{"gene":"CAVIN3","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2009,"finding":"SRBC/cavin-3 (CAVIN3) co-immunoprecipitates with caveolin-1, and a leucine zipper in SRBC is essential for both co-precipitation with caveolin-1 and localization to caveolae. SRBC binds PKCδ as a member of the STICK superfamily. SRBC remains associated with caveolin when caveolae bud to form vesicles (cavicles) that travel on microtubules, and in the absence of SRBC, intracellular cavicle traffic is markedly impaired.","method":"Co-immunoprecipitation, leucine zipper mutagenesis, live-cell imaging of cavicle trafficking","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with mutagenesis validation, defined cellular phenotype (impaired cavicle trafficking) on loss-of-function, replicated across multiple methods in single rigorous study","pmids":["19262564"],"is_preprint":false},{"year":2013,"finding":"Cavin-3 dictates the balance between ERK and Akt signaling: loss of cavin-3 increases Akt signaling at the expense of ERK, while gain of cavin-3 increases ERK signaling at the expense of Akt. Cavin-3 facilitates ERK signaling by anchoring caveolae to the membrane skeleton via myosin-1c; loss of this linkage reduces caveolae abundance and separates the ERK activation module from signaling receptors. Loss of cavin-3 also promotes Akt signaling through suppression of EGR1 and PTEN. In vivo consequences of cavin-3 knockout include increased lactate production and cachexia.","method":"Cavin-3 knockout mice, in vitro gain/loss-of-function, co-immunoprecipitation with myosin-1c, signaling pathway analysis (ERK/Akt phosphorylation), metabolic assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout plus in vitro complementary experiments, multiple orthogonal methods (KO mice, IP, signaling assays, metabolic readouts), two independent approaches (in vivo and in vitro)","pmids":["24069528"],"is_preprint":false},{"year":2012,"finding":"CAVIN-3 is a cytoplasmic PER2-interacting protein that influences circadian clock properties. Loss- and gain-of-function of CAVIN-3 shortened and lengthened, respectively, the circadian period in fibroblasts, and affected PER:CRY protein abundance and interaction. CAVIN-3 required its PKCδ-binding site to exert its effect on period length. Depletion of PKCδ alone had little effect, suggesting involvement of yet-uncharacterized kinases. CAVIN-3 activity in circadian gene expression was independent of caveolae.","method":"Co-immunoprecipitation (PER2 interaction), RNAi knockdown, overexpression, circadian period assays in fibroblasts, PKCδ-binding site mutagenesis","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus loss- and gain-of-function with defined molecular phenotype (period length, PER:CRY abundance), single lab with two orthogonal approaches","pmids":["23079727"],"is_preprint":false},{"year":2015,"finding":"Cavin3 is targeted to caveolae by cavin1, where it interacts with the scaffolding domain of caveolin1 and promotes caveolae dynamics. The N-terminal region of cavin3 binds a trimer of the cavin1 N-terminus in competition with a homologous cavin2 region, indicating that cavins form distinct subcomplexes through their N-terminal regions. Cavin3 is enriched at deeply invaginated caveolae, and loss of cavin3 increases the proportion of stable caveolae and decreases short-lived caveolae at the membrane.","method":"Co-immunoprecipitation, truncation/domain mapping, live-cell TIRF imaging of caveolae dynamics, siRNA knockdown","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, live-cell imaging with direct functional consequence, multiple orthogonal methods in a single rigorous study","pmids":["25588833"],"is_preprint":false},{"year":2008,"finding":"hSRBC (CAVIN3) increases p53 protein stability and expression of p53 target genes (p21Waf1, PUMA, NOXA). hSRBC-mediated cell cycle arrest and apoptosis were abolished by blockade of p53 function. Stable expression of hSRBC led to G1 cell cycle arrest, apoptosis, suppressed colony forming ability and xenograft tumor growth, and elevated sensitivity to genotoxic agents.","method":"Stable and transient overexpression, p53 functional blockade, xenograft tumor assay, western blot for p53 target genes","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular pathway (p53 stabilization), in vitro plus in vivo, single lab","pmids":["18059034"],"is_preprint":false},{"year":2011,"finding":"PRKCDBP (CAVIN3) gene transcription is directly activated by NF-κB in response to TNFα: luciferase reporter and ChIP assays demonstrate that TNFα-induced PRKCDBP promoter activity requires an intact κB site, and RelA transfection enhances PRKCDBP expression. PRKCDBP induction correlates with tumor cell sensitivity to TNFα-induced apoptosis.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), RelA transfection, siRNA knockdown, xenograft assay","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP plus reporter assay plus mutagenesis of κB site establishes direct NF-κB-dependent transcriptional regulation, two orthogonal methods in single lab","pmids":["21980136"],"is_preprint":false},{"year":2019,"finding":"ROR1 binds CAVIN3 at a site distinct from those for CAV1 and CAVIN1; this interaction is required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis but not caveolae formation itself. The ROR1-CAVIN3 interaction facilitates caveolae trafficking linked to pro-survival AKT signaling from early endosomes in lung adenocarcinoma cells.