{"gene":"PARD6B","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2005,"finding":"PARD6B protein localizes to the spindle during early mouse embryonic cleavages (before compaction) and then redistributes asymmetrically to the apical pole during compaction at the 8-cell stage, independently of cell-cell contacts. At the 16-cell stage it co-localizes with aPKCzeta, and in blastocysts PARD6B/PARD3/aPKCzeta co-localize at tight junctions.","method":"Immunofluorescence localization in preimplantation mouse embryos; cell-contact disruption experiments to test contact-dependence of apical localization","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with functional context (polarity establishment), single lab, two methods (immunofluorescence + contact disruption)","pmids":["15950600"],"is_preprint":false},{"year":2010,"finding":"PARD6B is required for blastocyst cavity formation, apical-basal polarity of outer cells, tight junction (TJ) formation (normal TJP1/ZO-1 distribution), and CDX2 expression in the mouse preimplantation embryo. Knockdown of Pard6b abolished apical localization of aPKCzeta and caused chimeric cavitation failure, demonstrating a cell-autonomous role upstream of aPKCzeta localization.","method":"RNAi knockdown via zygote microinjection; immunofluorescence for aPKCzeta, TJP1, CDX2; chimera assays","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with multiple orthogonal readouts (polarity, TJ, transcription factor), chimera rescue experiment, replicated in subsequent studies","pmids":["20505164"],"is_preprint":false},{"year":2012,"finding":"PAR6B is required for tight junction network formation and membrane localization of aPKCzeta in MCF7 breast cancer cells. siRNA-mediated depletion of PAR6B abolished TJ assembly and membrane aPKCzeta localization without affecting adherens junctions. siRNA depletion of CDC42 similarly abolished TJ networks, confirming that a complete PAR6B-aPKC-CDC42-PAR3 complex is necessary for TJ stabilization.","method":"siRNA knockdown of PAR6B and CDC42 in MCF7 cells; immunofluorescence for TJ markers and aPKCzeta; FISH copy number analysis; PARD6B mRNA/protein quantification","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype plus CDC42 epistasis, single lab, two orthogonal knockdown approaches","pmids":["22957302"],"is_preprint":false},{"year":2013,"finding":"In cochlear hair cells, aPKC/Par-3/Par-6b form an apical and distal asymmetrical expression domain that is opposite and complementary to the Gαi3/mPins domain, and non-overlapping with core PCP protein Vangl2, placing PARD6B in a distinct polarity module controlling apical cell identity separate from the core PCP pathway.","method":"Immunofluorescence co-localization in mouse cochlear hair cells; genetic deletion of Gαi3/mPins","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with genetic epistasis (Gαi3/mPins deletion), single lab","pmids":["23934215"],"is_preprint":false},{"year":2014,"finding":"RHO-ROCK signaling is required for segregation of apical (PARD6B, PRKCZ) and basal (SCRIB, LLGL1) polarity regulators in the mouse blastocyst. Treatment with ROCK inhibitor Y-27632 or RHO GTPase inhibitor dampened this segregation and disrupted Hippo signaling/YAP nuclear accumulation, placing RHO-ROCK upstream of PARD6B apical polarity in TE specification.","method":"Pharmacological inhibition (Y-27632, RHO GTPase inhibitor) of mouse embryos; immunofluorescence for PARD6B, PRKCZ, SCRIB, LLGL1, YAP; LATS1/2 co-inhibition rescue","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with multiple polarity markers and rescue experiment, single lab","pmids":["24997360"],"is_preprint":false},{"year":2015,"finding":"PAK4 phosphorylates Par6B at Ser143, and this phosphorylation blocks Par6B's interaction with Cdc42, providing a mechanism for controlling Par6B subcellular localization and its protein interactions downstream of Cdc42.","method":"In vitro kinase assay; site-directed mutagenesis (Ser143); Co-IP/interaction assays in human bronchial epithelial cells","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis identifying specific phosphorylation site and functional consequence on protein-protein interaction, single lab","pmids":["25662318"],"is_preprint":false},{"year":2015,"finding":"TFAP2C (AP-2γ) acts upstream of PARD6B: TFAP2C depletion caused downregulation of PARD6B and loss of apical cell polarity in outside blastomeres. Re-expression of Pard6b mRNA rescued cell polarity but only partially corrected position-dependent Hippo signaling, indicating TFAP2C controls Hippo signaling via PARD6B-dependent and PARD6B-independent pathways.","method":"RNAi knockdown of TFAP2C; Pard6b mRNA rescue; immunofluorescence for polarity markers; Hippo signaling readouts (YAP, CDX2)","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with mRNA rescue, multiple readouts, single lab","pmids":["25858457"],"is_preprint":false},{"year":2016,"finding":"CDC42 is required for apical localization of PARD6B in the ventral pharyngeal endoderm. Ablation of Cdc42 in post-gastrulation mouse embryos caused loss of apical-basal polarity and loss of apical PARD6B localization, linking CDC42 activity to PARD6B positioning during thyroid bud morphogenesis.","method":"Conditional Cdc42 knockout in mouse embryos; immunofluorescence for PARD6B localization","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with direct localization readout, single lab","pmids":["26772200"],"is_preprint":false},{"year":2017,"finding":"An RNAi screen identified PARD6B as required for apical endosome function. Pulse-chase kinetic transport assays showed a strong dependence on PARD6B for apical (but not basolateral) recycling, implicating PARD6B in assembly or maintenance of the apical endosomal system in polarized epithelial cells.","method":"High-throughput RNAi screen for FcRn-mediated transcytosis; pulse-chase kinetic transport assays; genetic separation of apical vs. basolateral pathways","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional screen validated by kinetic transport assays with pathway separation, single