{"gene":"PLCB3","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":1995,"finding":"The human PLCB3 gene encodes a 1234-amino acid phosphoinositide-specific phospholipase C beta 3 protein with a 4.4-kb transcript expressed in all tissues. The gene contains 31 exons spanning ~15 kb, with a GC-rich promoter lacking TATA/CAAT boxes (housekeeping promoter type), and the transcription initiation site was mapped 328-321 bp upstream of the translation start.","method":"cDNA sequencing, genomic sequencing of cosmid subclones, Northern blotting, primer extension for transcription start site","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — complete cDNA and genomic characterization with multiple orthogonal methods","pmids":["7607669"],"is_preprint":false},{"year":2011,"finding":"PLC-β3 constitutively interacts with FcεRI, Lyn, and SHP-1 in mast cells. Upon FcεRI stimulation, PLC-β3 recruits SHP-1 which dephosphorylates Lyn at Tyr396 (inhibitory site) to suppress Lyn activity, thereby reducing negative regulation and enabling MAPK-dependent cytokine production. Loss of Plcb3 reduces cytokine production but not degranulation, and phenocopies SHP-1 mutant mast cells.","method":"Plcb3(-/-) mouse model, co-immunoprecipitation, kinase activity assays, anaphylaxis models, cytokine ELISA, MAPK phosphorylation assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus KO mouse with defined cellular phenotype and mechanistic follow-up, multiple orthogonal methods","pmids":["21683628"],"is_preprint":false},{"year":2014,"finding":"PLC-β3 deficiency in mast cells leads to increased STAT5 activity and reduced SHP-1 activity, causing mast cell expansion and spontaneous AD-like skin lesions. PLC-β3 also regulates periostin expression in fibroblasts and TSLP expression in keratinocytes. Mast cell-specific Stat5 deletion rescues, while Shp1 deletion exacerbates, allergen-induced dermatitis in Plcb3(-/-) mice.","method":"Plcb3(-/-) mouse model, mast cell-specific conditional knockouts (Stat5, Shp1), allergen challenge models, Western blotting for phospho-STAT5","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple conditional KO models with defined cellular phenotypes and epistasis analysis","pmids":["24412367"],"is_preprint":false},{"year":2011,"finding":"In bronchial epithelial cells, PLCB3 mediates extracellular nucleotide-dependent intracellular calcium signaling that activates protein kinase Cα and Cβ and NF-κB p65, potentiating Toll-like receptor signaling to drive IL-8 release in response to Pseudomonas aeruginosa. Silencing PLCB3 attenuates this inflammatory cascade.","method":"siRNA knockdown in CF bronchial epithelial cells, calcium signaling assays, PKC activity assays, NF-κB reporter assays, IL-8 ELISA","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — siRNA KD with multiple downstream pathway readouts in primary disease-relevant cells","pmids":["21411730"],"is_preprint":false},{"year":2018,"finding":"The PLCB3-S845L variant (c.2534C>T) is a loss-of-function mutation that impairs agonist-induced Ca2+ release from the ER, reduces conventional PKCβ activation, and diminishes IL-8 release in CF bronchial epithelial cells. Synthetic catalytic-dead and activation-deficient PLCB3 mutants confirmed the requirement for enzymatic activity.","method":"Site-directed mutagenesis, Ca2+ imaging, PKC activation assays, IL-8 ELISA in CF bronchial epithelial cells exposed to P. aeruginosa","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis with multiple orthogonal functional readouts","pmids":["29668297"],"is_preprint":false},{"year":2017,"finding":"A homozygous missense variant (c.2632G>T; p.Ala878Ser) in PLCB3 disrupts the Ha2' element of the proximal C-terminal domain, destabilizing PLCB3 and causing elevated PIP2 levels in patient fibroblasts, leading to F-actin cytoskeleton disorganization and a new form of spondylometaphyseal dysplasia with corneal dystrophy.","method":"Whole exome sequencing, homozygosity mapping, patient fibroblast studies (PIP2 measurement, F-actin staining), protein stability assays","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 1-2 — variant identified and functionally validated in patient cells with biochemical and cytoskeletal readouts","pmids":["29122926"],"is_preprint":false},{"year":2008,"finding":"PLCB3 Ser1105 (S1105) is a convergent phosphorylation site for multiple kinases in human myometrial cells. PKA pathway (via cAMP/PRKA) and PKC (via oxytocin/Gq) both phosphorylate S1105; PKA-mediated phosphorylation inhibits oxytocin-stimulated phosphatidylinositol turnover in a S1105-dependent manner, demonstrated by S1105A mutant. PP2B/calcineurin preferentially dephosphorylates PKA-phosphorylated S1105 while PP1/PP2A acts on PKC-phosphorylated S1105. PLCB3 shRNA significantly attenuated oxytocin-stimulated intracellular Ca2+ increases.","method":"shRNA knockdown, S1105A mutagenesis, phosphatase inhibitors (cypermethrin, okadaic acid), kinase inhibitors, calcium imaging, PI turnover assays in immortalized and primary human myometrial cells","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis of phosphorylation site combined with pharmacological dissection and KD, multiple orthogonal methods","pmids":["18322273"],"is_preprint":false},{"year":2006,"finding":"In cat esophageal smooth muscle cells, S1P-induced contraction is mediated through S1P2 receptors coupled to PTX-sensitive Gi2 and PTX-insensitive Gq/Gβγ proteins, leading to PLCβ3 activation. Intracellular application of PLCβ3-specific antibody inhibited contraction, placing PLCβ3 upstream of PKCε and MEK/ERK in the S1P contractile signaling pathway.","method":"Intracellular antibody injection into permeabilized smooth muscle cells, pertussis toxin treatment, PLC inhibitor U73122, PKC and MEK inhibitors, contraction assays","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 — intracellular antibody inhibition with pharmacological pathway dissection, single study","pmids":["16511346"],"is_preprint":false},{"year":2011,"finding":"PLCβ3 (PLCB3) specifically mediates LH-induced differentiation of bovine granulosa cells. PLCB3 is upregulated in ovulatory-size follicles, predominantly cytoplasmic in these cells, and RNAi-mediated PLCB3 knockdown reduced LH-induced IP turnover and transcriptional upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2), while suppressing LH-induced downregulation of aromatase and estradiol production, without affecting cAMP responses.","method":"RNAi knockdown in primary bovine granulosa cells, inositol phosphate turnover assay, RT-PCR, estradiol measurement, cAMP assay, immunofluorescence localization","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi with multiple pathway readouts in primary cells, single lab","pmids":["21586561"],"is_preprint":false},{"year":1999,"finding":"Transfection of PLCB3 