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, endocytosis assays, subcellular fractionation/localization, AKT signaling readouts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with site mapping plus functional endocytosis assay and signaling readout, single lab with multiple methods","pmids":["30894682"],"is_preprint":false},{"year":2021,"finding":"Cavin3 is released from caveolae upon UV and mechanical stress-induced caveolae disassembly and directly interacts with BRCA1. Cavin3 deletion downregulates BRCA1 and BRCA1 A-complex components. Cavin3 sensitizes cancer cells to UV-induced apoptosis, and cavin3-deficient cells are sensitive to PARP inhibition; concomitant depletion of 53BP1 restored BRCA1-dependent sensitivity to PARP inhibition, placing cavin3 in the BRCA1 DNA repair pathway.","method":"Genome editing (CRISPR KO), label-free quantitative proteomics, cell-free expression interaction assays, RNAi depletion, UV-apoptosis assays, PARP inhibitor sensitivity, genetic epistasis (53BP1/BRCA1 double depletion)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR KO plus proteomics plus cell-free direct interaction assay plus genetic epistasis, multiple orthogonal methods establishing mechanism","pmids":["34142659"],"is_preprint":false},{"year":2014,"finding":"In cavin-3 knockout mice, loss of cavin-3 does not significantly affect caveolae abundance in adipose tissue or other widely studied tissues, and has no effect on body composition or glucose tolerance, indicating cavin-3 is not absolutely required for caveolae formation in these contexts.","method":"Cavin-3 knockout mouse generation, electron microscopy for caveolae counting, metabolic phenotyping (body weight, fat mass, glucose tolerance tests), microarray","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with EM quantification and metabolic phenotyping; this is a negative finding (cavin-3 not required for caveolae or metabolic regulation in adipose/liver) established by multiple in vivo methods","pmids":["25036884"],"is_preprint":false},{"year":2017,"finding":"Loss of cavin-3 in smooth muscle reduces cavin-1 protein levels by ~40% and reduces caveolae density by 40–45% in vascular and urinary bladder smooth muscle (but not in endothelial cells), demonstrating a tissue-specific role for cavin-3 in caveolae maintenance in smooth muscle. Enhanced nitric-oxide-dependent vascular relaxation was observed alongside elevated soluble guanylyl cyclase expression in KO mice.","method":"Cavin-3 knockout mice, electron microscopy (caveolae quantification), vascular contraction/relaxation assays, western blot for cavin-1/sGC protein levels","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO with EM caveolae quantification and functional vascular assays, single lab","pmids":["28285351"],"is_preprint":false},{"year":2014,"finding":"Cavin-3 overexpression in HT1080 fibrosarcoma cells reduces cell migration and inhibits PMA-induced MMP-9 secretion and gene expression, in part through prevention of AKT dephosphorylation. Cavin-3 gene silencing increases MMP-9 expression and secretion, establishing a cavin-3/AKT/MMP-9 signaling axis.","method":"Cavin-3 overexpression and siRNA knockdown, MMP-9 zymography/ELISA, cell migration assay, AKT phosphorylation western blot, PMA stimulation","journal":"Cancer growth and metastasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional (OE and KD) experiments with defined molecular pathway readouts (AKT phosphorylation, MMP-9), single lab","pmids":["25520561"],"is_preprint":false},{"year":2020,"finding":"Cavin-3 knockdown impairs adipocyte differentiation; its overexpression accelerates adipogenesis. Mechanistically, Cavin-3 modulates TACE (ADAM17)-mediated shedding of Pref-1 (preadipocyte factor-1), a known inhibitor of adipogenesis. Cavin-3 silencing markedly increases Pref-1 during adipocyte maturation while decreasing expression of adipogenesis genes (PPARγ, FAS, aP2, Adipoq).","method":"Stable knockdown/overexpression cell lines, qRT-PCR, western blot, confocal immunofluorescence, TACE activity assay, adipogenesis assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional loss/gain-of-function with mechanistic pathway (TACE/Pref-1), multiple methods, single lab","pmids":["32679831"],"is_preprint":false},{"year":2020,"finding":"Human parainfluenza virus type 2 (hPIV-2) V protein binds directly to Cavin3 (N-terminal region of Cavin3 and Trp residues in C-terminal region of V protein are required), inhibits Cavin3 proteasomal degradation, increases Cavin3 abundance in lipid raft microdomains, and thereby facilitates viral assembly and budding. Cavin3 knockdown suppresses hPIV-2 growth without affecting viral entry, replication, transcription, or translation.","method":"Co-immunoprecipitation, pulse-chase proteasomal degradation assay, V protein overexpression, siRNA knockdown, viral growth assays, lipid raft fractionation","journal":"Frontiers in microbiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus functional viral growth assay with specific mechanistic controls, single lab with multiple orthogonal methods","pmids":["32425917"],"is_preprint":false},{"year":2025,"finding":"CAVIN3 deficiency in endothelial cells inhibits ERK phosphorylation, which downregulates Jagged 1 (JAG1) expression, thereby promoting vascular normalization in pathological neovascularization. Transcription factor ZEB1 regulates CAVIN3 transcription in endothelial cells under hypoxic conditions. CAVIN3 knockdown disrupts EC proliferation and vascular sprouting, restores pericyte-EC interactions.","method":"siRNA knockdown in endothelial cells, in vivo CNV and OIR mouse models, ERK phosphorylation western blot, JAG1 expression assays, ZEB1 ChIP/reporter assays, pericyte-EC co-culture","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KD models plus in vitro mechanistic pathway (ERK/JAG1) with defined cellular and molecular phenotypes, single lab","pmids":["40337864"],"is_preprint":false},{"year":2024,"finding":"A phosphomimic mutation in a Thr-Ser pair proximal to the disordered C-terminal half of the Cavin1 HR1 coiled-coil domain selectively abolishes Cavin2 and Cavin3 association with Cavin1, revealing that phosphorylation near this region regulates the formation of Cavin1-Cavin2 and Cavin1-Cavin3 subcomplexes.","method":"Nanobody development, X-ray crystal structure of nanobody-HR1 complex, phosphomimic mutagenesis, co-immunoprecipitation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure with mutagenesis establishes regulatory mechanism, but preprint and finding is specifically about Cavin1 phosphorylation affecting Cavin3 association (indirect for CAVIN3 itself)","pmids":["bio_10.1101_2024.11.26.625551"],"is_preprint":true},{"year":2023,"finding":"PRKCDBP