lab","pmids":["28069747"],"is_preprint":false},{"year":2017,"finding":"Disrupting the PRKCZ-PARD6B interaction (by genetic manipulation) in prostate progenitor cells is sufficient to randomize mitotic spindle orientation and recapitulate spindle and cell lineage phenotypes caused by GATA3 loss, placing the PRKCZ-PARD6B complex downstream of GATA3 in spindle orientation control.","method":"Genetic disruption of PRKCZ-PARD6B interaction in mouse prostate progenitor cells; spindle orientation assays; lineage phenotype analysis","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with defined phenotypic readout (spindle orientation, lineage), single lab","pmids":["28285879"],"is_preprint":false},{"year":2017,"finding":"Knockdown of PKCζ/Pard3/Pard6b polarity complex components in lung cancer cells induced EMT, invasion, and in vivo colonization. Hypoxia downregulated this complex correlating with increased migration and invasion, placing PARD6B/PKCζ/PARD3 as regulators of lung cancer cell EMT.","method":"siRNA silencing of complex components; invasion and colonization assays in vitro and in vivo; hypoxia treatment","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes (EMT, invasion), in vivo validation, single lab","pmids":["28652146"],"is_preprint":false},{"year":2018,"finding":"HIPPO signaling antagonizes apical localization of PARD6B and aPKC in mouse embryos. YAP1/WWTR1 (activated HIPPO effectors) repress PARD6B/aPKC apical localization, and this negative feedback between HIPPO and Par complex components ensures robust lineage segregation between trophectoderm and ICM.","method":"Genetic manipulation of YAP1/WWTR1 in mouse embryos; immunofluorescence for PARD6B and aPKC localization; epistasis analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with direct localization readout, single lab","pmids":["30526858"],"is_preprint":false},{"year":2018,"finding":"In pleural fibrosis, increased Lgl1 competes with PAR-3A for binding to aPKC and PAR-6B within the PAR polarity complex, displacing PAR-3A and causing cell polarity loss in pleural mesothelial cells. Lgl1 siRNA or conditional Lgl1 knockout preserved PAR-6B complex integrity and cell polarity and attenuated fibrosis.","method":"Co-immunoprecipitation showing Lgl1-aPKC-PAR-6B interaction competing with PAR-3A; siRNA knockdown; conditional knockout mouse model","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating competition mechanism, genetic validation with KO mouse, single lab","pmids":["29842893"],"is_preprint":false},{"year":2022,"finding":"In response to viral or bacterial toxin entry via the apical membrane, PARD6B and aPKC (components of the PARD6B-aPKC-Cdc42 apical polarity complex) undergo rapid proteasome-dependent degradation. Perturbation of apical membrane glycosphingolipids by toxin/virus binding initiates PARD6B degradation, which depletes apical endosome function and renders cells resistant to further apical infection, constituting a cell-autonomous host defense mechanism.","method":"Biochemical fractionation and western blot for PARD6B/aPKC degradation; proteasome inhibitor rescue; glycosphingolipid perturbation assays; apical endosome functional assays","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (biochemical degradation assay, proteasome inhibition, lipid perturbation, functional endosome assays) establishing a novel mechanism, single lab","pmids":["35143768"],"is_preprint":false},{"year":2025,"finding":"PARD6B functions as part of the PAR3-PARD6B-PRKCI complex in type II alveolar epithelial cells (AEC2s). Reduced levels of this complex arrest AEC2 cell cycle in G0-G1 phase, impairing self-proliferation and promoting transdifferentiation into AEC1s. This was established by co-immunoprecipitation, mass spectrometry, and 3D spheroid formation experiments.","method":"Co-immunoprecipitation and mass spectrometry of PARD6B complex; viral transfection overexpression/knockdown; cell cycle analysis; 3D spheroid formation from primary mouse AEC2s","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — Co-IP/MS to define complex plus functional cell cycle and 3D organoid assays, single lab","pmids":["40001200"],"is_preprint":false},{"year":2025,"finding":"PARD6B promotes colorectal cancer cell proliferation and cell cycle progression by positively regulating MYC expression, at least in part by suppressing miR-34c, which directly targets and represses MYC. In vitro and in vivo experiments confirmed PARD6B's pro-proliferative function.","method":"In vitro (cell proliferation, cell cycle assays) and in vivo (xenograft) knockdown/overexpression; in silico pathway analysis; miR-34c/MYC reporter assays","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in silico plus in vitro/in vivo functional assays but miR-34c/MYC mechanism is primarily in silico supported with limited in vitro validation, single lab","pmids":["40533910"],"is_preprint":false}],"current_model":"PARD6B is a scaffold component of the apical PAR polarity complex (PARD6B-aPKC-CDC42-PAR3) that establishes and maintains apical-basal cell polarity in epithelia: it localizes apically in a CDC42-dependent manner, is phosphorylated at Ser143 by PAK4 to regulate its interaction with CDC42, controls tight junction assembly and apical endosome function, positions the mitotic spindle via its interaction with aPKC/PRKCZ, and undergoes proteasome-dependent degradation upon apical membrane perturbation to provide cell-autonomous host defense; upstream, its apical localization is promoted by RHO-ROCK signaling and TFAP2C, and antagonized by HIPPO pathway effectors YAP1/WWTR1 and by LGL1 competition within the PAR complex."