Affinage

PLCB3

1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 · UniProt Q01970

Length
1234 aa
Mass
138.8 kDa
Annotated
2026-06-10
41 papers in source corpus 15 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PLCB3 encodes phospholipase C-β3, a Gq-coupled effector that hydrolyzes PIP2 to mobilize intracellular Ca2+ and activate PKC isoforms, thereby transducing diverse receptor signals into downstream transcriptional and cytoskeletal outputs (PMID:29668297, PMID:18322273). Its catalytic activity—dependent on an intact active site (S845) and the Ha2' regulatory element that docks onto the catalytic core—drives agonist-induced ER Ca2+ release and conventional PKC activation; variants that impair catalysis or destabilize the protein cause PIP2 accumulation and F-actin disorganization, manifesting as spondylometaphyseal dysplasia with corneal dystrophy (PMID:29668297, PMID:29122926). PLCB3 acts downstream of multiple Gq-coupled receptors, including the LH receptor in granulosa cells where it mediates LH-induced steroidogenic gene expression via the Gq/PLC arm rather than the Gs/cAMP arm (PMID:21586561), the S1P2 receptor in smooth muscle where it drives PKCε–MAPK contraction (PMID:16511346), and the oxytocin receptor in myometrium, where its serine-1105 phosphorylation integrates antagonistic PKA (cAMP) and PKC (Gq) inputs through distinct phosphatases (PP2B versus PP1/PP2A) to gate phosphatidylinositol turnover and Ca2+ flux (PMID:18322273). Beyond catalysis, PLCB3 serves a scaffolding role in mast cells, where it constitutively assembles with FcεRI, Lyn, and SHP-1 and recruits SHP-1 to dephosphorylate Lyn at Tyr396, restraining mast cell activation and STAT5 signaling; its loss yields atopic-dermatitis-like skin pathology (PMID:21683628, PMID:24412367). In epithelial and immune contexts PLCB3-driven PKC/NF-κB signaling potentiates IL-8 release and inflammatory responses (PMID:21411730, PMID:29668297). PLCB3 protein stability is governed by OSBPL2, which binds PLCB3 and blocks its ubiquitylation; loss of this protection enhances PLCB3 degradation and causes epidermal hyperkeratosis (PMID:38701954).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 Medium

    Establishing the gene architecture and expression pattern was the necessary foundation, defining PLCB3 as a ubiquitously expressed housekeeping gene encoding a 1234-residue protein.

    Evidence cDNA cloning, genomic sequencing, Northern blotting and transcription start mapping

    PMID:7607669

    Open questions at the time
    • No functional or signaling role defined
    • Tissue-specific regulation not addressed
  2. 1999 Medium

    The first functional assignment came from gain-of-function in neuroendocrine tumor cells, indicating PLCB3 can restrain proliferation and tumorigenicity.

    Evidence PLCB3 transfection, thymidine incorporation, nude mouse xenografts with Ki-67 staining

    PMID:10359076

    Open questions at the time
    • Catalytic requirement not tested
    • Mechanism of growth suppression unresolved
  3. 2001 Low

    An attempt to link PLCB3 tumor suppression to transcriptional targets nominated DNA-repair and apoptosis-related genes, but only descriptively.

    Evidence RT-differential cDNA display in PLCB3-transfected BON-1 cells

    PMID:11178984

    Open questions at the time
    • Single descriptive method without validation
    • No mechanistic follow-up of nominated genes
    • No causal link to phenotype
  4. 2006 Medium

    Defining PLCB3 as the obligate effector for a specific GPCR established its role in receptor-driven contraction.

    Evidence Anti-PLCβ3 antibody microinjection into permeabilized smooth muscle cells with pharmacological pathway dissection and contractility assay

    PMID:16511346

    Open questions at the time
    • Direct receptor coupling not biochemically resolved
    • Antibody inhibition not paralleled by genetic loss
  5. 2008 High

    Identification of S1105 as a convergence point for PKA and PKC phosphorylation explained how PLCB3 integrates antagonistic signaling inputs.