into neuroendocrine tumor cell lines with low/absent PLCB3 expression suppressed growth in vitro (reduced [3H]thymidine incorporation) and reduced tumorigenicity in nude mice xenografts, with decreased Ki-67+ proliferating cells, indicating a tumor suppressor function for PLCB3 in neuroendocrine cells.","method":"PLCB3 cDNA transfection, [3H]thymidine incorporation, cell counting, nude mouse xenografts, Ki-67 immunostaining","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function reconstitution in vitro and in vivo with defined proliferation readouts, single lab","pmids":["10359076"],"is_preprint":false},{"year":2001,"finding":"Transfection of PLCB3 into BON-1 neuroendocrine tumor cells altered gene expression, inducing hMSH3 (mismatch repair protein 3) and TIS/MA-3 (topoisomerase suppressor/apoptosis gene) mRNAs while suppressing S100A3 and Chromogranin A, suggesting these downstream gene expression changes contribute to PLCB3-mediated tumor suppression.","method":"PLCB3 cDNA transfection, RT-differential cDNA display, sequence identification of differentially expressed transcripts","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single method (differential display) without mechanistic follow-up of individual targets","pmids":["11178984"],"is_preprint":false},{"year":2024,"finding":"OSBPL2 directly interacts with PLCB3 and inhibits ubiquitylation of PLCB3, thereby stabilizing it. OSBPL2 loss-of-function variants lead to enhanced ubiquitination and proteasomal degradation of PLCB3, resulting in epidermal hyperkeratosis with aberrant keratinocyte proliferation and delayed terminal differentiation.","method":"Co-immunoprecipitation (OSBPL2-PLCB3 interaction), ubiquitylation assays, patient fibroblast/keratinocyte studies, exome sequencing","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP plus ubiquitylation assay with cellular phenotype, single study","pmids":["38701954"],"is_preprint":false},{"year":2022,"finding":"Exosomal miR-24-3p from umbilical cord mesenchymal stem cells suppresses Plcb3 expression and NF-κB pathway activation in macrophages, promoting M2 polarization. RNA-seq identified Plcb3 as a key gene in macrophage polarization, and miR-24-3p overexpression or UMSC-Exo treatment reduced Plcb3 levels to enhance M2 polarization.","method":"RNA sequencing, miR-24-3p overexpression, UMSC-Exo treatment, macrophage polarization assays, Western blotting for NF-κB pathway","journal":"Advanced biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — miRNA-target relationship demonstrated with gain-of-function and exosome experiments, single lab","pmids":["35818695"],"is_preprint":false},{"year":2024,"finding":"PLCB3 knockdown in colorectal cancer cells inhibits CRC cell proliferation, migration, and invasion. Cetuximab treatment reduces β-catenin and PLCB3 expression while increasing E-cadherin, and combined application of a Wnt activator with PLCB3 modulation affects cetuximab efficacy, placing PLCB3 as a modulator of Wnt/β-catenin signaling in CRC.","method":"siRNA knockdown, Western blotting for β-catenin/E-cadherin/PLCB3, proliferation/migration/invasion assays, Wnt activator (IM12) rescue experiments","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 — KD with phenotype but pathway placement is correlative without direct mechanistic demonstration","pmids":["38724565"],"is_preprint":false}],"current_model":"PLCB3 encodes a phosphoinositide-specific phospholipase C that converts PIP2 to IP3 and DAG downstream of GPCRs and immune receptors; it constitutively assembles with FcεRI, Lyn, and SHP-1 in mast cells to regulate cytokine production via SHP-1-mediated Lyn dephosphorylation, mediates Toll-like receptor–potentiated NF-κB/PKC/Ca2+ signaling in epithelial cells, serves as a convergent phosphorylation node (Ser1105) for PKA and PKC cross-talk in myometrial cells, and its protein stability is regulated by OSBPL2-mediated protection from ubiquitin-dependent degradation, with loss-of-function causing elevated PIP2, F-actin disorganization, and a skeletal dysplasia syndrome."},"narrative":{"teleology":[{"year":1995,"claim":"Establishing the basic identity of PLCB3 as a ubiquitously expressed, housekeeping-type phospholipase C gene answered the foundational question of its genomic organization and tissue distribution.","evidence":"cDNA/genomic sequencing, Northern blotting, and primer extension in human tissues","pmids":["7607669"],"confidence":"High","gaps":["No enzymatic kinetics or substrate specificity data provided","No upstream activating receptors identified","Protein-level expression and subcellular localization not characterized"]},{"year":1999,"claim":"Reconstitution of PLCB3 in neuroendocrine tumor cells deficient for the protein revealed a growth-suppressive function, raising the question of whether PLCB3 acts as a tumor suppressor beyond its canonical lipase activity.","evidence":"PLCB3 cDNA transfection with thymidine incorporation assays and nude mouse xenografts","pmids":["10359076"],"confidence":"Medium","gaps":["Mechanism of growth suppression not defined","Downstream transcriptional changes identified by differential display (PMID:11178984) lack validation","Relevance to human neuroendocrine tumors in situ not established"]},{"year":2006,"claim":"Demonstrating that intracellular PLCB3-specific antibody blocked S1P-induced smooth muscle contraction placed PLCB3 downstream of both Gi and Gq pathways and upstream of PKCε/MEK/ERK in a contractile signaling cascade.","evidence":"Intracellular antibody injection in permeabilized cat esophageal smooth muscle cells with pertussis toxin and kinase inhibitors","pmids":["16511346"],"confidence":"Medium","gaps":["Antibody specificity for PLCB3 versus other PLC isoforms not independently validated","Single species/tissue system","Direct G-protein coupling not biochemically demonstrated"]},{"year":2008,"claim":"Identification of Ser1105 as a convergent PKA/PKC phosphorylation site with differential phosphatase control resolved how cAMP and Gq/oxytocin pathways cross-talk through PLCB3 in myometrial cells.","evidence":"S1105A mutagenesis, shRNA knockdown, pharmacological phosphatase and kinase inhibition, calcium imaging in human myometrial cells","pmids":["18322273"],"confidence":"High","gaps":["Structural basis for how S1105 phosphorylation inhibits catalytic activity unknown","In vivo relevance to labor/uterine contractility not tested","Whether other PLC-β isoforms are similarly regulated at homologous sites not addressed"]},{"year":2011,"claim":"Discovery that PLCB3 constitutively scaffolds FcεRI, Lyn, and SHP-1 in mast cells — and that Plcb3 knockout phenocopies SHP-1 loss for cytokine production — established a non-canonical adaptor/scaffold function independent of lipase activity per se.","evidence":"Plcb3−/− mouse, reciprocal