},"narrative":{"mechanistic_narrative":"PARD6B is a scaffold subunit of the apical PAR polarity complex (PARD6B-aPKC-CDC42-PAR3) that establishes and maintains apical-basal polarity in epithelial cells and asymmetric cell fate in development [PMID:20505164, PMID:22957302]. In the preimplantation mouse embryo it localizes asymmetrically to the apical pole during compaction and is required cell-autonomously for apical aPKCzeta localization, tight junction formation, blastocyst cavitation, and CDX2 expression [PMID:15950600, PMID:20505164]; in epithelial and cancer cell lines its depletion abolishes tight junction assembly and membrane aPKC localization without disrupting adherens junctions, a phenotype that depends on the complete PARD6B-aPKC-CDC42-PAR3 complex [PMID:22957302]. Apical positioning of PARD6B requires CDC42 activity [PMID:26772200], and the PARD6B-CDC42 interaction is gated by PAK4-mediated phosphorylation at Ser143 [PMID:25662318]. Through its interaction with aPKC/PRKCZ the complex orients the mitotic spindle and controls cell lineage in progenitor populations [PMID:28285879], and PARD6B is also required for apical (but not basolateral) endosomal recycling [PMID:28069747]. Upstream, apical PARD6B localization is promoted by RHO-ROCK signaling [PMID:24997360] and the transcription factor TFAP2C [PMID:25858457], and antagonized by HIPPO effectors YAP1/WWTR1 [PMID:30526858] and by LGL1, which competes with PAR-3A within the complex [PMID:29842893]. Upon apical membrane perturbation by viral or bacterial toxin binding, PARD6B and aPKC undergo rapid proteasome-dependent degradation that depletes apical endosome function and confers resistance to apical infection, a cell-autonomous host defense [PMID:35143768]. PARD6B further supports epithelial proliferative and tumor-associated programs, regulating AEC2 cell-cycle progression versus transdifferentiation [PMID:40001200] and promoting cancer cell EMT, invasion, and proliferation [PMID:28652146].","teleology":[{"year":2005,"claim":"Established that PARD6B is asymmetrically partitioned during early development, redistributing from the spindle to the apical pole at compaction independently of cell-cell contacts, marking it as an intrinsic apical polarity determinant.","evidence":"Immunofluorescence localization and contact-disruption experiments in preimplantation mouse embryos","pmids":["15950600"],"confidence":"Medium","gaps":["Does not define the molecular signal driving apical redistribution","Localization is correlative, not loss-of-function"]},{"year":2010,"claim":"Demonstrated that PARD6B is cell-autonomously required upstream of aPKCzeta apical localization for blastocyst polarity, tight junctions, cavitation, and CDX2 expression, establishing it as a functional driver rather than a passenger of polarity.","evidence":"RNAi knockdown via zygote microinjection with chimera assays and immunofluorescence in mouse embryos","pmids":["20505164"],"confidence":"High","gaps":["Does not resolve direct binding partners mediating aPKC recruitment","Does not address PARD6B function outside the embryo"]},{"year":2012,"claim":"Showed in human epithelial cells that a complete PARD6B-aPKC-CDC42-PAR3 complex is required specifically for tight junction assembly and membrane aPKC localization, separating its role from adherens junction control.","evidence":"siRNA knockdown of PAR6B and CDC42 with TJ marker immunofluorescence in MCF7 cells","pmids":["22957302"],"confidence":"Medium","gaps":["Single cell line","Does not establish stoichiometry or direct contacts within the complex"]},{"year":2013,"claim":"Placed PARD6B in an apical polarity module distinct from the core PCP pathway, complementary to the Gαi3/mPins domain in hair cells.","evidence":"Immunofluorescence co-localization and Gαi3/mPins genetic deletion in mouse cochlear hair cells","pmids":["23934215"],"confidence":"Medium","gaps":["Correlative localization","Does not test PARD6B loss-of-function in this tissue"]},{"year":2014,"claim":"Identified RHO-ROCK signaling as an upstream input segregating apical PARD6B from basal regulators, coupling polarity to Hippo/YAP-driven lineage specification.","evidence":"Pharmacological RHO/ROCK inhibition with polarity marker immunofluorescence and LATS1/2 rescue in mouse embryos","pmids":["24997360"],"confidence":"Medium","gaps":["Pharmacological inhibition lacks molecular specificity","Direct effector linking ROCK to PARD6B not defined"]},{"year":2015,"claim":"Defined a post-translational switch: PAK4 phosphorylates PARD6B at Ser143 to block its CDC42 interaction, providing a mechanism to control PARD6B localization and binding.","evidence":"In vitro kinase assay, Ser143 mutagenesis, and Co-IP interaction assays in human bronchial epithelial cells","pmids":["25662318"],"confidence":"High","gaps":["In vivo relevance of Ser143 phosphorylation not established","Does not address how phosphorylation alters apical targeting in tissue"]},{"year":2015,"claim":"Placed TFAP2C transcriptionally upstream of PARD6B, with PARD6B re-expression rescuing polarity but only partially correcting Hippo signaling, revealing PARD6B-dependent and -independent branches.","evidence":"RNAi knockdown of TFAP2C with Pard6b mRNA rescue and Hippo readouts in mouse embryos","pmids":["25858457"],"confidence":"Medium","gaps":["Does not define the PARD6B-independent Hippo branch","Direct transcriptional regulation of PARD6B by TFAP2C not shown"]},{"year":2016,"claim":"Showed CDC42 activity is required for apical PARD6B positioning in vivo during organ morphogenesis, linking the GTPase to PARD6B localization beyond the embryo.","evidence":"Conditional Cdc42 knockout with PARD6B localization immunofluorescence in mouse pharyngeal endoderm","pmids":["26772200"],"confidence":"Medium","gaps":["Does not separate direct CDC42-PARD6B binding from indirect polarity collapse","Single tissue context"]},{"year":2017,"claim":"Expanded PARD6B function to apical membrane trafficking, showing it is selectively required for apical (not basolateral) endosomal recycling.","evidence":"RNAi screen and pulse-chase transcytosis transport assays in polarized epithelial cells","pmids":["28069747"],"confidence":"Medium","gaps":["Molecular link between PARD6B and the endosomal machinery undefined","Does not establish whether trafficking role is separable from junction role"]},{"year":2017,"claim":"Demonstrated that the PRKCZ-PARD6B interaction controls mitotic spindle orientation and lineage, placing the complex downstream of GATA3 in progenitor