    Evidence Phospho-S1105 antibody, S1105A mutagenesis, kinase/phosphatase inhibitors, shRNA and PI-turnover/Ca2+ readouts in myometrial cells

    PMID:18322273

    Open questions at the time
    • Structural basis of S1105-mediated regulation unknown
    • Whether S1105 directly alters catalytic rate not resolved
  6. 2011 High

    The discovery that PLCB3 constitutively scaffolds FcεRI, Lyn, and SHP-1 revealed a catalysis-independent, inhibitory signaling function in mast cells.

    Evidence Reciprocal Co-IP, Plcb3-/- mast cell phenotype, epistasis with SHP-1 mutant

    PMID:21683628

    Open questions at the time
    • Whether scaffolding requires lipase activity not determined
    • Structural basis of SHP-1 recruitment unknown
  7. 2011 Medium

    Parallel work assigned PLCB3 to specific Gq pathways: LH-driven granulosa steroidogenesis and nucleotide-driven epithelial inflammation.

    Evidence RNAi knockdown with steroidogenic readouts in granulosa cells; shRNA with Ca2+/PKC/NF-κB/IL-8 readouts in CF bronchial epithelial cells

    PMID:21411730 PMID:21586561

    Open questions at the time
    • Receptor-effector coupling not biochemically resolved
    • Catalytic dependence of IL-8 output not yet tested at this stage
  8. 2014 High

    Whole-organism analysis tied PLCB3 loss to dysregulated STAT5/SHP-1 balance and an atopic-dermatitis-like skin phenotype, extending the mast cell scaffolding role to disease.

    Evidence Plcb3-/- mice, mast cell-specific Stat5 and Shp1 conditional knockouts, IHC and Western blot

    PMID:24412367

    Open questions at the time
    • Direct PLCB3 regulation of STAT5 not biochemically defined
    • Crosstalk with keratinocyte/fibroblast signals incompletely mapped
  9. 2017 Medium

    A human Mendelian variant established catalytic/structural integrity as essential, linking PLCB3 destabilization to PIP2 accumulation, actin disorganization, and skeletal/corneal disease.

    Evidence Exome sequencing, homozygosity mapping, PIP2 measurement and F-actin imaging in patient fibroblasts, structural domain analysis

    PMID:29122926

    Open questions at the time
    • Mechanism linking PIP2 accumulation to actin disorganization not detailed
    • Tissue specificity of phenotype unexplained
  10. 2018 Medium

    Variant and catalytic-dead mutagenesis confirmed that enzymatic activity (S845) is required for Ca2+ release, PKCβ activation, and IL-8 secretion.

    Evidence Expression of S845L and catalytic-dead mutants in CF bronchial epithelial cells with Ca2+, PKC, and IL-8 readouts

    PMID:29668297

    Open questions at the time
    • Structural impact of S845L not resolved
    • In vivo relevance to CF inflammation not established
  11. 2024 Medium

    Identification of OSBPL2 as a direct binder that blocks PLCB3 ubiquitylation revealed the post-translational control of PLCB3 abundance and its link to epidermal disease.

    Evidence Co-IP, ubiquitylation assay, exome sequencing, keratinocyte differentiation assays

    PMID:38701954

    Open questions at the time
    • E3 ligase targeting PLCB3 not identified
    • Whether stabilized PLCB3 acts catalytically or as scaffold in keratinocytes unknown
  12. 2024 Medium

    Additional contexts placed PLCB3 in NF-κB-dependent macrophage polarization and EGFR/Wnt signaling in cancer, broadening but not deepening its mechanistic role.

