core planar cell polarity (PCP) protein that acts as a post-synaptic scaffold (binding PSD-95 via the GK domain and forming complexes with NMDA receptors), regulates neuronal polarity by binding AnkG480 to modulate microtubule bundling at the axonal initial segment, promotes neurite outgrowth by antagonizing Dishevelled1, binds strained actin filaments through its LIM domains (suppressed by the PET domain and C-terminal region in the full-length protein), promotes apical junction remodeling and tissue fluidity through its Ser/Thr-rich region in a Rac1-dependent manner, requires nuclear localization (dependent on farnesylation) for establishing apical-basal cell polarity in early embryogenesis, and is regulated post-translationally by Vangl2-mediated Cullin-1/Lys48 polyubiquitination leading to proteasomal degradation."},"narrative":{"mechanistic_narrative":"PRICKLE2 is a core planar cell polarity (PCP) protein with a conserved PET domain, three LIM domains, and a C-terminal Prickle-homologous region that functions across neuronal development, epithelial morphogenesis, and ciliated organ formation [PMID:12525887, PMID:23711981, PMID:36176272]. In neurons it operates as a postsynaptic scaffold, binding directly to the guanylate kinase domain of PSD-95 and assembling into a complex with NMDA receptor subunits at asymmetric synapses [PMID:21324980]; loss of Prickle2 reduces dendrite branching, synapse number, PSD size, and synaptic currents, and autism- and epilepsy-associated PRICKLE2 variants recapitulate these deficits [PMID:23711981]. Beyond the synapse, Prickle2 directly binds AnkG480 at the axonal initial segment to modulate microtubule bundling, neuronal polarity, AIS maturation, and action-potential firing [PMID:36083912], and promotes neurite outgrowth by associating with and lowering Dishevelled1 levels [PMID:22218901]. During morphogenesis, Prickle2 drives apical-junction remodeling and tissue fluidity in a Rac1-dependent manner through its Ser/Thr-rich region [PMID:39951022], and its LIM-containing region binds strained actin filaments — a recruitment normally restrained by the PET domain and C-terminal region and abolished by epilepsy-associated variants [PMID:41160432]. In early embryogenesis, farnesylation-dependent nuclear localization of Prickle2 is required for active RhoA accumulation and apical-basal polarity establishment [PMID:22333836], and the protein is also required for normal motile cilia and ciliated-organ development [PMID:24708399, PMID:24938409, PMID:36176272]. Prickle2 protein levels are constrained post-translationally by Vangl2, which promotes its Cullin-1-dependent, Lys48-linked polyubiquitination and proteasomal degradation [PMID:30814664].","teleology":[{"year":2003,"claim":"Established the domain architecture defining PRICKLE2 as a vertebrate Prickle homolog, fixing the PET/LIM/PKH module that later structure-function studies would dissect.","evidence":"Bioinformatic sequence and domain comparison of human PRICKLE2 against Drosophila prickle","pmids":["12525887"],"confidence":"Low","gaps":["Computational prediction only with no functional validation","No cellular role or localization tested"]},{"year":2007,"claim":"Linked PRICKLE2 expression to postmitotic neurons and gave it a first functional readout — neurite outgrowth — defining a neuronal context for later mechanistic work.","evidence":"Immunohistochemistry, in situ hybridization, and siRNA knockdown in Neuro2a cells","pmids":["17868671"],"confidence":"Medium","gaps":["No molecular mechanism for the outgrowth phenotype","Single neuroblastoma line, no primary neurons"]},{"year":2011,"claim":"Resolved how Prickle2 acts at the synapse by identifying direct binding to the PSD-95 GK domain and complex formation with NMDA receptors, establishing a postsynaptic scaffolding role.","evidence":"Subcellular fractionation, immunoelectron microscopy, reciprocal co-IP, and GST pulldown","pmids":["21324980"],"confidence":"High","gaps":["Functional consequence of the complex for receptor signaling not measured here","Stoichiometry and regulation of complex assembly unknown"]},{"year":2012,"claim":"Placed Prickle2 upstream of Dishevelled1 in neurite outgrowth, providing a mechanistic link to PCP/Wnt machinery in neurons.","evidence":"Co-IP, overexpression western blot, and double-overexpression epistasis in C1300 cells","pmids":["22218901"],"confidence":"Medium","gaps":["Mechanism of Dvl1 level reduction not defined","Single cell line, overexpression-based"]},{"year":2012,"claim":"Demonstrated a farnesylation-dependent nuclear requirement for Prickle2 in early embryos, showing nuclear Pk2 drives active RhoA and apical-basal polarity — an unexpected non-cytoplasmic PCP function.","evidence":"Nuclear vs cytoplasmic rescue constructs, farnesylation inhibitor, RhoA activity assay in Pk2-/- mouse embryos","pmids":["22333836"],"confidence":"High","gaps":["Nuclear targets/effectors of Pk2 unidentified","Mechanism linking nuclear Pk2 to RhoA activation unknown"]},{"year":2013,"claim":"Connected Prickle2 loss to defined synaptic and dendritic