cells.","evidence":"Genetic disruption of PRKCZ-PARD6B interaction with spindle and lineage assays in mouse prostate progenitors","pmids":["28285879"],"confidence":"Medium","gaps":["Does not define the spindle-anchoring effectors recruited by the complex","Single progenitor system"]},{"year":2017,"claim":"Linked the PARD6B/PKCζ/PAR3 complex to suppression of EMT and invasion, with hypoxia-driven downregulation promoting cancer cell motility.","evidence":"siRNA silencing with invasion/colonization assays in vitro and in vivo in lung cancer cells","pmids":["28652146"],"confidence":"Medium","gaps":["Does not isolate PARD6B-specific contribution from other complex members","Mechanism linking hypoxia to complex downregulation unresolved"]},{"year":2018,"claim":"Identified HIPPO effectors YAP1/WWTR1 as repressors of apical PARD6B/aPKC localization, defining a negative feedback loop reinforcing lineage segregation.","evidence":"Genetic manipulation of YAP1/WWTR1 with localization immunofluorescence and epistasis in mouse embryos","pmids":["30526858"],"confidence":"Medium","gaps":["Does not identify the direct YAP/TEAD target mediating repression","Mechanism of apical exclusion unclear"]},{"year":2018,"claim":"Revealed a competition mechanism whereby LGL1 displaces PAR-3A from the aPKC-PAR-6B complex, with disease relevance to pleural fibrosis.","evidence":"Co-immunoprecipitation, siRNA, and conditional Lgl1 knockout in pleural mesothelial cells","pmids":["29842893"],"confidence":"Medium","gaps":["Direct vs. indirect competition not structurally resolved","Single disease model"]},{"year":2022,"claim":"Established a host-defense role: apical membrane perturbation triggers proteasome-dependent PARD6B/aPKC degradation that depletes apical endosome function and blocks further apical infection.","evidence":"Biochemical degradation assays, proteasome inhibition, glycosphingolipid perturbation, and apical endosome functional assays","pmids":["35143768"],"confidence":"High","gaps":["E3 ligase targeting PARD6B not identified","Signal coupling lipid perturbation to degradation undefined"]},{"year":2025,"claim":"Connected PARD6B-containing complex levels to alveolar epithelial cell fate, controlling AEC2 cell-cycle progression versus transdifferentiation.","evidence":"Co-IP/mass spectrometry, overexpression/knockdown, cell cycle analysis, and 3D spheroid assays in primary mouse AEC2s","pmids":["40001200"],"confidence":"Medium","gaps":["Does not define the signaling link between complex level and cell cycle arrest","Mechanism of transdifferentiation downstream of PARD6B unclear"]},{"year":2025,"claim":"Proposed a pro-proliferative role in colorectal cancer via miR-34c suppression and MYC upregulation.","evidence":"In vitro/in vivo knockdown and overexpression with in silico pathway analysis and miR-34c/MYC reporter assays","pmids":["40533910"],"confidence":"Low","gaps":["miR-34c/MYC axis is primarily in silico supported with limited in vitro validation","Does not connect this pathway to PARD6B's polarity function"]},{"year":null,"claim":"How PARD6B's apical scaffolding, endosomal, spindle-orientation, and proteostatic functions are mechanistically integrated, and the identity of the E3 ligase and direct effectors involved, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the PARD6B-aPKC-CDC42-PAR3 complex in the corpus","E3 ligase mediating PARD6B degradation unidentified","Direct effectors coupling the complex to endosomes and the spindle undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[8,13]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,9]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,11]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[2,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[8]}],"complexes":["PAR polarity complex (PARD6B-aPKC-CDC42-PAR3)"],"partners":["PRKCZ","PRKCI","CDC42","PARD3","PAK4","LLGL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BYG5","full_name":"Partitioning defective 6 homolog beta","aliases":[],"length_aa":372,"mass_kda":41.2,"function":"Adapter protein involved in asymmetrical cell division and cell polarization processes. Probably involved in formation of epithelial tight junctions. Association with PARD3 may prevent the interaction of PARD3 with F11R/JAM1, thereby preventing tight junction assembly. The PARD6-PARD3 complex links GTP-bound Rho small GTPases to atypical protein kinase C proteins","subcellular_location":"Cytoplasm; Cell membrane; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/Q9BYG5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PARD6B","classification":"Not Classified","n_dependent_lines":160,"n_total_lines":1208,"dependency_fraction":0.13245033112582782},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRKCI","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/search/PARD6B","total_profiled":1310},"omim":[{"mim_id":"608975","title":"PAR6 FAMILY CELL POLARITY REGULATOR BETA; PARD6B","url":"https://www.omim.org/entry/608975"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cell Junctions","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":15.0}],"url":"https://www.proteinatlas.org/search/PARD6B"},"hgnc":{"alias_symbol":["PAR-6B"],"prev_symbol":[]},"alphafold":{"accession":"Q9BYG5","domains":[{"cath_id":"3.10.20.90","chopping":"15-97","consensus_level":"high","plddt":90.8502,"start":15,"end":97},{"cath_id":"2.30.42.10","chopping":"142-252","consensus_level":"high","plddt":94.3577,"start":142,"end":252}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYG5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYG5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BYG5-F1-predicted_aligned_error_v6.png","plddt_mean":70.