    Evidence Exosomal miR-24-3p with Plcb3 knockdown and NF-κB readout in macrophages/MI model; PLCB3 knockdown with cetuximab and Wnt-activator rescue in CRC cells

    PMID:35818695 PMID:38724565

    Open questions at the time
    • Direct molecular links to NF-κB and Wnt not biochemically defined
    • CRC pathway placement rests on pharmacological rescue only
  13. 2024 Low

    Mapping PLCB3 to cerebellar Purkinje cells and deep nuclei suggested a compartmentalized neural role.

    Evidence Immunohistochemistry/immunofluorescence in macaque cerebellum

    PMID:39439015

    Open questions at the time
    • No functional consequence established
    • Localization only, single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PLCB3's catalytic (lipase) and non-catalytic (SHP-1/Lyn scaffolding) functions are partitioned across cell types, and the structural determinants of its regulation by phosphorylation and ubiquitylation, remain open.
  • No structure of full-length PLCB3 or its regulatory complexes
  • E3 ligase and detailed degradation pathway unidentified
  • Lipase-dependence of scaffolding functions untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 3 GO:0008289 lipid binding 2 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2
Partners
FCER1ALYNOSBPL2PTPN6
Complex memberships
FcεRI–Lyn–SHP-1 complex

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 PLC-β3 constitutively interacts with FcεRI, Lyn, and SHP-1 in mast cells. PLC-β3 recruits SHP-1 to dephosphorylate Lyn at Tyr396, thereby suppressing Lyn activity and enabling downstream MAPK activation required for cytokine production. Loss of PLCB3 phenocopies SHP-1 mutant mast cells: reduced cytokine production but normal degranulation after FcεRI stimulation. Co-immunoprecipitation (constitutive complex), Plcb3-/- mouse phenotype, comparison with SHP-1 mutant mast cells, genetic epistasis Immunity High 21683628
2014 PLC-β3 negatively regulates mast cell STAT5 activity and positively regulates SHP-1 activity in the skin. Plcb3-/- mice show increased STAT5 and reduced SHP-1 activities in mast cells, leading to spontaneous AD-like skin lesions. PLC-β3 also regulates periostin expression in fibroblasts and TSLP expression in keratinocytes. Plcb3-/- mouse model, mast cell-specific Stat5 and Shp1 conditional knockouts, immunohistochemistry, Western blotting Cell reports High 24412367
2011 PLCB3 mediates extracellular nucleotide-dependent intracellular calcium signaling in CF bronchial epithelial cells, leading to activation of protein kinase Cα and Cβ and NF-κB p65, which potentiates Toll-like receptor signaling and IL-8 release upon Pseudomonas aeruginosa exposure. PLCB3 silencing (shRNA) in bronchial epithelial cells, calcium signaling assays, PKC activity assays, NF-κB reporter, IL-8 ELISA Journal of immunology Medium 21411730
2018 The PLCB3-S845L variant (loss-of-function) shows defects in: (1) agonist-induced Ca2+ release from endoplasmic reticulum, (2) activation of conventional PKCβ, and (3) IL-8 release in CF bronchial epithelial cells. Synthetic catalytically-inactive mutants confirmed that enzymatic activity is required for these downstream signaling events. Expression of S845L variant and catalytic-dead mutants in CF bronchial epithelial cells, intracellular Ca2+ measurements, PKC activity assays, IL-8 ELISA, P. aeruginosa stimulation American journal of respiratory cell and molecular biology Medium 29668297
2008 PLCB3 serine-1105 (S1105) is phosphorylated by multiple kinases in human myometrial cells: PKA (via cAMP/PRKA pathway) and PKC (via oxytocin/Gq pathway). CPT-cAMP-mediated inhibition of oxytocin-stimulated phosphatidylinositol turnover requires S1105, as the S1105A mutant abolishes this negative cross-talk. Different protein phosphatases (PP2B for cAMP pathway; PP1/PP2A for oxytocin pathway) mediate S1105 dephosphorylation. PLCB3 shRNA significantly attenuated oxytocin-stimulated intracellular calcium increases. Phospho-S1105 antibody, PKA/PKC inhibitors, phosphatase inhibitors, PLCB3 shRNA knockdown, overexpression of WT and S1105A mutant PLCB3, phosphatidylinositol turnover assay, intracellular Ca2+ measurement Biology of reproduction High 18322273
2011 PLCB3 is specifically up-regulated in granulosa cells from ovulatory-size follicles and localizes predominantly to the cytoplasm in these cells. RNA interference-mediated PLCB3 knockdown reduced LH-induced transcriptional up-regulation of prostaglandin-endoperoxide synthase 2, reduced aromatase expression, and reduced estradiol production, without affecting cAMP responses to LH, indicating PLCB3 mediates LH signaling through the Gq/PLC pathway rather than the Gs/AC/cAMP pathway. Expression analysis (mRNA and protein) across follicle sizes, immunofluorescence localization, RNA interference knockdown, inositol phosphate assay, prostaglandin synthase 2 mRNA assay, estradiol ELISA, cAMP assay Endocrinology Medium 21586561