co-immunoprecipitation, Lyn kinase assays, anaphylaxis models, cytokine ELISA","pmids":["21683628"],"confidence":"High","gaps":["Whether the scaffold and lipase functions are separable (e.g., catalytic-dead knock-in) was not tested","Structural basis for the quaternary PLCB3–FcεRI–Lyn–SHP-1 complex unknown","Contribution of individual PLCB3 domains to complex assembly not mapped"]},{"year":2011,"claim":"Parallel work showed PLCB3 mediates nucleotide-stimulated Ca²⁺/PKC/NF-κB signaling that potentiates TLR-driven IL-8 release in bronchial epithelial cells, extending its functional role to innate immune amplification in the airway.","evidence":"siRNA knockdown in CF bronchial epithelial cells with calcium, PKC, NF-κB reporter, and IL-8 readouts","pmids":["21411730"],"confidence":"High","gaps":["Receptor identity (P2Y subtype) upstream of PLCB3 not definitively assigned","In vivo relevance in CF lung disease not tested"]},{"year":2014,"claim":"Epistasis experiments in Plcb3-deficient mice showed that PLCB3 restrains STAT5 activity via SHP-1, and that mast cell-specific Stat5 deletion rescues dermatitis, establishing the PLCB3→SHP-1⊣STAT5 axis as the driver of mast cell expansion and atopic skin disease.","evidence":"Plcb3−/− crossed with mast cell-specific Stat5 and Shp1 conditional knockouts, allergen challenge","pmids":["24412367"],"confidence":"High","gaps":["How PLCB3 regulates periostin in fibroblasts and TSLP in keratinocytes mechanistically unclear","Whether lipase activity is required for the STAT5 regulatory circuit not resolved"]},{"year":2017,"claim":"Identification of a homozygous destabilizing PLCB3 variant (p.Ala878Ser) in patients with spondylometaphyseal dysplasia with corneal dystrophy demonstrated that PLCB3 loss-of-function elevates PIP2, disrupts F-actin, and causes a Mendelian skeletal syndrome.","evidence":"Whole exome sequencing, homozygosity mapping, PIP2 measurement and F-actin staining in patient fibroblasts","pmids":["29122926"],"confidence":"High","gaps":["No animal model recapitulating the skeletal phenotype","How elevated PIP2 specifically leads to chondrocyte/corneal pathology not defined","Whether residual enzymatic activity exists with the A878S variant not quantified"]},{"year":2018,"claim":"Systematic active-site mutagenesis confirmed that PLCB3 catalytic activity is required for agonist-induced Ca²⁺ release, PKCβ activation, and IL-8 production, ruling out a purely scaffold-based mechanism in epithelial innate immunity.","evidence":"Catalytic-dead and activation-deficient mutants with Ca²⁺ imaging, PKC and IL-8 assays in CF bronchial epithelial cells","pmids":["29668297"],"confidence":"High","gaps":["S845L variant structural consequences not resolved crystallographically","Whether scaffold and catalytic functions both contribute in mast cells remains untested"]},{"year":2024,"claim":"Discovery that OSBPL2 directly binds and protects PLCB3 from ubiquitin-dependent proteasomal degradation revealed a post-translational stability mechanism, explaining how OSBPL2 loss-of-function causes keratinocyte hyperkeratosis via PLCB3 depletion.","evidence":"Reciprocal co-immunoprecipitation, ubiquitylation assays, patient fibroblast/keratinocyte studies","pmids":["38701954"],"confidence":"Medium","gaps":["E3 ubiquitin ligase targeting PLCB3 not identified","Ubiquitylation sites on PLCB3 not mapped","Whether OSBPL2 regulation of PLCB3 is relevant in non-epidermal tissues unknown"]},{"year":null,"claim":"Key unresolved questions include whether the scaffold and lipase functions of PLCB3 are separable in vivo, the identity of the E3 ligase controlling PLCB3 turnover, the structural basis for Ser1105 phospho-regulation, and the mechanism by which PIP2 accumulation drives skeletal dysplasia.","evidence":"","pmids":[],"confidence":"High","gaps":["No catalytic-dead knock-in mouse to dissect scaffold versus enzymatic roles","E3 ligase for PLCB3 ubiquitylation unknown","No high-resolution structure of full-length PLCB3 in a signaling complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,4,6,8]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,3,12]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[11]}],"complexes":["FcεRI–Lyn–SHP-1–PLCβ3 signaling complex"],"partners":["LYN","PTPN6","FCER1A","OSBPL2","STAT5A","PRKCA","PRKCB"],"other_free_text":[]},"mechanistic_narrative":"PLCB3 is a ubiquitously expressed phosphoinositide-specific phospholipase C that hydrolyzes PIP2 to generate IP3 and DAG downstream of heterotrimeric G proteins coupled to GPCRs and immune receptors, thereby controlling intracellular calcium mobilization, PKC activation, and NF-κB signaling across diverse cell types [PMID:7607669, PMID:21411730, PMID:29668297]. In mast cells, PLCB3 functions as a scaffold that constitutively associates with FcεRI, Lyn, and SHP-1; upon receptor activation it recruits SHP-1 to dephosphorylate Lyn, tuning MAPK-dependent cytokine production and STAT5-driven mast cell expansion, such that Plcb3 deficiency causes spontaneous atopic dermatitis–like disease [PMID:21683628, PMID:24412367]. Ser1105 serves as a convergent phosphorylation node for PKA and PKC, with differential dephosphorylation by calcineurin versus PP1/PP2A enabling cross-talk between cAMP and Gq pathways in myometrial cells [PMID:18322273]. A homozygous destabilizing missense variant (p.Ala878Ser) causes elevated PIP2, F-actin disorganization, and spondylometaphyseal dysplasia with corneal dystrophy, while PLCB3 protein stability is maintained by OSBPL2-mediated protection from ubiquitin-dependent degradation [PMID:29122926, PMID:38701954]."},"prefetch_data":{"uniprot":{"accession":"Q01970","full_name":"1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3","aliases":["Phosphoinositide phospholipase C-beta-3","Phospholipase C-beta-3","PLC-beta-3"],"length_aa":1234,"mass_kda":138.8,"function":"Catalyzes the production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) (PubMed:20966218, PubMed:29122926, PubMed:37991948, PubMed:9188725). Key transducer of G protein-coupled receptor signaling: activated by G(q)/G(11) G alpha proteins downstream of G protein-coupled receptors activation (PubMed:20966218, PubMed:37991948). In neutrophils, participates in a phospholipase C-activating N-formyl peptide-activated GPCR (G protein-coupled receptor) signaling pathway by promoting RASGRP4 activation by DAG, to promote neutrophil functional responses (By similarity)","subcellular_location":"Cytoplasm; Membrane; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q01970/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PLCB3","classification":"Not Classified","n_dependent_lines":24,"n_total_lines":1208,"dependency_fraction":0.019867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PLCB3","total_profiled":1310},"omim":[{"mim_id":"618961","title":"SPONDYLOMETAPHYSEAL