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PARD6B","jax_strain_url":"https://www.jax.org/strain/search?query=PARD6B"},"sequence":{"accession":"Q9BYG5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BYG5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BYG5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BYG5"}},"corpus_meta":[{"pmid":"26656844","id":"PMC_26656844","title":"Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26656844","citation_count":301,"is_preprint":false},{"pmid":"15950600","id":"PMC_15950600","title":"Asymmetric distribution of PAR proteins in the mouse embryo begins at the 8-cell stage during compaction.","date":"2005","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15950600","citation_count":136,"is_preprint":false},{"pmid":"20505164","id":"PMC_20505164","title":"Cell polarity regulator PARD6B is essential for trophectoderm formation in the preimplantation mouse embryo.","date":"2010","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/20505164","citation_count":115,"is_preprint":false},{"pmid":"23934215","id":"PMC_23934215","title":"Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton.","date":"2013","source":"Nature cell 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research","url":"https://pubmed.ncbi.nlm.nih.gov/41277781","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":24820,"output_tokens":4191,"usd":0.068663,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12017,"output_tokens":4875,"usd":0.09098,"stage2_stop_reason":"end_turn"},"total_usd":0.159643,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"PARD6B protein localizes to the spindle during early mouse embryonic cleavages (before compaction) and then redistributes asymmetrically to the apical pole during compaction at the 8-cell stage, independently of cell-cell contacts. At the 16-cell stage it co-localizes with aPKCzeta, and in blastocysts PARD6B/PARD3/aPKCzeta co-localize at tight junctions.\",\n      \"method\": \"Immunofluorescence localization in preimplantation mouse embryos; cell-contact disruption experiments to test contact-dependence of apical localization\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with functional context (polarity establishment), single lab, two methods (immunofluorescence + contact disruption)\",\n      \"pmids\": [\"15950600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PARD6B is required for blastocyst cavity formation, apical-basal polarity of outer cells, tight junction (TJ) formation (normal TJP1/ZO-1 distribution), and CDX2 expression in the mouse preimplantation embryo. Knockdown of Pard6b abolished apical localization of aPKCzeta and caused chimeric cavitation failure, demonstrating a cell-autonomous role upstream of aPKCzeta localization.\",\n      \"method\": \"RNAi knockdown via zygote microinjection; immunofluorescence for aPKCzeta, TJP1, CDX2; chimera assays\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with multiple orthogonal readouts (polarity, TJ, transcription factor), chimera rescue experiment, replicated in subsequent studies\",\n      \"pmids\": [\"20505164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PAR6B is required for tight junction network formation and membrane localization of aPKCzeta in MCF7 breast cancer cells. siRNA-mediated depletion of PAR6B abolished TJ assembly and membrane aPKCzeta localization without affecting adherens junctions. siRNA depletion of CDC42 similarly abolished TJ networks, confirming that a complete PAR6B-aPKC-CDC42-PAR3 complex is necessary for TJ stabilization.\",\n      \"method\": \"siRNA knockdown of PAR6B and CDC42 in MCF7 cells; immunofluorescence for TJ markers and aPKCzeta; FISH copy number analysis; PARD6B mRNA/protein quantification\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype plus CDC42 epistasis, single lab, two orthogonal knockdown approaches\",\n      \"pmids\": [\"22957302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In cochlear hair cells, aPKC/Par-3/Par-6b form an apical and distal asymmetrical expression domain that is opposite and complementary to the Gαi3/mPins domain, and non-overlapping with core PCP protein Vangl2, placing PARD6B in a distinct polarity module controlling apical cell identity separate from the core PCP pathway.\",\n      \"method\": \"Immunofluorescence co-localization in mouse cochlear hair cells; genetic deletion of Gαi3/mPins\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with genetic epistasis (Gαi3/mPins deletion), single lab\",\n      \"pmids\": [\"23934215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RHO-ROCK signaling is required for segregation of apical (PARD6B, PRKCZ) and basal (SCRIB, LLGL1) polarity regulators in the mouse blastocyst. Treatment with ROCK inhibitor Y-27632 or RHO GTPase inhibitor dampened this segregation and disrupted Hippo signaling/YAP nuclear accumulation, placing RHO-ROCK upstream of PARD6B apical polarity in TE specification.\",\n      \"method\": \"Pharmacological inhibition (Y-27632, RHO GTPase inhibitor) of mouse embryos; immunofluorescence for PARD6B, PRKCZ, SCRIB, LLGL1, YAP; LATS1/2 co-inhibition rescue\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with multiple polarity markers and rescue experiment, single lab\",\n      \"pmids\": [\"24997360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PAK4 phosphorylates Par6B at Ser143, and this phosphorylation blocks Par6B's interaction with Cdc42, providing a mechanism for controlling Par6B subcellular localization and its protein interactions downstream of Cdc42.\",\n      \"method\": \"In vitro kinase assay; site-directed mutagenesis (Ser143); Co-IP/interaction assays in human bronchial epithelial cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis identifying specific phosphorylation site and functional consequence on protein-protein interaction, single lab\",\n      \"pmids\": [\"25662318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TFAP2C (AP-2γ) acts upstream of PARD6B: TFAP2C depletion caused downregulation of PARD6B and loss of apical cell polarity in outside blastomeres. Re-expression of Pard6b mRNA rescued cell polarity but only partially corrected position-dependent Hippo signaling, indicating TFAP2C controls Hippo signaling via PARD6B-dependent and PARD6B-independent pathways.