deficits and showed human ASD-associated variants are functionally impaired, tying the gene to neurodevelopmental disease.","evidence":"Prickle2 knockout mouse, hippocampal neuron morphology, patch-clamp electrophysiology, human variant assays","pmids":["23711981"],"confidence":"High","gaps":["Molecular pathway linking Pk2 to spine/synapse maintenance not fully resolved","Variant mechanism at the protein level not dissected"]},{"year":2014,"claim":"Extended Prickle2 function to motile cilia and directional intracellular transport, and showed PCP and BBS pathways act independently.","evidence":"Prickle2 KO mouse cilia imaging/EM; zebrafish morpholino knockdown, melanosome transport and Kupffer's vesicle assays, BBS complex IP","pmids":["24708399","24938409"],"confidence":"Medium","gaps":["Molecular basis of the transport defect unknown","How Pk2 affects ciliary motility mechanistically not defined"]},{"year":2015,"claim":"Integrated Vangl2 into the synaptic Pk2-PSD-95 complex via its PDZ interaction, linking core PCP components at the postsynaptic density.","evidence":"Co-IP in cells and hippocampal neurons with PDZ-binding motif deletion constructs","pmids":["26257100"],"confidence":"Medium","gaps":["Functional output of the tripartite complex not measured","Single lab, no structural detail"]},{"year":2019,"claim":"Defined how Prickle2 levels are controlled, showing Vangl2 drives Cullin-1-dependent, Lys48-linked polyubiquitination and proteasomal degradation of Pk2.","evidence":"Co-IP, proteasome inhibitor, Cullin-1 dominant-negative/siRNA, ubiquitin K48 mutant, in-cell ubiquitination assay in HEK293T","pmids":["30814664"],"confidence":"High","gaps":["Physiological contexts where Vangl2-driven degradation operates not mapped","Substrate recognition adaptor not identified"]},{"year":2022,"claim":"Identified AnkG480 as a direct Prickle2 partner at the axonal initial segment, mechanistically connecting Pk2 to microtubule bundling, neuronal polarity, and excitability.","evidence":"Colocalization, co-IP binding assay, siRNA knockdown, microtubule bundling assay, patch-clamp in neurons","pmids":["36083912"],"confidence":"High","gaps":["How Pk2 regulates AnkG480 bundling activity biochemically unclear","Relationship between AIS and synaptic Pk2 pools unknown"]},{"year":2022,"claim":"Confirmed Prickle2 behaves as an asymmetrically segregating core PCP protein in multiciliated airway cells and genetically interacts with Prickle1, indicating partial functional redundancy.","evidence":"Immunofluorescence localization, Prickle2 mutant phenotyping, double-mutant genetic interaction in mouse airway","pmids":["36176272"],"confidence":"Medium","gaps":["Modest single-mutant phenotype limits resolution of Pk2-specific role","Molecular basis of asymmetric segregation not addressed"]},{"year":2025,"claim":"Revealed mechanochemical regulation of Prickle2: its LIM-containing region binds strained actin, restrained by the PET and C-terminal domains, with epilepsy-associated variants abolishing actin recruitment.","evidence":"Live imaging in Xenopus mesoderm with domain deletion/fusion constructs and patient-variant assays","pmids":["41160432"],"confidence":"High","gaps":["Functional consequence of strained-actin binding in vivo not fully defined","How node vs actin partitioning is switched physiologically unknown"]},{"year":2025,"claim":"Showed Prickle2 promotes tissue fluidity through Rac1-dependent apical-junction remodeling via its Ser/Thr-rich region, linking molecular activity to cell-shape and convergent-extension behavior.","evidence":"Xenopus loss/gain-of-function, live imaging of junction dynamics, STR domain mapping, Rac1 inhibition","pmids":["39951022"],"confidence":"High","gaps":["How the STR engages Rac1 signaling biochemically not defined","Mammalian relevance of the fluidity role untested"]},{"year":2025,"claim":"Implicated Prickle2 in dentinogenesis via Wnt/PCP signaling, broadening its developmental roles.","evidence":"In situ hybridization, siRNA knockdown in tooth organ culture, transplantation, pulp exposure model","pmids":["40916368"],"confidence":"Medium","gaps":["Direct molecular targets in dentinogenesis not identified","Pathway placement inferred rather than directly demonstrated"]},{"year":null,"claim":"How Prickle2's distinct molecular activities — synaptic scaffolding, AIS microtubule regulation, nuclear RhoA control, and mechanosensitive actin binding — are coordinated within a single cell, and which are shared versus context-specific, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking nuclear, synaptic, AIS, and junctional pools","Structural basis of LIM-domain partner selection unknown","Upstream signals switching Pk2 between functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,8,10]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[10,12]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,11]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[6,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,13]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,5,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,13,11]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[9]}],"complexes":["PSD-95/NMDA