DYSPLASIA WITH CORNEAL DYSTROPHY; SMDCD","url":"https://www.omim.org/entry/618961"},{"mim_id":"615706","title":"AURICULOCONDYLAR SYNDROME 3; ARCND3","url":"https://www.omim.org/entry/615706"},{"mim_id":"612798","title":"QUESTION MARK EARS, ISOLATED; QME","url":"https://www.omim.org/entry/612798"},{"mim_id":"608455","title":"GLYCOGEN PHOSPHORYLASE, MUSCLE; PYGM","url":"https://www.omim.org/entry/608455"},{"mim_id":"607811","title":"p21-ACTIVATED KINASE- AND PHOSPHOLIPASE C-INTERACTING PROTEIN 1; PAK1IP1","url":"https://www.omim.org/entry/607811"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"intestine","ntpm":107.1}],"url":"https://www.proteinatlas.org/search/PLCB3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q01970","domains":[{"cath_id":"2.30.29.240","chopping":"21-221","consensus_level":"medium","plddt":93.51,"start":21,"end":221},{"cath_id":"1.10.238.10","chopping":"225-302","consensus_level":"high","plddt":94.0433,"start":225,"end":302},{"cath_id":"3.20.20.190","chopping":"327-472_576-706","consensus_level":"medium","plddt":95.7491,"start":327,"end":706},{"cath_id":"2.60.40.150","chopping":"727-857","consensus_level":"high","plddt":96.4885,"start":727,"end":857},{"cath_id":"1.20.1230.10","chopping":"957-997_1032-1077_1149-1193","consensus_level":"medium","plddt":90.3177,"start":957,"end":1193}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01970","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01970-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01970-F1-predicted_aligned_error_v6.png","plddt_mean":82.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PLCB3","jax_strain_url":"https://www.jax.org/strain/search?query=PLCB3"},"sequence":{"accession":"Q01970","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01970.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01970/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01970"}},"corpus_meta":[{"pmid":"26029847","id":"PMC_26029847","title":"The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML.","date":"2015","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/26029847","citation_count":88,"is_preprint":false},{"pmid":"24412367","id":"PMC_24412367","title":"Critical role for mast cell Stat5 activity in skin inflammation.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24412367","citation_count":75,"is_preprint":false},{"pmid":"27191743","id":"PMC_27191743","title":"CAPE suppresses migration and invasion of prostate cancer cells via activation of non-canonical Wnt signaling.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27191743","citation_count":43,"is_preprint":false},{"pmid":"21411730","id":"PMC_21411730","title":"Phospholipase C-β3 is a key modulator of IL-8 expression in cystic fibrosis bronchial epithelial cells.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21411730","citation_count":39,"is_preprint":false},{"pmid":"24096177","id":"PMC_24096177","title":"Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders.","date":"2013","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/24096177","citation_count":39,"is_preprint":false},{"pmid":"21683628","id":"PMC_21683628","title":"Phospholipase C-β3 regulates FcɛRI-mediated mast cell activation by recruiting the protein phosphatase SHP-1.","date":"2011","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21683628","citation_count":35,"is_preprint":false},{"pmid":"28453527","id":"PMC_28453527","title":"Altered nucleocytoplasmic proteome and transcriptome distributions in an in vitro model of amyotrophic lateral sclerosis.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28453527","citation_count":32,"is_preprint":false},{"pmid":"26308735","id":"PMC_26308735","title":"Pathway Analysis Based on a Genome-Wide Association Study of Polycystic Ovary Syndrome.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26308735","citation_count":32,"is_preprint":false},{"pmid":"35818695","id":"PMC_35818695","title":"Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate Myocardial Infarction Injury via miR-24-3p-Promoted M2 Macrophage Polarization.","date":"2022","source":"Advanced biology","url":"https://pubmed.ncbi.nlm.nih.gov/35818695","citation_count":28,"is_preprint":false},{"pmid":"9286704","id":"PMC_9286704","title":"Construction of a 1.2-Mb sequence-ready contig of chromosome 11q13 encompassing the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9286704","citation_count":28,"is_preprint":false},{"pmid":"8838322","id":"PMC_8838322","title":"Isolation and characterization of a novel gene close to the human phosphoinositide-specific phospholipase C beta 3 gene on chromosomal region 11q13.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8838322","citation_count":24,"is_preprint":false},{"pmid":"7607669","id":"PMC_7607669","title":"Genomic organization and complete cDNA sequence of the human phosphoinositide-specific phospholipase C beta 3 gene (PLCB3).","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7607669","citation_count":21,"is_preprint":false},{"pmid":"25219847","id":"PMC_25219847","title":"Ovarian superstimulation using FSH combined with equine chorionic gonadotropin (eCG) upregulates mRNA-encoding proteins involved with LH receptor intracellular signaling in granulosa cells from Nelore cows.","date":"2014","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/25219847","citation_count":17,"is_preprint":false},{"pmid":"16511346","id":"PMC_16511346","title":"Sphingosine 1-phosphate-induced signal transduction in cat esophagus smooth muscle cells.","date":"2006","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/16511346","citation_count":16,"is_preprint":false},{"pmid":"11178984","id":"PMC_11178984","title":"Differentially expressed cDNAs in PLCbeta3-induced tumor suppression in a human endocrine pancreatic tumor cell line: activation of the human mismatch repair protein 3 gene.","date":"2001","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/11178984","citation_count":15,"is_preprint":false},{"pmid":"18322273","id":"PMC_18322273","title":"Multiple signals regulate phospholipase CBeta3 in human myometrial cells.","date":"2008","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/18322273","citation_count":15,"is_preprint":false},{"pmid":"29668297","id":"PMC_29668297","title":"PLCB3 Loss of Function Reduces Pseudomonas aeruginosa-Dependent IL-8 Release in Cystic Fibrosis.","date":"2018","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29668297","citation_count":14,"is_preprint":false},{"pmid":"21586561","id":"PMC_21586561","title":"Phospholipase Cβ3 mediates LH-induced granulosa cell differentiation.","date":"2011","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/21586561","citation_count":14,"is_preprint":false},{"pmid":"33405298","id":"PMC_33405298","title":"iTRAQ-based proteomic analysis of the molecular mechanisms