2017 A homozygous missense variant (c.2632G>T; p.A878S) in PLCB3 disrupts binding of the Ha2' element to the catalytic core, destabilizing PLCB3. This hypomorphic variant leads to elevated PIP2 levels in patient fibroblasts and disorganization of the F-actin cytoskeleton, causing spondylometaphyseal dysplasia with corneal dystrophy. Whole exome sequencing, homozygosity mapping, PIP2 measurement in patient fibroblasts, F-actin immunofluorescence, structural domain analysis Journal of medical genetics Medium 29122926
2006 In cat esophageal smooth muscle cells, S1P-induced contraction is mediated via PLCβ3. Introduction of PLCβ3 antibody into permeabilized cells inhibited S1P-induced contraction. The PLCβ3 activation leads to PKCε activation and subsequent p44/p42 MAPK pathway activation, downstream of S1P2 receptor coupled to Gi2, Gq, and Gβ proteins. Antibody microinjection into permeabilized smooth muscle cells, PLC inhibitor (U73122), PKC inhibitors, MEK inhibitor, contractility assay Molecules and cells Medium 16511346
1999 Transfection of PLCB3 into neuroendocrine tumor cell lines with low endogenous PLCB3 expression caused significant in vitro growth inhibition and reduced tumorigenicity in vivo (reduced tumor weight and Ki-67-positive proliferating cells in xenografts), indicating a tumor-suppressive role. PLCB3 transfection into neuroendocrine cell lines, [3H]thymidine incorporation, cell counting, nude mouse xenograft, Ki-67 immunostaining FEBS letters Medium 10359076
2001 PLCB3 transfection into BON-1 neuroendocrine tumor cells activates hMSH3 (mismatch repair protein 3) and a TIS/MA-3 homolog, while inhibiting S100A3 and Chromogranin A expression, indicating PLCB3-induced tumor suppression involves downstream transcriptional changes in DNA repair and apoptosis-related genes. RT-Differential cDNA Display of PLCB3-transfected vs. control BON-1 cells Biochemical and biophysical research communications Low 11178984
2024 OSBPL2 directly interacts with PLCB3 and inhibits PLCB3 ubiquitylation, thereby stabilizing PLCB3 protein. Loss-of-function OSBPL2 variants lead to enhanced ubiquitination and degradation of PLCB3, causing epidermal hyperkeratosis with aberrant keratinocyte proliferation and delayed terminal differentiation. Co-immunoprecipitation (direct interaction), ubiquitylation assay, exome sequencing, cell-based keratinocyte differentiation assays Biochimica et biophysica acta. Molecular basis of disease Medium 38701954
1995 The human PLCB3 gene contains 31 exons spanning ~15 kb on chromosome 11q13, encodes a 1234 amino acid protein, produces a single 4.4 kb transcript ubiquitously expressed, and has a GC-rich housekeeping promoter with multiple Sp1 sites but lacking TATA and CAAT boxes. The transcription initiation site was mapped 328-321 bp upstream of the translation start. cDNA cloning, genomic sequencing, Northern blotting, primer extension/transcription initiation mapping Genomics Medium 7607669
2022 Exosomal miR-24-3p from human umbilical cord mesenchymal stem cells suppresses Plcb3 expression in macrophages, leading to reduced NF-κB pathway activation and promotion of M2 macrophage polarization. Knockdown of miR-24-3p in exosomes attenuated M2 polarization, while increasing miR-24-3p in macrophages enhanced M2 polarization by suppressing Plcb3. RNA sequencing, miRNA transfection, Plcb3 knockdown, NF-κB reporter/Western blot, macrophage polarization markers, in vivo myocardial infarction model Advanced biology Medium 35818695
2024 PLCB3 knockdown inhibited colorectal cancer cell proliferation, migration, and invasion. Cetuximab treatment reduced both β-catenin and PLCB3 expression while augmenting E-cadherin expression; simultaneous application of a Wnt activator with PLCB3 reversed cetuximab-mediated inhibition, placing PLCB3 downstream of EGFR and upstream of Wnt/β-catenin signaling in CRC. PLCB3 knockdown in CRC cell lines, cetuximab treatment, β-catenin/E-cadherin Western blotting, Wnt activator (IM12) rescue experiments, proliferation/migration/invasion assays Scientific reports Low 38724565
2024 PLCB3 is expressed in the cerebellar cortex (Purkinje cells) and deep nuclei of rhesus macaque monkeys, showing striped compartmentalization in the vermis and intense signals throughout the hemisphere, with distinct zonal patterns in the fastigial and dentate nuclei, indicating a conserved role in cerebellar molecular organization. Immunohistochemistry, immunofluorescence in non-human primate cerebellar tissue sections The Journal of comparative neurology Low 39439015