receptor postsynaptic complex","Vangl2-Cullin-1 ubiquitination complex"],"partners":["PSD-95","NMDA RECEPTOR SUBUNITS","DVL1","VANGL2","ANKG480","CULLIN-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z3G6","full_name":"Prickle-like protein 2","aliases":[],"length_aa":844,"mass_kda":95.6,"function":"Is involved in the organization and maintenance of axon initial segment (AIS) architecture, likely cooperating with IGSF9B to regulate ANK3/ANKG localization to AIS (By similarity). By binding to and regulating ANK3/ANKG, it modulates its ability to bundle microtubules, a crucial mechanism for establishing neuronal polarity and AIS formation (By similarity). During early embryonic development, has a role in blastocyst formation, likely controlling the redistribution of the microtubule network during embryo compaction and the establishment of apical/basal cell polarity (By similarity)","subcellular_location":"Postsynaptic density; Cell projection, axon; Cell projection, dendrite; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q7Z3G6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRICKLE2","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/PRICKLE2","total_profiled":1310},"omim":[{"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"},{"mim_id":"607590","title":"BBS7 GENE; BBS7","url":"https://www.omim.org/entry/607590"},{"mim_id":"607459","title":"SENSORY ATAXIC NEUROPATHY, DYSARTHRIA, AND OPHTHALMOPARESIS; SANDO","url":"https://www.omim.org/entry/607459"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PRICKLE2"},"hgnc":{"alias_symbol":["DKFZp686D143"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z3G6","domains":[{"cath_id":"2.10.110.10","chopping":"33-192","consensus_level":"medium","plddt":92.6467,"start":33,"end":192},{"cath_id":"2.10.110.10","chopping":"259-313","consensus_level":"medium","plddt":92.4375,"start":259,"end":313}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z3G6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z3G6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z3G6-F1-predicted_aligned_error_v6.png","plddt_mean":56.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRICKLE2","jax_strain_url":"https://www.jax.org/strain/search?query=PRICKLE2"},"sequence":{"accession":"Q7Z3G6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z3G6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z3G6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z3G6"}},"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":"23711981","id":"PMC_23711981","title":"Disruption of the non-canonical Wnt gene PRICKLE2 leads to autism-like behaviors with evidence for hippocampal synaptic dysfunction.","date":"2013","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/23711981","citation_count":76,"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":"22333836","id":"PMC_22333836","title":"Nuclear localization of Prickle2 is required to establish cell polarity during early mouse embryogenesis.","date":"2012","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22333836","citation_count":39,"is_preprint":false},{"pmid":"21324980","id":"PMC_21324980","title":"Prickle2 is localized in the postsynaptic density and interacts with PSD-95 and NMDA receptors in the brain.","date":"2011","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21324980","citation_count":29,"is_preprint":false},{"pmid":"25193415","id":"PMC_25193415","title":"3p interstitial deletion including PRICKLE2 in identical twins with autistic features.","date":"2014","source":"Pediatric neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25193415","citation_count":18,"is_preprint":false},{"pmid":"36083912","id":"PMC_36083912","title":"The core PCP protein Prickle2 regulates axon number and AIS maturation by binding to AnkG and modulating microtubule bundling.","date":"2022","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36083912","citation_count":15,"is_preprint":false},{"pmid":"30814664","id":"PMC_30814664","title":"Vangl2 interaction plays a role in the proteasomal degradation of Prickle2.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30814664","citation_count":15,"is_preprint":false},{"pmid":"26257100","id":"PMC_26257100","title":"PDZ interaction of Vangl2 links PSD-95 and Prickle2 but plays only a limited role in the synaptic localisation of Vangl2.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26257100","citation_count":15,"is_preprint":false},{"pmid":"33015060","id":"PMC_33015060","title":"Upregulation of Prickle2 Ameliorates Alzheimer's Disease-Like Pathology in a Transgenic Mouse Model of Alzheimer's Disease.