promotes pyroptosis by activating the NLRP3 inflammasome, resulting in cleavage of CASP1, IL-1β, and GSDMD in NSCLC cells. PRKCDBP is upregulated through a ceRNA mechanism in which lncRNA TCONS-14036 sequesters miR-1228-5p, relieving miR-1228-5p-mediated suppression of PRKCDBP.","method":"Flow cytometry, TUNEL assay, ASC speck formation, ELISA, dual-luciferase reporter assay, RNA immunoprecipitation, western blot, siRNA/overexpression","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assays for pyroptosis with NLRP3/CASP1/GSDMD readouts plus dual-luciferase and RIP for upstream pathway, single lab with multiple methods","pmids":["36696967"],"is_preprint":false}],"current_model":"CAVIN3 (cavin-3/SRBC/PRKCDBP) is a caveolae-associated adapter protein that binds PKCδ and caveolin-1 via a leucine zipper, is recruited to caveolae by cavin1 through N-terminal coiled-coil interactions, and regulates caveolae dynamics, cavicle trafficking, and the balance between ERK and Akt signaling by anchoring caveolae to the membrane skeleton via myosin-1c; upon cellular stress it is released from caveolae to directly interact with BRCA1 and support DNA repair; it also binds PER2 in the cytoplasm to modulate circadian period length independent of caveolae, stabilizes p53 to promote apoptosis, suppresses MMP-9 via AKT, activates NLRP3-dependent pyroptosis, regulates TACE-mediated Pref-1 shedding during adipogenesis, and controls pathological neovascularization through an ERK/JAG1 axis—consistent with its role as a multi-functional tumor suppressor whose expression is frequently silenced by promoter hypermethylation."},"narrative":{"mechanistic_narrative":"CAVIN3 (cavin-3/SRBC/PRKCDBP) is a caveolae-associated adapter protein that governs caveolae dynamics and intracellular trafficking while coupling caveolar membrane organization to growth-factor signaling and stress responses [PMID:19262564, PMID:24069528, PMID:25588833]. It localizes to caveolae through a leucine zipper required for co-precipitation with caveolin-1 and is recruited there by cavin1, whose trimeric N-terminus it binds in competition with cavin2 to define distinct cavin subcomplexes; CAVIN3 is enriched at deeply invaginated caveolae and shifts the population toward short-lived, dynamic structures, and its loss markedly impairs microtubule-based trafficking of caveolar vesicles (cavicles) [PMID:19262564, PMID:25588833]. CAVIN3 also binds PKCδ as a member of the STICK superfamily [PMID:19262564]. Through anchoring of caveolae to the membrane skeleton via myosin-1c, CAVIN3 sets the balance between ERK and Akt signaling: its loss suppresses ERK while elevating Akt (via reduced EGR1/PTEN), and CAVIN3 knockout mice show increased lactate production and cachexia [PMID:24069528]. Beyond caveolae, CAVIN3 acts as a stress-responsive tumor suppressor: it is released from disassembling caveolae upon UV and mechanical stress to directly interact with BRCA1 and sustain the BRCA1 A-complex DNA-repair pathway, with CAVIN3-deficient cells showing PARP-inhibitor sensitivity reversed by 53BP1 co-depletion [PMID:34142659]. It stabilizes p53 to drive p53-dependent G1 arrest and apoptosis [PMID:18059034], and its transcription is directly activated by NF-κB downstream of TNFα [PMID:21980136]. CAVIN3 additionally functions in a caveolae-independent context as a cytoplasmic PER2-interacting protein that modulates circadian period length in a PKCδ-binding-site-dependent manner [PMID:23079727].","teleology":[{"year":2008,"claim":"Established CAVIN3 as a growth-suppressive protein acting through p53, providing the first mechanistic link to tumor suppression.","evidence":"Stable/transient overexpression with p53 functional blockade and xenograft assays measuring p53 target gene induction","pmids":["18059034"],"confidence":"Medium","gaps":["Did not define how CAVIN3 physically stabilizes p53","No endogenous loss-of-function tumor data"]},{"year":2009,"claim":"Identified the molecular basis for CAVIN3's caveolar localization and its requirement for caveolar vesicle trafficking, establishing it as a caveolae adapter.","evidence":"Reciprocal Co-IP with caveolin-1, leucine-zipper mutagenesis, PKCδ binding, and live-cell imaging of cavicle trafficking","pmids":["19262564"],"confidence":"High","gaps":["Did not resolve how CAVIN3 controls cavicle motility on microtubules","Functional role of PKCδ binding left open"]},{"year":2011,"claim":"Showed CAVIN3 is a direct NF-κB transcriptional target induced by TNFα, linking its expression to inflammatory signaling and apoptotic sensitivity.","evidence":"Luciferase reporter, ChIP, κB-site mutagenesis, RelA transfection in tumor cells","pmids":["21980136"],"confidence":"High","gaps":["Did not connect transcriptional induction to a downstream CAVIN3 effector mechanism"]},{"year":2012,"claim":"Revealed a caveolae-independent role: CAVIN3 binds PER2 in the cytoplasm to set circadian period length, expanding its functional repertoire.","evidence":"Co-IP of PER2, RNAi/overexpression circadian period assays, PKCδ-binding-site mutagenesis in fibroblasts","pmids":["23079727"],"confidence":"Medium","gaps":["The kinase mediating the PKCδ-site-dependent effect remains unidentified","Direct vs indirect PER2 interaction not resolved"]},{"year":2013,"claim":"Defined CAVIN3 as a switch between ERK and Akt signaling by anchoring caveolae to the membrane skeleton through myosin-1c, connecting caveolar architecture to signaling outcomes and organismal metabolism.","evidence":"Knockout mice, gain/loss-of-function, Co-IP with myosin-1c, ERK/Akt phosphorylation and metabolic assays","pmids":["24069528"],"confidence":"High","gaps":["Mechanism by which CAVIN3 suppresses EGR1/PTEN not detailed","Tissue specificity of the signaling balance unresolved"]},{"year":2014,"claim":"Clarified that CAVIN3 is dispensable for caveolae formation and metabolic homeostasis in adipose and other tissues, distinguishing it from core caveolae structural cavins.","evidence":"Knockout mice with EM caveolae counting and metabolic