and downstream effects of fatty acid synthase in osteosarcoma cells.","date":"2021","source":"Journal of clinical laboratory analysis","url":"https://pubmed.ncbi.nlm.nih.gov/33405298","citation_count":14,"is_preprint":false},{"pmid":"25753874","id":"PMC_25753874","title":"Effect evaluation of cisplatin-gemcitabine combination chemotherapy for advanced non-small cell lung cancer patients using microarray data.","date":"2015","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25753874","citation_count":13,"is_preprint":false},{"pmid":"9003510","id":"PMC_9003510","title":"Exclusion of the phosphoinositide-specific phospholipase C beta 3 (PLCB3) gene as a candidate for multiple endocrine neoplasia type 1.","date":"1997","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9003510","citation_count":11,"is_preprint":false},{"pmid":"10359076","id":"PMC_10359076","title":"Suppression of the neoplastic phenotype by transfection of phospholipase C beta 3 to neuroendocrine tumor cells.","date":"1999","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10359076","citation_count":10,"is_preprint":false},{"pmid":"7789993","id":"PMC_7789993","title":"Localization of the human phosphatidylinositol-specific phospholipase c beta 3 gene (PLCB3) within chromosome band 11q13.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7789993","citation_count":9,"is_preprint":false},{"pmid":"35942506","id":"PMC_35942506","title":"The genetic architecture of blood pressure variability: A genome-wide association study of 9370 participants from UK Biobank.","date":"2022","source":"Journal of clinical hypertension (Greenwich, Conn.)","url":"https://pubmed.ncbi.nlm.nih.gov/35942506","citation_count":9,"is_preprint":false},{"pmid":"29122926","id":"PMC_29122926","title":"Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.","date":"2017","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29122926","citation_count":8,"is_preprint":false},{"pmid":"12894496","id":"PMC_12894496","title":"In situ RNA-RNA hybridisation of phospholipase C beta 3 shows lack of expression in neuroendocrine tumours.","date":"2003","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12894496","citation_count":8,"is_preprint":false},{"pmid":"35156189","id":"PMC_35156189","title":"Insulin-like growth factor-1 inhibits apoptosis of rat gastric smooth muscle cells under high glucose condition via adenosine monophosphate-activated protein kinase (AMPK) pathway.","date":"2022","source":"Folia histochemica et cytobiologica","url":"https://pubmed.ncbi.nlm.nih.gov/35156189","citation_count":8,"is_preprint":false},{"pmid":"38954658","id":"PMC_38954658","title":"Tibial cortex transverse transport surgery improves wound healing in patients with severe type 2 DFUs by activating a systemic immune response: a cross-sectional study.","date":"2025","source":"International journal of surgery (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38954658","citation_count":8,"is_preprint":false},{"pmid":"12823437","id":"PMC_12823437","title":"The ichq mutant mouse, a model for the human skin disorder harlequin ichthyosis: mapping, keratinocyte culture, and consideration of candidate genes involved in epidermal growth regulation.","date":"2003","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/12823437","citation_count":7,"is_preprint":false},{"pmid":"31737645","id":"PMC_31737645","title":"Is MYND Domain-Mediated Assembly of SMYD3 Complexes Involved in Calcium Dependent Signaling?","date":"2019","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/31737645","citation_count":6,"is_preprint":false},{"pmid":"27122524","id":"PMC_27122524","title":"Expression of inflammation/pain-related genes in the dorsal root ganglion following disc puncture in rats.","date":"2016","source":"Journal of orthopaedic surgery (Hong Kong)","url":"https://pubmed.ncbi.nlm.nih.gov/27122524","citation_count":6,"is_preprint":false},{"pmid":"38405768","id":"PMC_38405768","title":"Fine-mapping genomic loci refines bipolar disorder risk genes.","date":"2024","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38405768","citation_count":5,"is_preprint":false},{"pmid":"29725345","id":"PMC_29725345","title":"A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants.","date":"2018","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29725345","citation_count":5,"is_preprint":false},{"pmid":"7587389","id":"PMC_7587389","title":"Assignment of the mouse homologue of a human MEN1 candidate gene, phospholipase C-beta 3 (Plcb3), to chromosome region 19B by FISH.","date":"1995","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7587389","citation_count":4,"is_preprint":false},{"pmid":"39802100","id":"PMC_39802100","title":"First Indonesian Nasopharyngeal Cancer Whole Epigenome Sequencing Identify Tumour Suppressor CpG Methylation.","date":"2025","source":"Biologics : targets & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/39802100","citation_count":4,"is_preprint":false},{"pmid":"38724565","id":"PMC_38724565","title":"Cetuximab inhibits colorectal cancer development through inactivating the Wnt/β-catenin pathway and modulating PLCB3 expression.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38724565","citation_count":3,"is_preprint":false},{"pmid":"37832654","id":"PMC_37832654","title":"Illuminating (HTLV-1)-induced adult T-cell leukemia/lymphoma transcriptomic signature: A systems virology approach.","date":"2023","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/37832654","citation_count":2,"is_preprint":false},{"pmid":"38701954","id":"PMC_38701954","title":"OSBPL2 compound heterozygous variants cause dyschromatosis, ichthyosis, deafness and atopic disease syndrome.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38701954","citation_count":0,"is_preprint":false},{"pmid":"37592823","id":"PMC_37592823","title":"Extension domain of amyloid processor protein inhibits amyloidogenic cleavage and balances neural activity in a traumatic brain injury mouse model.","date":"2023","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37592823","citation_count":0,"is_preprint":false},{"pmid":"39439015","id":"PMC_39439015","title":"Cerebellar Molecular Signatures in Non-Human Primates.","date":"2024","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39439015","citation_count":0,"is_preprint":false},{"pmid":"40892863","id":"PMC_40892863","title":"Transcriptional profiling identification of inflammatory signaling pathways in ulcerative colitis.