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33015060","citation_count":11,"is_preprint":false},{"pmid":"34092786","id":"PMC_34092786","title":"PRICKLE2 revisited-further evidence implicating PRICKLE2 in neurodevelopmental disorders.","date":"2021","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/34092786","citation_count":10,"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":"24708399","id":"PMC_24708399","title":"Defective motile cilia in Prickle2-deficient mice.","date":"2014","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/24708399","citation_count":9,"is_preprint":false},{"pmid":"33850895","id":"PMC_33850895","title":"Circular RNA hsa-circ-000881 suppresses the progression of lung adenocarcinoma in vitro via a miR-665/PRICKLE2 axis.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33850895","citation_count":9,"is_preprint":false},{"pmid":"39951022","id":"PMC_39951022","title":"Prickle2 regulates apical junction remodeling and tissue fluidity during vertebrate neurulation.","date":"2025","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/39951022","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":"24938409","id":"PMC_24938409","title":"Functional characterization of Prickle2 and BBS7 identify overlapping phenotypes yet distinct mechanisms.","date":"2014","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/24938409","citation_count":7,"is_preprint":false},{"pmid":"38165577","id":"PMC_38165577","title":"Knockdown of the Non-canonical Wnt Gene Prickle2 Leads to Cerebellar Purkinje Cell Abnormalities While Cerebellar-Mediated Behaviors Remain Intact.","date":"2024","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38165577","citation_count":5,"is_preprint":false},{"pmid":"40916368","id":"PMC_40916368","title":"Modulation of Prickle2 Expression to Facilitate Dentine Formation: A Laboratory Investigation.","date":"2025","source":"International endodontic journal","url":"https://pubmed.ncbi.nlm.nih.gov/40916368","citation_count":1,"is_preprint":false},{"pmid":"39754765","id":"PMC_39754765","title":"Decoding Epilepsy: Prickle2 and Multifaceted Molecular Pathway Connections.","date":"2025","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/39754765","citation_count":0,"is_preprint":false},{"pmid":"40009262","id":"PMC_40009262","title":"Evolving Insights into Prickle2 in Neurodevelopment and Neurological Disorders.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40009262","citation_count":0,"is_preprint":false},{"pmid":"39005435","id":"PMC_39005435","title":"Prickle2 regulates apical junction remodeling and tissue fluidity during vertebrate neurulation.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39005435","citation_count":0,"is_preprint":false},{"pmid":"41160432","id":"PMC_41160432","title":"Strained actin binding by the Prickle2 LIM domains and their regulation in the full-length protein.","date":"2025","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/41160432","citation_count":0,"is_preprint":false},{"pmid":"40501967","id":"PMC_40501967","title":"Stressed Actin Binding by the Prickle2 LIM Domains and its Regulation in the Full-Length Protein.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40501967","citation_count":0,"is_preprint":false},{"pmid":"41794019","id":"PMC_41794019","title":"Generation of hiPSCs lines from PRICKLE2-mutant individuals with epilepsy.","date":"2026","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41794019","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":14056,"output_tokens":3858,"usd":0.050019,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11600,"output_tokens":4497,"usd":0.085212,"stage2_stop_reason":"end_turn"},"total_usd":0.135231,"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\": 2003,\n      \"finding\": \"Human PRICKLE2 (corresponding to DKFZp686D143 cDNA) was identified as a homolog of Drosophila prickle, sharing conserved PET domain, three LIM domains, and a C-terminal Prickle homologous (PKH) domain. The PKH domain distinguishes PRICKLE1/2 from related LIM-domain proteins LMO6 and TESTIN.\",\n      \"method\": \"Bioinformatics/sequence analysis and domain architecture comparison\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental functional validation\",\n      \"pmids\": [\"12525887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Mouse Prickle2 is expressed specifically in postmitotic neurons throughout embryonic brain development, and siRNA-mediated depletion of Prickle2 in Neuro2a neuroblastoma cells decreases neurite outgrowth levels.\",\n      \"method\": \"Immunohistochemistry, in situ hybridization, siRNA knockdown in Neuro2a cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — knockdown with defined cellular phenotype, replicated for both Prickle1 and Prickle2, single lab\",\n      \"pmids\": [\"17868671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Prickle2 is tightly associated with the postsynaptic density (PSD) fraction and localizes at the PSD of asymmetric synapses in the hippocampal CA1 region. Biochemical assays showed that Pk2 forms a complex with PSD-95 and NMDA receptor subunits via direct binding to the C-terminal guanylate kinase (GK) domain of PSD-95.