Source papers

Stage 0 corpus · 41 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The PRKAA1/AMPKα1 pathway triggers autophagy during CSF1-induced human monocyte differentiation and is a potential target in CMML. Autophagy 88 26029847
2014 Critical role for mast cell Stat5 activity in skin inflammation. Cell reports 76 24412367
2016 CAPE suppresses migration and invasion of prostate cancer cells via activation of non-canonical Wnt signaling. Oncotarget 44 27191743
2013 Contribution of genetic and epigenetic mechanisms to Wnt pathway activity in prevalent skeletal disorders. Gene 39 24096177
2011 Phospholipase C-β3 is a key modulator of IL-8 expression in cystic fibrosis bronchial epithelial cells. Journal of immunology (Baltimore, Md. : 1950) 39 21411730
2011 Phospholipase C-β3 regulates FcɛRI-mediated mast cell activation by recruiting the protein phosphatase SHP-1. Immunity 35 21683628
2017 Altered nucleocytoplasmic proteome and transcriptome distributions in an in vitro model of amyotrophic lateral sclerosis. PloS one 32 28453527
2015 Pathway Analysis Based on a Genome-Wide Association Study of Polycystic Ovary Syndrome. PloS one 32 26308735
2022 Human Umbilical Cord Mesenchymal Stem Cell-Derived Exosomes Attenuate Myocardial Infarction Injury via miR-24-3p-Promoted M2 Macrophage Polarization. Advanced biology 29 35818695
1997 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. Genomics 28 9286704
1996 Isolation and characterization of a novel gene close to the human phosphoinositide-specific phospholipase C beta 3 gene on chromosomal region 11q13. Genomics 24 8838322
1995 Genomic organization and complete cDNA sequence of the human phosphoinositide-specific phospholipase C beta 3 gene (PLCB3). Genomics 21 7607669
2014 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. Theriogenology 17 25219847
2006 Sphingosine 1-phosphate-induced signal transduction in cat esophagus smooth muscle cells. Molecules and cells 16 16511346
2008 Multiple signals regulate phospholipase CBeta3 in human myometrial cells. Biology of reproduction 15 18322273
2001 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. Biochemical and biophysical research communications 15 11178984
2021 iTRAQ-based proteomic analysis of the molecular mechanisms and downstream effects of fatty acid synthase in osteosarcoma cells. Journal of clinical laboratory analysis 14 33405298
2018 PLCB3 Loss of Function Reduces Pseudomonas aeruginosa-Dependent IL-8 Release in Cystic Fibrosis. American journal of respiratory cell and molecular biology 14 29668297
2011 Phospholipase Cβ3 mediates LH-induced granulosa cell differentiation. Endocrinology 14 21586561
2015 Effect evaluation of cisplatin-gemcitabine combination chemotherapy for advanced non-small cell lung cancer patients using microarray data. European review for medical and pharmacological sciences 13 25753874
1997 Exclusion of the phosphoinositide-specific phospholipase C beta 3 (PLCB3) gene as a candidate for multiple endocrine neoplasia type 1. Human genetics 11 9003510