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/40892863","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.17.24313718","title":"Exome wide association study for blood lipids in 1,158,017 individuals from diverse populations","date":"2024-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.17.24313718","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23901,"output_tokens":3894,"usd":0.065057},"stage2":{"model":"claude-opus-4-6","input_tokens":7362,"output_tokens":3032,"usd":0.168915},"total_usd":0.233972,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"The human PLCB3 gene encodes a 1234-amino acid phosphoinositide-specific phospholipase C beta 3 protein with a 4.4-kb transcript expressed in all tissues. The gene contains 31 exons spanning ~15 kb, with a GC-rich promoter lacking TATA/CAAT boxes (housekeeping promoter type), and the transcription initiation site was mapped 328-321 bp upstream of the translation start.\",\n      \"method\": \"cDNA sequencing, genomic sequencing of cosmid subclones, Northern blotting, primer extension for transcription start site\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete cDNA and genomic characterization with multiple orthogonal methods\",\n      \"pmids\": [\"7607669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PLC-β3 constitutively interacts with FcεRI, Lyn, and SHP-1 in mast cells. Upon FcεRI stimulation, PLC-β3 recruits SHP-1 which dephosphorylates Lyn at Tyr396 (inhibitory site) to suppress Lyn activity, thereby reducing negative regulation and enabling MAPK-dependent cytokine production. Loss of Plcb3 reduces cytokine production but not degranulation, and phenocopies SHP-1 mutant mast cells.\",\n      \"method\": \"Plcb3(-/-) mouse model, co-immunoprecipitation, kinase activity assays, anaphylaxis models, cytokine ELISA, MAPK phosphorylation assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus KO mouse with defined cellular phenotype and mechanistic follow-up, multiple orthogonal methods\",\n      \"pmids\": [\"21683628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PLC-β3 deficiency in mast cells leads to increased STAT5 activity and reduced SHP-1 activity, causing mast cell expansion and spontaneous AD-like skin lesions. PLC-β3 also regulates periostin expression in fibroblasts and TSLP expression in keratinocytes. Mast cell-specific Stat5 deletion rescues, while Shp1 deletion exacerbates, allergen-induced dermatitis in Plcb3(-/-) mice.\",\n      \"method\": \"Plcb3(-/-) mouse model, mast cell-specific conditional knockouts (Stat5, Shp1), allergen challenge models, Western blotting for phospho-STAT5\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple conditional KO models with defined cellular phenotypes and epistasis analysis\",\n      \"pmids\": [\"24412367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In bronchial epithelial cells, PLCB3 mediates extracellular nucleotide-dependent intracellular calcium signaling that activates protein kinase Cα and Cβ and NF-κB p65, potentiating Toll-like receptor signaling to drive IL-8 release in response to Pseudomonas aeruginosa. Silencing PLCB3 attenuates this inflammatory cascade.\",\n      \"method\": \"siRNA knockdown in CF bronchial epithelial cells, calcium signaling assays, PKC activity assays, NF-κB reporter assays, IL-8 ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA KD with multiple downstream pathway readouts in primary disease-relevant cells\",\n      \"pmids\": [\"21411730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The PLCB3-S845L variant (c.2534C>T) is a loss-of-function mutation that impairs agonist-induced Ca2+ release from the ER, reduces conventional PKCβ activation, and diminishes IL-8 release in CF bronchial epithelial cells. Synthetic catalytic-dead and activation-deficient PLCB3 mutants confirmed the requirement for enzymatic activity.\",\n      \"method\": \"Site-directed mutagenesis, Ca2+ imaging, PKC activation assays, IL-8 ELISA in CF bronchial epithelial cells exposed to P. aeruginosa\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis with multiple orthogonal functional readouts\",\n      \"pmids\": [\"29668297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A homozygous missense variant (c.2632G>T; p.Ala878Ser) in PLCB3 disrupts the Ha2' element of the proximal C-terminal domain, destabilizing PLCB3 and causing elevated PIP2 levels in patient fibroblasts, leading to F-actin cytoskeleton disorganization and a new form of spondylometaphyseal dysplasia with corneal dystrophy.\",\n      \"method\": \"Whole exome sequencing, homozygosity mapping, patient fibroblast studies (PIP2 measurement, F-actin staining), protein stability assays\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — variant identified and functionally validated in patient cells with biochemical and cytoskeletal readouts\",\n      \"pmids\": [\"29122926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PLCB3 Ser1105 (S1105) is a convergent phosphorylation site for multiple kinases in human myometrial cells. PKA pathway (via cAMP/PRKA) and PKC (via oxytocin/Gq) both phosphorylate S1105; PKA-mediated phosphorylation inhibits oxytocin-stimulated phosphatidylinositol turnover in a S1105-dependent manner, demonstrated by S1105A mutant. PP2B/calcineurin preferentially dephosphorylates PKA-phosphorylated S1105 while PP1/PP2A acts on PKC-phosphorylated S1105. PLCB3 shRNA significantly attenuated oxytocin-stimulated intracellular Ca2+ increases.\",\n      \"method\": \"shRNA knockdown, S1105A mutagenesis, phosphatase inhibitors (cypermethrin, okadaic acid), kinase inhibitors, calcium imaging, PI turnover assays in immortalized and primary human myometrial cells\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis of phosphorylation site combined with pharmacological dissection and KD, multiple orthogonal methods\",\n      \"pmids\": [\"18322273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In cat esophageal smooth muscle cells, S1P-induced contraction is mediated through S1P2 receptors coupled to PTX-sensitive Gi2 and PTX-insensitive Gq/Gβγ proteins, leading to PLCβ3 activation. Intracellular application of PLCβ3-specific antibody inhibited contraction, placing PLCβ3 upstream of PKCε and MEK/ERK in the S1P contractile signaling pathway.\",\n      \"method\": \"Intracellular antibody injection into permeabilized smooth muscle cells, pertussis toxin treatment, PLC inhibitor U73122, PKC and MEK inhibitors, contraction assays\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — intracellular antibody inhibition with pharmacological pathway dissection, single study\",\n      \"pmids\": [\"16511346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PLCβ3 (PLCB3) specifically mediates LH-induced differentiation of bovine granulosa cells. PLCB3 is upregulated in ovulatory-size follicles, predominantly cytoplasmic in these cells, and RNAi-mediated PLCB3 knockdown reduced LH-induced IP turnover and transcriptional upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2), while suppressing LH-induced downregulation of aromatase and estradiol production, without affecting cAMP responses.