phenotyping","pmids":["25036884"],"confidence":"Medium","gaps":["Negative finding does not exclude tissue-specific roles tested elsewhere"]},{"year":2014,"claim":"Extended CAVIN3's tumor-suppressive function to invasion control via an AKT/MMP-9 axis.","evidence":"Overexpression/knockdown with MMP-9 zymography, migration assays, AKT phosphorylation western blot","pmids":["25520561"],"confidence":"Medium","gaps":["How CAVIN3 prevents AKT dephosphorylation mechanistically unclear"]},{"year":2015,"claim":"Mapped the structural logic of cavin subcomplex assembly, showing CAVIN3's N-terminus binds a cavin1 trimer competitively with cavin2 and biases caveolae toward dynamic short-lived states.","evidence":"Co-IP, truncation/domain mapping, live-cell TIRF imaging of caveolae dynamics, siRNA","pmids":["25588833"],"confidence":"High","gaps":["Stoichiometry of mixed cavin1/2/3 complexes not fully resolved"]},{"year":2017,"claim":"Demonstrated a tissue-specific requirement for CAVIN3 in caveolae maintenance in smooth muscle and an effect on NO-dependent vascular relaxation.","evidence":"Knockout mice, EM caveolae quantification, vascular contraction/relaxation assays, cavin-1/sGC western blots","pmids":["28285351"],"confidence":"Medium","gaps":["Why dependence is restricted to smooth muscle unexplained"]},{"year":2019,"claim":"Identified ROR1 as a CAVIN3 partner required for its proper localization and caveolae-dependent endocytosis feeding pro-survival AKT signaling.","evidence":"Co-IP with site mapping, siRNA, endocytosis assays, fractionation, AKT readouts in lung adenocarcinoma","pmids":["30894682"],"confidence":"Medium","gaps":["Direct vs scaffold-mediated ROR1 interaction not distinguished"]},{"year":2020,"claim":"Showed CAVIN3 promotes adipogenesis by modulating TACE/ADAM17-mediated shedding of the inhibitor Pref-1.","evidence":"Stable knockdown/overexpression, qRT-PCR, western blot, TACE activity and adipogenesis assays","pmids":["32679831"],"confidence":"Medium","gaps":["How CAVIN3 regulates TACE activity mechanistically undefined"]},{"year":2020,"claim":"Revealed CAVIN3 as a host factor hijacked by hPIV-2 V protein, which stabilizes CAVIN3 in lipid rafts to support viral assembly and budding.","evidence":"Co-IP with domain mapping, pulse-chase degradation, siRNA, viral growth assays, lipid raft fractionation","pmids":["32425917"],"confidence":"Medium","gaps":["Cellular function co-opted by V protein binding not defined"]},{"year":2021,"claim":"Established CAVIN3 as a stress-released caveolar protein that directly engages BRCA1 to support the BRCA1 A-complex DNA-repair pathway, mechanistically unifying caveolae disassembly with genome maintenance.","evidence":"CRISPR KO, label-free proteomics, cell-free direct interaction assays, UV-apoptosis, PARP-inhibitor sensitivity, 53BP1/BRCA1 epistasis","pmids":["34142659"],"confidence":"High","gaps":["Precise binding interface with BRCA1 not structurally defined","Trigger signal linking caveolae disassembly to nuclear BRCA1 unclear"]},{"year":2023,"claim":"Linked CAVIN3 to NLRP3-dependent pyroptosis and identified a lncRNA/miRNA ceRNA axis controlling its expression in NSCLC.","evidence":"Pyroptosis assays (ASC specks, CASP1/IL-1β/GSDMD), dual-luciferase, RNA immunoprecipitation","pmids":["36696967"],"confidence":"Medium","gaps":["How CAVIN3 activates NLRP3 mechanistically unknown"]},{"year":2025,"claim":"Placed CAVIN3 in endothelial neovascularization control through an ERK/JAG1 axis regulated by hypoxic ZEB1.","evidence":"siRNA in endothelial cells, CNV/OIR mouse models, ERK/JAG1 assays, ZEB1 ChIP/reporter, pericyte-EC co-culture","pmids":["40337864"],"confidence":"Medium","gaps":["Connection to caveolar function in endothelium not established"]},{"year":null,"claim":"How CAVIN3's distinct caveolar, signaling, stress/DNA-repair, and circadian activities are coordinated within a single cell, and the structural basis for its multiple direct interactions, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model for CAVIN3's separable interaction modes","Switch governing caveolar vs cytoplasmic vs nuclear pools undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,15]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3]}],"complexes":["caveolae cavin coat (cavin1-cavin3 subcomplex)"],"partners":["CAV1","CAVIN1","PRKCD","MYO1C","BRCA1","PER2","ROR1","TP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969G5","full_name":"Caveolae-associated protein 3","aliases":["Cavin-3","Protein kinase C delta-binding protein","Serum deprivation response factor-related gene product that binds to C-kinase","hSRBC"],"length_aa":261,"mass_kda":27.7,"function":"Regulates the traffic and/or budding of caveolae (PubMed:19262564). Plays a role in caveola formation in a tissue-specific manner. Required for the formation of caveolae in smooth muscle but not in the lung and heart endothelial cells. Regulates the equilibrium between cell surface-associated and cell surface-dissociated caveolae by promoting the rapid release of caveolae from the cell surface. Plays a role in the regulation of the circadian clock. Modulates the period length and phase of circadian gene expression and also regulates expression and interaction of the core clock components PER1/2 and CRY1/2 (By similarity)","subcellular_location":"Cytoplasm; Membrane, caveola; Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q969G5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAVIN3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CAVIN3","total_profiled":1310},"omim":[{"mim_id":"618303","title":"CAVEOLAE-ASSOCIATED PROTEIN 3; CAVIN3","url":"https://www.omim.org/entry/618303"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":292.4}],"url":"https://www.proteinatlas.org/search/CAVIN3"},"hgnc":{"alias_symbol":["SRBC","HSRBC","MGC20400","cavin-3"],"prev_symbol":["PRKCDBP"]},"alphafold":{"accession":"Q969G5","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969G5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969G5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969G5-F1-predicted_aligned_error_v6.png","plddt_mean":71.