\",\n      \"method\": \"Subcellular fractionation, immunoelectron microscopy, co-immunoprecipitation, direct binding assay (GST pulldown)\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, direct binding assay identifying specific domain interaction, immunoelectron microscopy for localization, replicated by independent labs\",\n      \"pmids\": [\"21324980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Prickle2 associates with Dishevelled1 (Dvl1) and overexpression of Prickle2 reduces Dvl1 protein levels in C1300 neuroblastoma cells. Prickle2-induced neurite-like process formation is blocked by Dvl1 overexpression, placing Prickle2 upstream of Dvl1 in promoting neurite outgrowth.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and western blot in C1300 cells, epistasis by double overexpression\",\n      \"journal\": \"Methods in molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus genetic epistasis (double overexpression rescue), single lab\",\n      \"pmids\": [\"22218901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Prickle2 localizes to the nucleus (not cytoplasm) from the 2-cell to ~16-cell stage in mouse embryos. Farnesylation is required for nuclear localization of Pk2, and nuclear (but not cytoplasmic) Pk2 rescues the apical-basal polarity defect in Pk2-/- embryos. Nuclear Pk2 is required for GTP-bound active RhoA accumulation during compaction and proper apical-basal polarity establishment.\",\n      \"method\": \"Live imaging, nuclear/cytoplasmic rescue constructs, farnesylation inhibitor treatment, RhoA activity assay, Pk2 knockout mouse embryo analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rescue experiments with defined constructs (nuclear vs cytoplasmic), KO phenotype, farnesylation inhibitor, multiple orthogonal methods in single study\",\n      \"pmids\": [\"22333836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Disruption of Prickle2 in mice leads to reduced dendrite branching, decreased synapse number, reduced PSD size, and decreased frequency and size of spontaneous miniature synaptic currents in hippocampal neurons. Human ASD-associated PRICKLE2 variants (p.E8Q, p.V153I) show deficits in these morphological and electrophysiological assays compared to wild-type PRICKLE2.\",\n      \"method\": \"Prickle2 knockout/disrupted mouse model, hippocampal neuron culture morphology analysis, whole-cell patch clamp electrophysiology, human variant functional assays\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined cellular phenotype, electrophysiology, functional testing of human variants, multiple orthogonal methods\",\n      \"pmids\": [\"23711981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Prickle2-deficient mice display abnormal morphology and motility of ependymal motile cilia and abnormal tracheal motile cilia morphology, demonstrating that Prickle2 is required for normal motile cilia development and function.\",\n      \"method\": \"Prickle2 knockout mouse analysis, high-speed video microscopy of cilia, electron microscopy of cilia morphology\",\n      \"journal\": \"Journal of neurogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotype, single lab\",\n      \"pmids\": [\"24708399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"pk2 knockdown in zebrafish disrupts Kupffer's vesicle (a ciliated organ) formation. pk2 knockdown suppresses bbs7-related retrograde intracellular transport delay. pk2 knockdown itself causes a delay in anterograde intracellular transport, revealing a novel role for Pk2 in directional intracellular transport. BBS protein complex formation was preserved in Pk2-/- mice, indicating PCP and BBS pathways function independently.\",\n      \"method\": \"Morpholino knockdown in zebrafish, melanosome transport assay, Kupffer's vesicle formation assay, genetic epistasis (double knockdown), BBS complex immunoprecipitation in Pk2-/- mouse\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple knockdown experiments with defined phenotypes, genetic epistasis, cross-validated in mouse and zebrafish\",\n      \"pmids\": [\"24938409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The PDZ interaction of Vangl2 enhances protein interactions between PSD-95 and Prickle2 at the postsynaptic density, linking these three proteins into a complex at synapses.\",\n      \"method\": \"Co-immunoprecipitation in transfected cells and hippocampal neurons, PDZ-binding motif deletion constructs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with deletion mutants, single lab, functional link established through domain analysis\",\n      \"pmids\": [\"26257100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Vangl2 physically interacts with Prickle2 and promotes its proteasomal degradation. Vangl2 enhances polyubiquitination of Prickle2 in a Cullin-1 E3 ubiquitin ligase-dependent manner via Lys48-linked polyubiquitin chains, establishing a post-translational regulatory mechanism that limits Prickle2 protein levels.