\",\n      \"method\": \"RNAi knockdown of TFAP2C; Pard6b mRNA rescue; immunofluorescence for polarity markers; Hippo signaling readouts (YAP, CDX2)\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with mRNA rescue, multiple readouts, single lab\",\n      \"pmids\": [\"25858457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CDC42 is required for apical localization of PARD6B in the ventral pharyngeal endoderm. Ablation of Cdc42 in post-gastrulation mouse embryos caused loss of apical-basal polarity and loss of apical PARD6B localization, linking CDC42 activity to PARD6B positioning during thyroid bud morphogenesis.\",\n      \"method\": \"Conditional Cdc42 knockout in mouse embryos; immunofluorescence for PARD6B localization\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with direct localization readout, single lab\",\n      \"pmids\": [\"26772200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"An RNAi screen identified PARD6B as required for apical endosome function. Pulse-chase kinetic transport assays showed a strong dependence on PARD6B for apical (but not basolateral) recycling, implicating PARD6B in assembly or maintenance of the apical endosomal system in polarized epithelial cells.\",\n      \"method\": \"High-throughput RNAi screen for FcRn-mediated transcytosis; pulse-chase kinetic transport assays; genetic separation of apical vs. basolateral pathways\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional screen validated by kinetic transport assays with pathway separation, single lab\",\n      \"pmids\": [\"28069747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Disrupting the PRKCZ-PARD6B interaction (by genetic manipulation) in prostate progenitor cells is sufficient to randomize mitotic spindle orientation and recapitulate spindle and cell lineage phenotypes caused by GATA3 loss, placing the PRKCZ-PARD6B complex downstream of GATA3 in spindle orientation control.\",\n      \"method\": \"Genetic disruption of PRKCZ-PARD6B interaction in mouse prostate progenitor cells; spindle orientation assays; lineage phenotype analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with defined phenotypic readout (spindle orientation, lineage), single lab\",\n      \"pmids\": [\"28285879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Knockdown of PKCζ/Pard3/Pard6b polarity complex components in lung cancer cells induced EMT, invasion, and in vivo colonization. Hypoxia downregulated this complex correlating with increased migration and invasion, placing PARD6B/PKCζ/PARD3 as regulators of lung cancer cell EMT.\",\n      \"method\": \"siRNA silencing of complex components; invasion and colonization assays in vitro and in vivo; hypoxia treatment\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotypes (EMT, invasion), in vivo validation, single lab\",\n      \"pmids\": [\"28652146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HIPPO signaling antagonizes apical localization of PARD6B and aPKC in mouse embryos. YAP1/WWTR1 (activated HIPPO effectors) repress PARD6B/aPKC apical localization, and this negative feedback between HIPPO and Par complex components ensures robust lineage segregation between trophectoderm and ICM.\",\n      \"method\": \"Genetic manipulation of YAP1/WWTR1 in mouse embryos; immunofluorescence for PARD6B and aPKC localization; epistasis analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with direct localization readout, single lab\",\n      \"pmids\": [\"30526858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In pleural fibrosis, increased Lgl1 competes with PAR-3A for binding to aPKC and PAR-6B within the PAR polarity complex, displacing PAR-3A and causing cell polarity loss in pleural mesothelial cells. Lgl1 siRNA or conditional Lgl1 knockout preserved PAR-6B complex integrity and cell polarity and attenuated fibrosis.\",\n      \"method\": \"Co-immunoprecipitation showing Lgl1-aPKC-PAR-6B interaction competing with PAR-3A; siRNA knockdown; conditional knockout mouse model\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating competition mechanism, genetic validation with KO mouse, single lab\",\n      \"pmids\": [\"29842893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In response to viral or bacterial toxin entry via the apical membrane, PARD6B and aPKC (components of the PARD6B-aPKC-Cdc42 apical polarity complex) undergo rapid proteasome-dependent degradation. Perturbation of apical membrane glycosphingolipids by toxin/virus binding initiates PARD6B degradation, which depletes apical endosome function and renders cells resistant to further apical infection, constituting a cell-autonomous host defense mechanism.\",\n      \"method\": \"Biochemical fractionation and western blot for PARD6B/aPKC degradation; proteasome inhibitor rescue; glycosphingolipid perturbation assays; apical endosome functional assays\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (biochemical degradation assay, proteasome inhibition, lipid perturbation, functional endosome assays) establishing a novel mechanism, single lab\",\n      \"pmids\": [\"35143768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARD6B functions as part of the PAR3-PARD6B-PRKCI complex in type II alveolar epithelial cells (AEC2s). Reduced levels of this complex arrest AEC2 cell cycle in G0-G1 phase, impairing self-proliferation and promoting transdifferentiation into AEC1s. This was established by co-immunoprecipitation, mass spectrometry, and 3D spheroid formation experiments.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry of PARD6B complex; viral transfection overexpression/knockdown; cell cycle analysis; 3D spheroid formation from primary mouse AEC2s\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — Co-IP/MS to define complex plus functional cell cycle and 3D organoid assays, single lab\",\n      \"pmids\": [\"40001200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PARD6B promotes colorectal cancer cell proliferation and cell cycle progression by positively regulating MYC expression, at least in part by suppressing miR-34c, which directly targets and represses MYC. In vitro and in vivo experiments confirmed PARD6B's pro-proliferative function.