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAVIN3","jax_strain_url":"https://www.jax.org/strain/search?query=CAVIN3"},"sequence":{"accession":"Q969G5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969G5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969G5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969G5"}},"corpus_meta":[{"pmid":"19262564","id":"PMC_19262564","title":"SRBC/cavin-3 is a caveolin adapter protein that regulates caveolae function.","date":"2009","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/19262564","citation_count":170,"is_preprint":false},{"pmid":"24069528","id":"PMC_24069528","title":"Cavin-3 dictates the balance between ERK and Akt signaling.","date":"2013","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/24069528","citation_count":62,"is_preprint":false},{"pmid":"21980136","id":"PMC_21980136","title":"Epigenetic alteration of PRKCDBP in colorectal cancers and its implication in tumor cell resistance to TNFα-induced apoptosis.","date":"2011","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/21980136","citation_count":48,"is_preprint":false},{"pmid":"25588833","id":"PMC_25588833","title":"Cavin3 interacts with cavin1 and caveolin1 to increase surface dynamics of caveolae.","date":"2015","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/25588833","citation_count":45,"is_preprint":false},{"pmid":"18059034","id":"PMC_18059034","title":"Frequent epigenetic inactivation of hSRBC in gastric cancer and its implication in attenuated p53 response to stresses.","date":"2008","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/18059034","citation_count":39,"is_preprint":false},{"pmid":"15940253","id":"PMC_15940253","title":"Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15940253","citation_count":39,"is_preprint":false},{"pmid":"25391456","id":"PMC_25391456","title":"CRY1, CRY2 and PRKCDBP genetic variants in metabolic syndrome.","date":"2014","source":"Hypertension research : official journal of the Japanese Society of Hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/25391456","citation_count":32,"is_preprint":false},{"pmid":"20423276","id":"PMC_20423276","title":"Frequent inactivation of hSRBC in ovarian cancers by promoter CpG island hypermethylation.","date":"2010","source":"Acta obstetricia et gynecologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/20423276","citation_count":24,"is_preprint":false},{"pmid":"27721187","id":"PMC_27721187","title":"PRKCDBP (CAVIN3) and CRY2 associate with major depressive disorder.","date":"2016","source":"Journal of affective disorders","url":"https://pubmed.ncbi.nlm.nih.gov/27721187","citation_count":22,"is_preprint":false},{"pmid":"30894682","id":"PMC_30894682","title":"ROR1-CAVIN3 interaction required for caveolae-dependent endocytosis and pro-survival signaling in lung adenocarcinoma.","date":"2019","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30894682","citation_count":19,"is_preprint":false},{"pmid":"23118876","id":"PMC_23118876","title":"Clinical relevance of loss of 11p15 in primary and metastatic breast cancer: association with loss of PRKCDBP expression in brain metastases.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23118876","citation_count":17,"is_preprint":false},{"pmid":"34142659","id":"PMC_34142659","title":"Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34142659","citation_count":16,"is_preprint":false},{"pmid":"25036884","id":"PMC_25036884","title":"Cavin-3 knockout mice show that cavin-3 is not essential for caveolae formation, for maintenance of body composition, or for glucose tolerance.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25036884","citation_count":15,"is_preprint":false},{"pmid":"36696967","id":"PMC_36696967","title":"The sodium new houttuyfonate suppresses NSCLC via activating pyroptosis through TCONS-14036/miR-1228-5p/PRKCDBP pathway.","date":"2023","source":"Cell proliferation","url":"https://pubmed.ncbi.nlm.nih.gov/36696967","citation_count":14,"is_preprint":false},{"pmid":"23079727","id":"PMC_23079727","title":"CAVIN-3 regulates circadian period length and PER:CRY protein abundance and interactions.","date":"2012","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/23079727","citation_count":14,"is_preprint":false},{"pmid":"25520561","id":"PMC_25520561","title":"A Role for the Cavin-3/Matrix Metalloproteinase-9 Signaling Axis in the Regulation of PMA-Activated Human HT1080 Fibrosarcoma Cell Neoplastic Phenotype.","date":"2014","source":"Cancer growth and metastasis","url":"https://pubmed.ncbi.nlm.nih.gov/25520561","citation_count":10,"is_preprint":false},{"pmid":"28285351","id":"PMC_28285351","title":"Cavin-3 (PRKCDBP) deficiency reduces the density of caveolae in smooth muscle.","date":"2017","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/28285351","citation_count":9,"is_preprint":false},{"pmid":"32862598","id":"PMC_32862598","title":"Matrine induces apoptosis and autophagy in human lung adenocarcinoma cells via upregulation of Cavin3 and suppression of PI3K/AKT pathway.","date":"2020","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32862598","citation_count":9,"is_preprint":false},{"pmid":"34455714","id":"PMC_34455714","title":"Assessment of DAPK1 and CAVIN3 Gene Promoter Methylation in Breast Invasive Ductal Carcinoma and Metastasis.","date":"2021","source":"Cell journal","url":"https://pubmed.ncbi.nlm.nih.gov/34455714","citation_count":8,"is_preprint":false},{"pmid":"32945503","id":"PMC_32945503","title":"Low expression of PRKCDBP promoted cisplatin resistance in lung adenocarcinoma by DNMT1 and TNF‑α.","date":"2020","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/32945503","citation_count":7,"is_preprint":false},{"pmid":"33101009","id":"PMC_33101009","title":"Cavin3 Suppresses Breast Cancer Metastasis via Inhibiting AKT Pathway.","date":"2020","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33101009","citation_count":7,"is_preprint":false},{"pmid":"25052149","id":"PMC_25052149","title":"Elevation of PRKCDBP, a novel transcriptional target of TNF-α, and its downregulation by infliximab in patients with ulcerative colitis.","date":"2014","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25052149","citation_count":5,"is_preprint":false},{"pmid":"32679831","id":"PMC_32679831","title":"Caveolae-Associated Protein 3 (Cavin-3) Influences Adipogenesis via TACE-Mediated Pref-1 Shedding.