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor treatment, Cullin-1 dominant-negative and siRNA, ubiquitin Lys48 mutant co-expression, polyubiquitination assay in HEK293T cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in-cell ubiquitination assay with mechanistic dissection (specific ubiquitin chain type, specific E3 ligase identified), multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30814664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Prickle2 colocalizes with AnkG480 (the AIS master organizer) at the axonal initial segment (AIS) and directly binds AnkG480. By regulating AnkG480, Prickle2 modulates its ability to bundle microtubules, which is required for neuronal polarity establishment and AIS formation. Prickle2 depletion alters cytoskeleton organization, reduces axon number, impairs AIS maturation, and decreases action potential firing.\",\n      \"method\": \"Immunofluorescence colocalization, co-immunoprecipitation (binding assay), siRNA knockdown in neurons, microtubule bundling assay, whole-cell patch clamp electrophysiology\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay identifying specific interaction partner (AnkG480), functional consequence (microtubule bundling, AP firing) via KD with multiple orthogonal methods\",\n      \"pmids\": [\"36083912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In the mouse airway epithelium, Prickle2 segregates asymmetrically within multiciliated cells (consistent with core PCP protein behavior) but is absent from other airway cell types. Prickle2 mutant mice show modest ciliary polarity defects. Prickle1 and Prickle2 mutants genetically interact, indicating partially overlapping functions in airway epithelial polarization.\",\n      \"method\": \"Immunofluorescence localization in airway epithelium, Prickle2 mutant mouse phenotyping, genetic interaction analysis (double mutant)\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cellular phenotype, direct localization experiment, genetic epistasis, single lab\",\n      \"pmids\": [\"36176272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The LIM domain-containing region (LCR) of Prickle2 binds strained/stressed actin filaments in Xenopus mesoderm. In the full-length protein, both the structured PET domain and the unstructured C-terminal region suppress LCR recruitment to strained actin and instead promote recruitment to Pk2-rich nodes. Two human patient-derived epilepsy-associated variants result in loss of Pk2-LCR recruitment to actin filaments.\",\n      \"method\": \"Live imaging in Xenopus mesoderm, structure-function analysis with domain deletion/fusion constructs, human variant functional assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo actin binding assay with domain dissection and mutagenesis, functional testing of patient variants, multiple orthogonal constructs in single study\",\n      \"pmids\": [\"41160432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Prickle2 increases tissue fluidity in Xenopus neuroectoderm by promoting remodeling of apical junctions (AJs). This activity requires Rac1 and is mediated by the evolutionarily conserved Ser/Thr-rich region (STR) in the C-terminal half of Pk2. Pk2 depletion leads to accumulation of mediolaterally oriented cells, and overexpression promotes anteroposterior cell elongation.\",\n      \"method\": \"Xenopus loss-of-function/gain-of-function, live imaging of junction dynamics (C-cadherin dynamics, tricellular junctions), domain mapping (STR constructs), Rac1 inhibition\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain mapping, genetic epistasis with Rac1, live imaging of junction dynamics, KD and OE with defined phenotypes, multiple orthogonal methods\",\n      \"pmids\": [\"39951022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Prickle2 knockdown in tooth organ cultures alters histogenesis and signaling molecule expression. In a pulp exposure animal model, siRNA-mediated knockdown of Prickle2 facilitated dentinal bridge formation, suggesting Prickle2 regulates dentinogenesis through Wnt/PCP signaling.\",\n      \"method\": \"In situ hybridization, siRNA knockdown in organ culture, renal capsule transplantation, pulp exposure animal model\",\n      \"journal\": \"International endodontic journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo knockdown with defined phenotypic readout (dentinal bridge formation), single lab, mechanistic pathway placement inferred\",\n      \"pmids\": [\"40916368\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRICKLE2 is a core planar cell polarity (PCP) protein that acts as a post-synaptic scaffold (binding PSD-95 via the GK domain and forming complexes with NMDA receptors), regulates neuronal polarity by binding AnkG480 to modulate microtubule bundling at the axonal initial segment, promotes neurite outgrowth by antagonizing Dishevelled1, binds strained actin filaments through its LIM domains (suppressed by the PET domain and C-terminal region in the full-length protein), promotes apical junction remodeling and tissue fluidity through its Ser/Thr-rich region in a Rac1-dependent manner, requires nuclear localization (dependent on farnesylation) for establishing apical-basal cell polarity in early embryogenesis, and is regulated post-translationally by Vangl2-mediated Cullin-1/Lys48 polyubiquitination leading to proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRICKLE2 is a core planar cell polarity (PCP) protein with a conserved PET domain, three LIM domains, and a C-terminal Prickle-homologous region that functions across neuronal development, epithelial morphogenesis, and ciliated organ formation [#0, #5, #11]. In neurons it operates as a postsynaptic scaffold, binding directly to the guanylate kinase domain of PSD-95 and assembling into a complex with NMDA receptor subunits at asymmetric synapses [#2]; loss of Prickle2 reduces dendrite branching, synapse number, PSD size, and synaptic currents, and autism- and epilepsy-associated PRICKLE2 variants recapitulate these deficits [#5]. Beyond the synapse, Prickle2 directly binds AnkG480 at the axonal initial segment to modulate microtubule bundling, neuronal polarity, AIS maturation, and action-potential firing [#10], and promotes neurite outgrowth by associating with and lowering Dishevelled1 levels [#3]. During morphogenesis, Prickle2 drives apical-junction remodeling and tissue fluidity in a Rac1-dependent manner through its Ser/Thr-rich region [#13], and its LIM-containing region binds strained actin filaments — a recruitment normally restrained by the PET domain and C-terminal region and abolished by epilepsy-associated variants [#12]. In early embryogenesis, farnesylation-dependent nuclear localization of Prickle2 is required for active RhoA accumulation and apical-basal polarity establishment [#4], and the protein is also required for normal motile cilia and ciliated-organ development [#6, #7, #11]. Prickle2 protein levels are constrained post-translationally by Vangl2, which promotes its Cullin-1-dependent, Lys48-linked polyubiquitination and proteasomal degradation [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the domain architecture defining PRICKLE2 as a vertebrate Prickle homolog, fixing the PET/LIM/PKH module that later structure-function studies would dissect.\",\n      \"evidence\": \"Bioinformatic sequence and domain comparison of human PRICKLE2 against Drosophila prickle\",\n      \"pmids\": [\"12525887\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational prediction only with no functional validation\", \"No cellular role or localization tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked PRICKLE2 expression to postmitotic neurons and gave it a first functional readout — neurite outgrowth — defining a neuronal context for later mechanistic work.\",\n      \"evidence\": \"Immunohistochemistry, in situ hybridization, and siRNA knockdown in Neuro2a cells\",\n      \"pmids\": [\"17868671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for the outgrowth phenotype\", \"Single neuroblastoma line, no primary neurons\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved how Prickle2 acts at the synapse by identifying direct binding to the PSD-95 GK domain and complex formation with NMDA receptors, establishing a postsynaptic scaffolding role.\",\n      \"evidence\": \"Subcellular fractionation, immunoelectron microscopy, reciprocal co-IP, and GST pulldown\",\n      \"pmids\": [\"21324980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the complex for receptor signaling not measured here\", \"Stoichiometry and regulation of complex assembly unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed Prickle2 upstream of Dishevelled1 in neurite outgrowth, providing a mechanistic link to PCP/Wnt machinery in neurons.\",\n      \"evidence\": \"Co-IP, overexpression western blot, and double-overexpression epistasis in C1300 cells\",\n      \"pmids\": [\"22218901\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Dvl1 level reduction not defined\", \"Single cell line, overexpression-based\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated a farnesylation-dependent nuclear requirement for Prickle2 in early embryos, showing nuclear Pk2 drives active RhoA and apical-basal polarity — an unexpected non-cytoplasmic PCP function.\",\n      \"evidence\": \"Nuclear vs cytoplasmic rescue constructs, farnesylation inhibitor, RhoA activity assay in Pk2-/- mouse embryos\",\n      \"pmids\": [\"22333836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear targets/effectors of Pk2 unidentified\", \"Mechanism linking nuclear Pk2 to RhoA activation unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected Prickle2 loss to defined synaptic and dendritic deficits and showed human ASD-associated variants are functionally impaired, tying the gene to neurodevelopmental disease.\",\n      \"evidence\": \"Prickle2 knockout mouse, hippocampal neuron morphology, patch-clamp electrophysiology, human variant assays\",\n      \"pmids\": [\"23711981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular pathway linking Pk2 to spine/synapse maintenance not fully resolved\", \"Variant mechanism at the protein level not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended Prickle2 function to motile cilia and directional intracellular transport, and showed PCP and BBS pathways act independently.