\",\n      \"method\": \"RNAi knockdown in primary bovine granulosa cells, inositol phosphate turnover assay, RT-PCR, estradiol measurement, cAMP assay, immunofluorescence localization\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with multiple pathway readouts in primary cells, single lab\",\n      \"pmids\": [\"21586561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Transfection of PLCB3 into neuroendocrine tumor cell lines with low/absent PLCB3 expression suppressed growth in vitro (reduced [3H]thymidine incorporation) and reduced tumorigenicity in nude mice xenografts, with decreased Ki-67+ proliferating cells, indicating a tumor suppressor function for PLCB3 in neuroendocrine cells.\",\n      \"method\": \"PLCB3 cDNA transfection, [3H]thymidine incorporation, cell counting, nude mouse xenografts, Ki-67 immunostaining\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function reconstitution in vitro and in vivo with defined proliferation readouts, single lab\",\n      \"pmids\": [\"10359076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Transfection of PLCB3 into BON-1 neuroendocrine tumor cells altered gene expression, inducing hMSH3 (mismatch repair protein 3) and TIS/MA-3 (topoisomerase suppressor/apoptosis gene) mRNAs while suppressing S100A3 and Chromogranin A, suggesting these downstream gene expression changes contribute to PLCB3-mediated tumor suppression.\",\n      \"method\": \"PLCB3 cDNA transfection, RT-differential cDNA display, sequence identification of differentially expressed transcripts\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (differential display) without mechanistic follow-up of individual targets\",\n      \"pmids\": [\"11178984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OSBPL2 directly interacts with PLCB3 and inhibits ubiquitylation of PLCB3, thereby stabilizing it. OSBPL2 loss-of-function variants lead to enhanced ubiquitination and proteasomal degradation of PLCB3, resulting in epidermal hyperkeratosis with aberrant keratinocyte proliferation and delayed terminal differentiation.\",\n      \"method\": \"Co-immunoprecipitation (OSBPL2-PLCB3 interaction), ubiquitylation assays, patient fibroblast/keratinocyte studies, exome sequencing\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus ubiquitylation assay with cellular phenotype, single study\",\n      \"pmids\": [\"38701954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Exosomal miR-24-3p from umbilical cord mesenchymal stem cells suppresses Plcb3 expression and NF-κB pathway activation in macrophages, promoting M2 polarization. RNA-seq identified Plcb3 as a key gene in macrophage polarization, and miR-24-3p overexpression or UMSC-Exo treatment reduced Plcb3 levels to enhance M2 polarization.\",\n      \"method\": \"RNA sequencing, miR-24-3p overexpression, UMSC-Exo treatment, macrophage polarization assays, Western blotting for NF-κB pathway\",\n      \"journal\": \"Advanced biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — miRNA-target relationship demonstrated with gain-of-function and exosome experiments, single lab\",\n      \"pmids\": [\"35818695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PLCB3 knockdown in colorectal cancer cells inhibits CRC cell proliferation, migration, and invasion. Cetuximab treatment reduces β-catenin and PLCB3 expression while increasing E-cadherin, and combined application of a Wnt activator with PLCB3 modulation affects cetuximab efficacy, placing PLCB3 as a modulator of Wnt/β-catenin signaling in CRC.\",\n      \"method\": \"siRNA knockdown, Western blotting for β-catenin/E-cadherin/PLCB3, proliferation/migration/invasion assays, Wnt activator (IM12) rescue experiments\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — KD with phenotype but pathway placement is correlative without direct mechanistic demonstration\",\n      \"pmids\": [\"38724565\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PLCB3 encodes a phosphoinositide-specific phospholipase C that converts PIP2 to IP3 and DAG downstream of GPCRs and immune receptors; it constitutively assembles with FcεRI, Lyn, and SHP-1 in mast cells to regulate cytokine production via SHP-1-mediated Lyn dephosphorylation, mediates Toll-like receptor–potentiated NF-κB/PKC/Ca2+ signaling in epithelial cells, serves as a convergent phosphorylation node (Ser1105) for PKA and PKC cross-talk in myometrial cells, and its protein stability is regulated by OSBPL2-mediated protection from ubiquitin-dependent degradation, with loss-of-function causing elevated PIP2, F-actin disorganization, and a skeletal dysplasia syndrome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PLCB3 is a ubiquitously expressed phosphoinositide-specific phospholipase C that hydrolyzes PIP2 to generate IP3 and DAG downstream of heterotrimeric G proteins coupled to GPCRs and immune receptors, thereby controlling intracellular calcium mobilization, PKC activation, and NF-κB signaling across diverse cell types [PMID:7607669, PMID:21411730, PMID:29668297]. In mast cells, PLCB3 functions as a scaffold that constitutively associates with FcεRI, Lyn, and SHP-1; upon receptor activation it recruits SHP-1 to dephosphorylate Lyn, tuning MAPK-dependent cytokine production and STAT5-driven mast cell expansion, such that Plcb3 deficiency causes spontaneous atopic dermatitis–like disease [PMID:21683628, PMID:24412367]. Ser1105 serves as a convergent phosphorylation node for PKA and PKC, with differential dephosphorylation by calcineurin versus PP1/PP2A enabling cross-talk between cAMP and Gq pathways in myometrial cells [PMID:18322273]. A homozygous destabilizing missense variant (p.Ala878Ser) causes elevated PIP2, F-actin disorganization, and spondylometaphyseal dysplasia with corneal dystrophy, while PLCB3 protein stability is maintained by OSBPL2-mediated protection from ubiquitin-dependent degradation [PMID:29122926, PMID:38701954].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing the basic identity of PLCB3 as a ubiquitously expressed, housekeeping-type phospholipase C gene answered the foundational question of its genomic organization and tissue distribution.\",\n      \"evidence\": \"cDNA/genomic sequencing, Northern blotting, and primer extension in human tissues\",\n      \"pmids\": [\"7607669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No enzymatic kinetics or substrate specificity data provided\", \"No upstream activating receptors identified\", \"Protein-level expression and subcellular localization not characterized\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Reconstitution of PLCB3 in neuroendocrine tumor cells deficient for the protein revealed a growth-suppressive function, raising the question of whether PLCB3 acts as a tumor suppressor beyond its canonical lipase activity.