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32679831","citation_count":4,"is_preprint":false},{"pmid":"26130999","id":"PMC_26130999","title":"Polymorphisms in PRKCDBP, a Transcriptional Target of TNF-α, Are Associated With Inflammatory Bowel Disease in Korean.","date":"2015","source":"Intestinal research","url":"https://pubmed.ncbi.nlm.nih.gov/26130999","citation_count":4,"is_preprint":false},{"pmid":"40337864","id":"PMC_40337864","title":"CAVIN3 deficiency promotes vascular normalization in ocular neovascular disease via ERK/JAG1 signaling pathway.","date":"2025","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/40337864","citation_count":3,"is_preprint":false},{"pmid":"35224960","id":"PMC_35224960","title":"PRKCDBP Methylation is a Potential and Promising Candidate Biomarker for Non-small Cell Lung Cancer.","date":"2022","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/35224960","citation_count":3,"is_preprint":false},{"pmid":"32352004","id":"PMC_32352004","title":"The Role of Cavin3 in the Progression of Lung Cancer and Its Mechanism.","date":"2020","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/32352004","citation_count":3,"is_preprint":false},{"pmid":"32425917","id":"PMC_32425917","title":"Inhibition of Cavin3 Degradation by the Human Parainfluenza Virus Type 2 V Protein Is Important for Efficient Viral Growth.","date":"2020","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32425917","citation_count":3,"is_preprint":false},{"pmid":"40292077","id":"PMC_40292077","title":"The Role of Cavin3 in the Development of Malignant Tumors.","date":"2025","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/40292077","citation_count":1,"is_preprint":false},{"pmid":"41314262","id":"PMC_41314262","title":"Cavin-3 promotes TNF expression via the MAPK signaling pathway in lung squamous cell carcinoma.","date":"2025","source":"Biochimica et biophysica acta. General subjects","url":"https://pubmed.ncbi.nlm.nih.gov/41314262","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.26.625551","title":"Cavin1 binding nanobodies reveal structural flexibility and regulated interactions of the N-terminal coiled-coil domain","date":"2024-11-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.26.625551","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17543,"output_tokens":4844,"usd":0.062645,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12971,"output_tokens":4534,"usd":0.089103,"stage2_stop_reason":"end_turn"},"total_usd":0.151748,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"SRBC/cavin-3 (CAVIN3) co-immunoprecipitates with caveolin-1, and a leucine zipper in SRBC is essential for both co-precipitation with caveolin-1 and localization to caveolae. SRBC binds PKCδ as a member of the STICK superfamily. SRBC remains associated with caveolin when caveolae bud to form vesicles (cavicles) that travel on microtubules, and in the absence of SRBC, intracellular cavicle traffic is markedly impaired.\",\n      \"method\": \"Co-immunoprecipitation, leucine zipper mutagenesis, live-cell imaging of cavicle trafficking\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with mutagenesis validation, defined cellular phenotype (impaired cavicle trafficking) on loss-of-function, replicated across multiple methods in single rigorous study\",\n      \"pmids\": [\"19262564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Cavin-3 dictates the balance between ERK and Akt signaling: loss of cavin-3 increases Akt signaling at the expense of ERK, while gain of cavin-3 increases ERK signaling at the expense of Akt. Cavin-3 facilitates ERK signaling by anchoring caveolae to the membrane skeleton via myosin-1c; loss of this linkage reduces caveolae abundance and separates the ERK activation module from signaling receptors. Loss of cavin-3 also promotes Akt signaling through suppression of EGR1 and PTEN. In vivo consequences of cavin-3 knockout include increased lactate production and cachexia.\",\n      \"method\": \"Cavin-3 knockout mice, in vitro gain/loss-of-function, co-immunoprecipitation with myosin-1c, signaling pathway analysis (ERK/Akt phosphorylation), metabolic assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout plus in vitro complementary experiments, multiple orthogonal methods (KO mice, IP, signaling assays, metabolic readouts), two independent approaches (in vivo and in vitro)\",\n      \"pmids\": [\"24069528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CAVIN-3 is a cytoplasmic PER2-interacting protein that influences circadian clock properties. Loss- and gain-of-function of CAVIN-3 shortened and lengthened, respectively, the circadian period in fibroblasts, and affected PER:CRY protein abundance and interaction. CAVIN-3 required its PKCδ-binding site to exert its effect on period length. Depletion of PKCδ alone had little effect, suggesting involvement of yet-uncharacterized kinases. CAVIN-3 activity in circadian gene expression was independent of caveolae.\",\n      \"method\": \"Co-immunoprecipitation (PER2 interaction), RNAi knockdown, overexpression, circadian period assays in fibroblasts, PKCδ-binding site mutagenesis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus loss- and gain-of-function with defined molecular phenotype (period length, PER:CRY abundance), single lab with two orthogonal approaches\",\n      \"pmids\": [\"23079727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cavin3 is targeted to caveolae by cavin1, where it interacts with the scaffolding domain of caveolin1 and promotes caveolae dynamics. The N-terminal region of cavin3 binds a trimer of the cavin1 N-terminus in competition with a homologous cavin2 region, indicating that cavins form distinct subcomplexes through their N-terminal regions. Cavin3 is enriched at deeply invaginated caveolae, and loss of cavin3 increases the proportion of stable caveolae and decreases short-lived caveolae at the membrane.