\",\n      \"evidence\": \"Prickle2 KO mouse cilia imaging/EM; zebrafish morpholino knockdown, melanosome transport and Kupffer's vesicle assays, BBS complex IP\",\n      \"pmids\": [\"24708399\", \"24938409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the transport defect unknown\", \"How Pk2 affects ciliary motility mechanistically not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Integrated Vangl2 into the synaptic Pk2-PSD-95 complex via its PDZ interaction, linking core PCP components at the postsynaptic density.\",\n      \"evidence\": \"Co-IP in cells and hippocampal neurons with PDZ-binding motif deletion constructs\",\n      \"pmids\": [\"26257100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional output of the tripartite complex not measured\", \"Single lab, no structural detail\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined how Prickle2 levels are controlled, showing Vangl2 drives Cullin-1-dependent, Lys48-linked polyubiquitination and proteasomal degradation of Pk2.\",\n      \"evidence\": \"Co-IP, proteasome inhibitor, Cullin-1 dominant-negative/siRNA, ubiquitin K48 mutant, in-cell ubiquitination assay in HEK293T\",\n      \"pmids\": [\"30814664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where Vangl2-driven degradation operates not mapped\", \"Substrate recognition adaptor not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified AnkG480 as a direct Prickle2 partner at the axonal initial segment, mechanistically connecting Pk2 to microtubule bundling, neuronal polarity, and excitability.\",\n      \"evidence\": \"Colocalization, co-IP binding assay, siRNA knockdown, microtubule bundling assay, patch-clamp in neurons\",\n      \"pmids\": [\"36083912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Pk2 regulates AnkG480 bundling activity biochemically unclear\", \"Relationship between AIS and synaptic Pk2 pools unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed Prickle2 behaves as an asymmetrically segregating core PCP protein in multiciliated airway cells and genetically interacts with Prickle1, indicating partial functional redundancy.\",\n      \"evidence\": \"Immunofluorescence localization, Prickle2 mutant phenotyping, double-mutant genetic interaction in mouse airway\",\n      \"pmids\": [\"36176272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Modest single-mutant phenotype limits resolution of Pk2-specific role\", \"Molecular basis of asymmetric segregation not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed mechanochemical regulation of Prickle2: its LIM-containing region binds strained actin, restrained by the PET and C-terminal domains, with epilepsy-associated variants abolishing actin recruitment.\",\n      \"evidence\": \"Live imaging in Xenopus mesoderm with domain deletion/fusion constructs and patient-variant assays\",\n      \"pmids\": [\"41160432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of strained-actin binding in vivo not fully defined\", \"How node vs actin partitioning is switched physiologically unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed Prickle2 promotes tissue fluidity through Rac1-dependent apical-junction remodeling via its Ser/Thr-rich region, linking molecular activity to cell-shape and convergent-extension behavior.\",\n      \"evidence\": \"Xenopus loss/gain-of-function, live imaging of junction dynamics, STR domain mapping, Rac1 inhibition\",\n      \"pmids\": [\"39951022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the STR engages Rac1 signaling biochemically not defined\", \"Mammalian relevance of the fluidity role untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated Prickle2 in dentinogenesis via Wnt/PCP signaling, broadening its developmental roles.\",\n      \"evidence\": \"In situ hybridization, siRNA knockdown in tooth organ culture, transplantation, pulp exposure model\",\n      \"pmids\": [\"40916368\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets in dentinogenesis not identified\", \"Pathway placement inferred rather than directly demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Prickle2's distinct molecular activities — synaptic scaffolding, AIS microtubule regulation, nuclear RhoA control, and mechanosensitive actin binding — are coordinated within a single cell, and which are shared versus context-specific, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking nuclear, synaptic, AIS, and junctional pools\", \"Structural basis of LIM-domain partner selection unknown\", \"Upstream signals switching Pk2 between functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 8, 10]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [6, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 4, 13]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 5, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 13, 11]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [\n      \"PSD-95/NMDA receptor postsynaptic complex\",\n      \"Vangl2-Cullin-1 ubiquitination complex\"\n    ],\n    \"partners\": [\n      \"PSD-95\",\n      \"NMDA receptor subunits\",\n      \"DVL1\",\n      \"VANGL2\",\n      \"AnkG480\",\n      \"Cullin-1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}