\",\n      \"evidence\": \"PLCB3 cDNA transfection with thymidine incorporation assays and nude mouse xenografts\",\n      \"pmids\": [\"10359076\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of growth suppression not defined\", \"Downstream transcriptional changes identified by differential display (PMID:11178984) lack validation\", \"Relevance to human neuroendocrine tumors in situ not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrating that intracellular PLCB3-specific antibody blocked S1P-induced smooth muscle contraction placed PLCB3 downstream of both Gi and Gq pathways and upstream of PKCε/MEK/ERK in a contractile signaling cascade.\",\n      \"evidence\": \"Intracellular antibody injection in permeabilized cat esophageal smooth muscle cells with pertussis toxin and kinase inhibitors\",\n      \"pmids\": [\"16511346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antibody specificity for PLCB3 versus other PLC isoforms not independently validated\", \"Single species/tissue system\", \"Direct G-protein coupling not biochemically demonstrated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of Ser1105 as a convergent PKA/PKC phosphorylation site with differential phosphatase control resolved how cAMP and Gq/oxytocin pathways cross-talk through PLCB3 in myometrial cells.\",\n      \"evidence\": \"S1105A mutagenesis, shRNA knockdown, pharmacological phosphatase and kinase inhibition, calcium imaging in human myometrial cells\",\n      \"pmids\": [\"18322273\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how S1105 phosphorylation inhibits catalytic activity unknown\", \"In vivo relevance to labor/uterine contractility not tested\", \"Whether other PLC-β isoforms are similarly regulated at homologous sites not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that PLCB3 constitutively scaffolds FcεRI, Lyn, and SHP-1 in mast cells — and that Plcb3 knockout phenocopies SHP-1 loss for cytokine production — established a non-canonical adaptor/scaffold function independent of lipase activity per se.\",\n      \"evidence\": \"Plcb3−/− mouse, reciprocal co-immunoprecipitation, Lyn kinase assays, anaphylaxis models, cytokine ELISA\",\n      \"pmids\": [\"21683628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the scaffold and lipase functions are separable (e.g., catalytic-dead knock-in) was not tested\", \"Structural basis for the quaternary PLCB3–FcεRI–Lyn–SHP-1 complex unknown\", \"Contribution of individual PLCB3 domains to complex assembly not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Parallel work showed PLCB3 mediates nucleotide-stimulated Ca²⁺/PKC/NF-κB signaling that potentiates TLR-driven IL-8 release in bronchial epithelial cells, extending its functional role to innate immune amplification in the airway.\",\n      \"evidence\": \"siRNA knockdown in CF bronchial epithelial cells with calcium, PKC, NF-κB reporter, and IL-8 readouts\",\n      \"pmids\": [\"21411730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity (P2Y subtype) upstream of PLCB3 not definitively assigned\", \"In vivo relevance in CF lung disease not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Epistasis experiments in Plcb3-deficient mice showed that PLCB3 restrains STAT5 activity via SHP-1, and that mast cell-specific Stat5 deletion rescues dermatitis, establishing the PLCB3→SHP-1⊣STAT5 axis as the driver of mast cell expansion and atopic skin disease.\",\n      \"evidence\": \"Plcb3−/− crossed with mast cell-specific Stat5 and Shp1 conditional knockouts, allergen challenge\",\n      \"pmids\": [\"24412367\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PLCB3 regulates periostin in fibroblasts and TSLP in keratinocytes mechanistically unclear\", \"Whether lipase activity is required for the STAT5 regulatory circuit not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of a homozygous destabilizing PLCB3 variant (p.Ala878Ser) in patients with spondylometaphyseal dysplasia with corneal dystrophy demonstrated that PLCB3 loss-of-function elevates PIP2, disrupts F-actin, and causes a Mendelian skeletal syndrome.\",\n      \"evidence\": \"Whole exome sequencing, homozygosity mapping, PIP2 measurement and F-actin staining in patient fibroblasts\",\n      \"pmids\": [\"29122926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No animal model recapitulating the skeletal phenotype\", \"How elevated PIP2 specifically leads to chondrocyte/corneal pathology not defined\", \"Whether residual enzymatic activity exists with the A878S variant not quantified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Systematic active-site mutagenesis confirmed that PLCB3 catalytic activity is required for agonist-induced Ca²⁺ release, PKCβ activation, and IL-8 production, ruling out a purely scaffold-based mechanism in epithelial innate immunity.\",\n      \"evidence\": \"Catalytic-dead and activation-deficient mutants with Ca²⁺ imaging, PKC and IL-8 assays in CF bronchial epithelial cells\",\n      \"pmids\": [\"29668297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"S845L variant structural consequences not resolved crystallographically\", \"Whether scaffold and catalytic functions both contribute in mast cells remains untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that OSBPL2 directly binds and protects PLCB3 from ubiquitin-dependent proteasomal degradation revealed a post-translational stability mechanism, explaining how OSBPL2 loss-of-function causes keratinocyte hyperkeratosis via PLCB3 depletion.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, ubiquitylation assays, patient fibroblast/keratinocyte studies\",\n      \"pmids\": [\"38701954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ubiquitin ligase targeting PLCB3 not identified\", \"Ubiquitylation sites on PLCB3 not mapped\", \"Whether OSBPL2 regulation of PLCB3 is relevant in non-epidermal tissues unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include whether the scaffold and lipase functions of PLCB3 are separable in vivo, the identity of the E3 ligase controlling PLCB3 turnover, the structural basis for Ser1105 phospho-regulation, and the mechanism by which PIP2 accumulation drives skeletal dysplasia.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No catalytic-dead knock-in mouse to dissect scaffold versus enzymatic roles\", \"E3 ligase for PLCB3 ubiquitylation unknown\", \"No high-resolution structure of full-length PLCB3 in a signaling complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 4, 6, 8]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 3, 12]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"complexes\": [\n      \"FcεRI–Lyn–SHP-1–PLCβ3 signaling complex\"\n    ],\n    \"partners\": [\n      \"LYN\",\n      \"PTPN6\",\n      \"FCER1A\",\n      \"OSBPL2\",\n      \"STAT5A\",\n      \"PRKCA\",\n      \"PRKCB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}