\",\n      \"method\": \"Co-immunoprecipitation, truncation/domain mapping, live-cell TIRF imaging of caveolae dynamics, siRNA knockdown\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, live-cell imaging with direct functional consequence, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"25588833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"hSRBC (CAVIN3) increases p53 protein stability and expression of p53 target genes (p21Waf1, PUMA, NOXA). hSRBC-mediated cell cycle arrest and apoptosis were abolished by blockade of p53 function. Stable expression of hSRBC led to G1 cell cycle arrest, apoptosis, suppressed colony forming ability and xenograft tumor growth, and elevated sensitivity to genotoxic agents.\",\n      \"method\": \"Stable and transient overexpression, p53 functional blockade, xenograft tumor assay, western blot for p53 target genes\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular pathway (p53 stabilization), in vitro plus in vivo, single lab\",\n      \"pmids\": [\"18059034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PRKCDBP (CAVIN3) gene transcription is directly activated by NF-κB in response to TNFα: luciferase reporter and ChIP assays demonstrate that TNFα-induced PRKCDBP promoter activity requires an intact κB site, and RelA transfection enhances PRKCDBP expression. PRKCDBP induction correlates with tumor cell sensitivity to TNFα-induced apoptosis.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), RelA transfection, siRNA knockdown, xenograft assay\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP plus reporter assay plus mutagenesis of κB site establishes direct NF-κB-dependent transcriptional regulation, two orthogonal methods in single lab\",\n      \"pmids\": [\"21980136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ROR1 binds CAVIN3 at a site distinct from those for CAV1 and CAVIN1; this interaction is required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis but not caveolae formation itself. The ROR1-CAVIN3 interaction facilitates caveolae trafficking linked to pro-survival AKT signaling from early endosomes in lung adenocarcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, endocytosis assays, subcellular fractionation/localization, AKT signaling readouts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with site mapping plus functional endocytosis assay and signaling readout, single lab with multiple methods\",\n      \"pmids\": [\"30894682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Cavin3 is released from caveolae upon UV and mechanical stress-induced caveolae disassembly and directly interacts with BRCA1. Cavin3 deletion downregulates BRCA1 and BRCA1 A-complex components. Cavin3 sensitizes cancer cells to UV-induced apoptosis, and cavin3-deficient cells are sensitive to PARP inhibition; concomitant depletion of 53BP1 restored BRCA1-dependent sensitivity to PARP inhibition, placing cavin3 in the BRCA1 DNA repair pathway.\",\n      \"method\": \"Genome editing (CRISPR KO), label-free quantitative proteomics, cell-free expression interaction assays, RNAi depletion, UV-apoptosis assays, PARP inhibitor sensitivity, genetic epistasis (53BP1/BRCA1 double depletion)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR KO plus proteomics plus cell-free direct interaction assay plus genetic epistasis, multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"34142659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In cavin-3 knockout mice, loss of cavin-3 does not significantly affect caveolae abundance in adipose tissue or other widely studied tissues, and has no effect on body composition or glucose tolerance, indicating cavin-3 is not absolutely required for caveolae formation in these contexts.\",\n      \"method\": \"Cavin-3 knockout mouse generation, electron microscopy for caveolae counting, metabolic phenotyping (body weight, fat mass, glucose tolerance tests), microarray\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with EM quantification and metabolic phenotyping; this is a negative finding (cavin-3 not required for caveolae or metabolic regulation in adipose/liver) established by multiple in vivo methods\",\n      \"pmids\": [\"25036884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of cavin-3 in smooth muscle reduces cavin-1 protein levels by ~40% and reduces caveolae density by 40–45% in vascular and urinary bladder smooth muscle (but not in endothelial cells), demonstrating a tissue-specific role for cavin-3 in caveolae maintenance in smooth muscle. Enhanced nitric-oxide-dependent vascular relaxation was observed alongside elevated soluble guanylyl cyclase expression in KO mice.\",\n      \"method\": \"Cavin-3 knockout mice, electron microscopy (caveolae quantification), vascular contraction/relaxation assays, western blot for cavin-1/sGC protein levels\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO with EM caveolae quantification and functional vascular assays, single lab\",\n      \"pmids\": [\"28285351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cavin-3 overexpression in HT1080 fibrosarcoma cells reduces cell migration and inhibits PMA-induced MMP-9 secretion and gene expression, in part through prevention of AKT dephosphorylation. Cavin-3 gene silencing increases MMP-9 expression and secretion, establishing a cavin-3/AKT/MMP-9 signaling axis.\",\n      \"method\": \"Cavin-3 overexpression and siRNA knockdown, MMP-9 zymography/ELISA, cell migration assay, AKT phosphorylation western blot, PMA stimulation\",\n      \"journal\": \"Cancer growth and metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional (OE and KD) experiments with defined molecular pathway readouts (AKT phosphorylation, MMP-9), single lab\",\n      \"pmids\": [\"25520561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cavin-3 knockdown impairs adipocyte differentiation; its overexpression accelerates adipogenesis. Mechanistically, Cavin-3 modulates TACE (ADAM17)-mediated shedding of Pref-1 (preadipocyte factor-1), a known inhibitor of adipogenesis. Cavin-3 silencing markedly increases Pref-1 during adipocyte maturation while decreasing expression of adipogenesis genes (PPARγ, FAS, aP2, Adipoq).