\",\n      \"method\": \"In vitro (cell proliferation, cell cycle assays) and in vivo (xenograft) knockdown/overexpression; in silico pathway analysis; miR-34c/MYC reporter assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in silico plus in vitro/in vivo functional assays but miR-34c/MYC mechanism is primarily in silico supported with limited in vitro validation, single lab\",\n      \"pmids\": [\"40533910\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PARD6B is a scaffold component of the apical PAR polarity complex (PARD6B-aPKC-CDC42-PAR3) that establishes and maintains apical-basal cell polarity in epithelia: it localizes apically in a CDC42-dependent manner, is phosphorylated at Ser143 by PAK4 to regulate its interaction with CDC42, controls tight junction assembly and apical endosome function, positions the mitotic spindle via its interaction with aPKC/PRKCZ, and undergoes proteasome-dependent degradation upon apical membrane perturbation to provide cell-autonomous host defense; upstream, its apical localization is promoted by RHO-ROCK signaling and TFAP2C, and antagonized by HIPPO pathway effectors YAP1/WWTR1 and by LGL1 competition within the PAR complex.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PARD6B is a scaffold subunit of the apical PAR polarity complex (PARD6B-aPKC-CDC42-PAR3) that establishes and maintains apical-basal polarity in epithelial cells and asymmetric cell fate in development [#1, #2]. In the preimplantation mouse embryo it localizes asymmetrically to the apical pole during compaction and is required cell-autonomously for apical aPKCzeta localization, tight junction formation, blastocyst cavitation, and CDX2 expression [#0, #1]; in epithelial and cancer cell lines its depletion abolishes tight junction assembly and membrane aPKC localization without disrupting adherens junctions, a phenotype that depends on the complete PARD6B-aPKC-CDC42-PAR3 complex [#2]. Apical positioning of PARD6B requires CDC42 activity [#7], and the PARD6B-CDC42 interaction is gated by PAK4-mediated phosphorylation at Ser143 [#5]. Through its interaction with aPKC/PRKCZ the complex orients the mitotic spindle and controls cell lineage in progenitor populations [#9], and PARD6B is also required for apical (but not basolateral) endosomal recycling [#8]. Upstream, apical PARD6B localization is promoted by RHO-ROCK signaling [#4] and the transcription factor TFAP2C [#6], and antagonized by HIPPO effectors YAP1/WWTR1 [#11] and by LGL1, which competes with PAR-3A within the complex [#12]. Upon apical membrane perturbation by viral or bacterial toxin binding, PARD6B and aPKC undergo rapid proteasome-dependent degradation that depletes apical endosome function and confers resistance to apical infection, a cell-autonomous host defense [#13]. PARD6B further supports epithelial proliferative and tumor-associated programs, regulating AEC2 cell-cycle progression versus transdifferentiation [#14] and promoting cancer cell EMT, invasion, and proliferation [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that PARD6B is asymmetrically partitioned during early development, redistributing from the spindle to the apical pole at compaction independently of cell-cell contacts, marking it as an intrinsic apical polarity determinant.\",\n      \"evidence\": \"Immunofluorescence localization and contact-disruption experiments in preimplantation mouse embryos\",\n      \"pmids\": [\"15950600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the molecular signal driving apical redistribution\", \"Localization is correlative, not loss-of-function\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that PARD6B is cell-autonomously required upstream of aPKCzeta apical localization for blastocyst polarity, tight junctions, cavitation, and CDX2 expression, establishing it as a functional driver rather than a passenger of polarity.\",\n      \"evidence\": \"RNAi knockdown via zygote microinjection with chimera assays and immunofluorescence in mouse embryos\",\n      \"pmids\": [\"20505164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve direct binding partners mediating aPKC recruitment\", \"Does not address PARD6B function outside the embryo\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed in human epithelial cells that a complete PARD6B-aPKC-CDC42-PAR3 complex is required specifically for tight junction assembly and membrane aPKC localization, separating its role from adherens junction control.\",\n      \"evidence\": \"siRNA knockdown of PAR6B and CDC42 with TJ marker immunofluorescence in MCF7 cells\",\n      \"pmids\": [\"22957302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line\", \"Does not establish stoichiometry or direct contacts within the complex\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed PARD6B in an apical polarity module distinct from the core PCP pathway, complementary to the Gαi3/mPins domain in hair cells.\",\n      \"evidence\": \"Immunofluorescence co-localization and Gαi3/mPins genetic deletion in mouse cochlear hair cells\",\n      \"pmids\": [\"23934215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative localization\", \"Does not test PARD6B loss-of-function in this tissue\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified RHO-ROCK signaling as an upstream input segregating apical PARD6B from basal regulators, coupling polarity to Hippo/YAP-driven lineage specification.\",\n      \"evidence\": \"Pharmacological RHO/ROCK inhibition with polarity marker immunofluorescence and LATS1/2 rescue in mouse embryos\",\n      \"pmids\": [\"24997360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inhibition lacks molecular specificity\", \"Direct effector linking ROCK to PARD6B not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a post-translational switch: PAK4 phosphorylates PARD6B at Ser143 to block its CDC42 interaction, providing a mechanism to control PARD6B localization and binding.