2025 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. International journal of surgery (London, England) 10 38954658
1999 Suppression of the neoplastic phenotype by transfection of phospholipase C beta 3 to neuroendocrine tumor cells. FEBS letters 10 10359076
2022 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. Folia histochemica et cytobiologica 9 35156189
2022 The genetic architecture of blood pressure variability: A genome-wide association study of 9370 participants from UK Biobank. Journal of clinical hypertension (Greenwich, Conn.) 9 35942506
1995 Localization of the human phosphatidylinositol-specific phospholipase c beta 3 gene (PLCB3) within chromosome band 11q13. Genomics 9 7789993
2017 Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy. Journal of medical genetics 8 29122926
2003 In situ RNA-RNA hybridisation of phospholipase C beta 3 shows lack of expression in neuroendocrine tumours. Anticancer research 8 12894496
2003 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. Experimental dermatology 7 12823437
2024 Fine-mapping genomic loci refines bipolar disorder risk genes. medRxiv : the preprint server for health sciences 6 38405768
2019 Is MYND Domain-Mediated Assembly of SMYD3 Complexes Involved in Calcium Dependent Signaling? Frontiers in molecular biosciences 6 31737645
2016 Expression of inflammation/pain-related genes in the dorsal root ganglion following disc puncture in rats. Journal of orthopaedic surgery (Hong Kong) 6 27122524
2018 A Genome-Wide Linkage Study for Chronic Obstructive Pulmonary Disease in a Dutch Genetic Isolate Identifies Novel Rare Candidate Variants. Frontiers in genetics 5 29725345
2025 First Indonesian Nasopharyngeal Cancer Whole Epigenome Sequencing Identify Tumour Suppressor CpG Methylation. Biologics : targets & therapy 4 39802100
1995 Assignment of the mouse homologue of a human MEN1 candidate gene, phospholipase C-beta 3 (Plcb3), to chromosome region 19B by FISH. Cytogenetics and cell genetics 4 7587389
2024 Cetuximab inhibits colorectal cancer development through inactivating the Wnt/β-catenin pathway and modulating PLCB3 expression. Scientific reports 3 38724565
2023 Illuminating (HTLV-1)-induced adult T-cell leukemia/lymphoma transcriptomic signature: A systems virology approach. Virus research 3 37832654
2025 Transcriptional profiling identification of inflammatory signaling pathways in ulcerative colitis. PloS one 0 40892863
2024 OSBPL2 compound heterozygous variants cause dyschromatosis, ichthyosis, deafness and atopic disease syndrome. Biochimica et biophysica acta. Molecular basis of disease 0 38701954
2024 Cerebellar Molecular Signatures in Non-Human Primates. The Journal of comparative neurology 0 39439015
2023 Extension domain of amyloid processor protein inhibits amyloidogenic cleavage and balances neural activity in a traumatic brain injury mouse model. CNS neuroscience & therapeutics 0 37592823

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