\",\n      \"evidence\": \"In vitro kinase assay, Ser143 mutagenesis, and Co-IP interaction assays in human bronchial epithelial cells\",\n      \"pmids\": [\"25662318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of Ser143 phosphorylation not established\", \"Does not address how phosphorylation alters apical targeting in tissue\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed TFAP2C transcriptionally upstream of PARD6B, with PARD6B re-expression rescuing polarity but only partially correcting Hippo signaling, revealing PARD6B-dependent and -independent branches.\",\n      \"evidence\": \"RNAi knockdown of TFAP2C with Pard6b mRNA rescue and Hippo readouts in mouse embryos\",\n      \"pmids\": [\"25858457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the PARD6B-independent Hippo branch\", \"Direct transcriptional regulation of PARD6B by TFAP2C not shown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CDC42 activity is required for apical PARD6B positioning in vivo during organ morphogenesis, linking the GTPase to PARD6B localization beyond the embryo.\",\n      \"evidence\": \"Conditional Cdc42 knockout with PARD6B localization immunofluorescence in mouse pharyngeal endoderm\",\n      \"pmids\": [\"26772200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not separate direct CDC42-PARD6B binding from indirect polarity collapse\", \"Single tissue context\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Expanded PARD6B function to apical membrane trafficking, showing it is selectively required for apical (not basolateral) endosomal recycling.\",\n      \"evidence\": \"RNAi screen and pulse-chase transcytosis transport assays in polarized epithelial cells\",\n      \"pmids\": [\"28069747\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between PARD6B and the endosomal machinery undefined\", \"Does not establish whether trafficking role is separable from junction role\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that the PRKCZ-PARD6B interaction controls mitotic spindle orientation and lineage, placing the complex downstream of GATA3 in progenitor cells.\",\n      \"evidence\": \"Genetic disruption of PRKCZ-PARD6B interaction with spindle and lineage assays in mouse prostate progenitors\",\n      \"pmids\": [\"28285879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the spindle-anchoring effectors recruited by the complex\", \"Single progenitor system\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked the PARD6B/PKCζ/PAR3 complex to suppression of EMT and invasion, with hypoxia-driven downregulation promoting cancer cell motility.\",\n      \"evidence\": \"siRNA silencing with invasion/colonization assays in vitro and in vivo in lung cancer cells\",\n      \"pmids\": [\"28652146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not isolate PARD6B-specific contribution from other complex members\", \"Mechanism linking hypoxia to complex downregulation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified HIPPO effectors YAP1/WWTR1 as repressors of apical PARD6B/aPKC localization, defining a negative feedback loop reinforcing lineage segregation.\",\n      \"evidence\": \"Genetic manipulation of YAP1/WWTR1 with localization immunofluorescence and epistasis in mouse embryos\",\n      \"pmids\": [\"30526858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the direct YAP/TEAD target mediating repression\", \"Mechanism of apical exclusion unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a competition mechanism whereby LGL1 displaces PAR-3A from the aPKC-PAR-6B complex, with disease relevance to pleural fibrosis.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA, and conditional Lgl1 knockout in pleural mesothelial cells\",\n      \"pmids\": [\"29842893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect competition not structurally resolved\", \"Single disease model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a host-defense role: apical membrane perturbation triggers proteasome-dependent PARD6B/aPKC degradation that depletes apical endosome function and blocks further apical infection.\",\n      \"evidence\": \"Biochemical degradation assays, proteasome inhibition, glycosphingolipid perturbation, and apical endosome functional assays\",\n      \"pmids\": [\"35143768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase targeting PARD6B not identified\", \"Signal coupling lipid perturbation to degradation undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected PARD6B-containing complex levels to alveolar epithelial cell fate, controlling AEC2 cell-cycle progression versus transdifferentiation.\",\n      \"evidence\": \"Co-IP/mass spectrometry, overexpression/knockdown, cell cycle analysis, and 3D spheroid assays in primary mouse AEC2s\",\n      \"pmids\": [\"40001200\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the signaling link between complex level and cell cycle arrest\", \"Mechanism of transdifferentiation downstream of PARD6B unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a pro-proliferative role in colorectal cancer via miR-34c suppression and MYC upregulation.\",\n      \"evidence\": \"In vitro/in vivo knockdown and overexpression with in silico pathway analysis and miR-34c/MYC reporter assays\",\n      \"pmids\": [\"40533910\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"miR-34c/MYC axis is primarily in silico supported with limited in vitro validation\", \"Does not connect this pathway to PARD6B's polarity function\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PARD6B's apical scaffolding, endosomal, spindle-orientation, and proteostatic functions are mechanistically integrated, and the identity of the E3 ligase and direct effectors involved, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the PARD6B-aPKC-CDC42-PAR3 complex in the corpus\", \"E3 ligase mediating PARD6B degradation unidentified\", \"Direct effectors coupling the complex to endosomes and the spindle undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\n      \"PAR polarity complex (PARD6B-aPKC-CDC42-PAR3)\"\n    ],\n    \"partners\": [\n      \"PRKCZ\",\n      \"PRKCI\",\n      \"CDC42\",\n      \"PARD3\",\n      \"PAK4\",\n      \"LLGL1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}