\",\n      \"method\": \"Stable knockdown/overexpression cell lines, qRT-PCR, western blot, confocal immunofluorescence, TACE activity assay, adipogenesis assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional loss/gain-of-function with mechanistic pathway (TACE/Pref-1), multiple methods, single lab\",\n      \"pmids\": [\"32679831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Human parainfluenza virus type 2 (hPIV-2) V protein binds directly to Cavin3 (N-terminal region of Cavin3 and Trp residues in C-terminal region of V protein are required), inhibits Cavin3 proteasomal degradation, increases Cavin3 abundance in lipid raft microdomains, and thereby facilitates viral assembly and budding. Cavin3 knockdown suppresses hPIV-2 growth without affecting viral entry, replication, transcription, or translation.\",\n      \"method\": \"Co-immunoprecipitation, pulse-chase proteasomal degradation assay, V protein overexpression, siRNA knockdown, viral growth assays, lipid raft fractionation\",\n      \"journal\": \"Frontiers in microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus functional viral growth assay with specific mechanistic controls, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32425917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CAVIN3 deficiency in endothelial cells inhibits ERK phosphorylation, which downregulates Jagged 1 (JAG1) expression, thereby promoting vascular normalization in pathological neovascularization. Transcription factor ZEB1 regulates CAVIN3 transcription in endothelial cells under hypoxic conditions. CAVIN3 knockdown disrupts EC proliferation and vascular sprouting, restores pericyte-EC interactions.\",\n      \"method\": \"siRNA knockdown in endothelial cells, in vivo CNV and OIR mouse models, ERK phosphorylation western blot, JAG1 expression assays, ZEB1 ChIP/reporter assays, pericyte-EC co-culture\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KD models plus in vitro mechanistic pathway (ERK/JAG1) with defined cellular and molecular phenotypes, single lab\",\n      \"pmids\": [\"40337864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A phosphomimic mutation in a Thr-Ser pair proximal to the disordered C-terminal half of the Cavin1 HR1 coiled-coil domain selectively abolishes Cavin2 and Cavin3 association with Cavin1, revealing that phosphorylation near this region regulates the formation of Cavin1-Cavin2 and Cavin1-Cavin3 subcomplexes.\",\n      \"method\": \"Nanobody development, X-ray crystal structure of nanobody-HR1 complex, phosphomimic mutagenesis, co-immunoprecipitation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure with mutagenesis establishes regulatory mechanism, but preprint and finding is specifically about Cavin1 phosphorylation affecting Cavin3 association (indirect for CAVIN3 itself)\",\n      \"pmids\": [\"bio_10.1101_2024.11.26.625551\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PRKCDBP promotes pyroptosis by activating the NLRP3 inflammasome, resulting in cleavage of CASP1, IL-1β, and GSDMD in NSCLC cells. PRKCDBP is upregulated through a ceRNA mechanism in which lncRNA TCONS-14036 sequesters miR-1228-5p, relieving miR-1228-5p-mediated suppression of PRKCDBP.\",\n      \"method\": \"Flow cytometry, TUNEL assay, ASC speck formation, ELISA, dual-luciferase reporter assay, RNA immunoprecipitation, western blot, siRNA/overexpression\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assays for pyroptosis with NLRP3/CASP1/GSDMD readouts plus dual-luciferase and RIP for upstream pathway, single lab with multiple methods\",\n      \"pmids\": [\"36696967\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAVIN3 (cavin-3/SRBC/PRKCDBP) is a caveolae-associated adapter protein that binds PKCδ and caveolin-1 via a leucine zipper, is recruited to caveolae by cavin1 through N-terminal coiled-coil interactions, and regulates caveolae dynamics, cavicle trafficking, and the balance between ERK and Akt signaling by anchoring caveolae to the membrane skeleton via myosin-1c; upon cellular stress it is released from caveolae to directly interact with BRCA1 and support DNA repair; it also binds PER2 in the cytoplasm to modulate circadian period length independent of caveolae, stabilizes p53 to promote apoptosis, suppresses MMP-9 via AKT, activates NLRP3-dependent pyroptosis, regulates TACE-mediated Pref-1 shedding during adipogenesis, and controls pathological neovascularization through an ERK/JAG1 axis—consistent with its role as a multi-functional tumor suppressor whose expression is frequently silenced by promoter hypermethylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAVIN3 (cavin-3/SRBC/PRKCDBP) is a caveolae-associated adapter protein that governs caveolae dynamics and intracellular trafficking while coupling caveolar membrane organization to growth-factor signaling and stress responses [#0, #1, #3]. It localizes to caveolae through a leucine zipper required for co-precipitation with caveolin-1 and is recruited there by cavin1, whose trimeric N-terminus it binds in competition with cavin2 to define distinct cavin subcomplexes; CAVIN3 is enriched at deeply invaginated caveolae and shifts the population toward short-lived, dynamic structures, and its loss markedly impairs microtubule-based trafficking of caveolar vesicles (cavicles) [#0, #3]. CAVIN3 also binds PKC\\u03b4 as a member of the STICK superfamily [#0]. Through anchoring of caveolae to the membrane skeleton via myosin-1c, CAVIN3 sets the balance between ERK and Akt signaling: its loss suppresses ERK while elevating Akt (via reduced EGR1/PTEN), and CAVIN3 knockout mice show increased lactate production and cachexia [#1]. Beyond caveolae, CAVIN3 acts as a stress-responsive tumor suppressor: it is released from disassembling caveolae upon UV and mechanical stress to directly interact with BRCA1 and sustain the BRCA1 A-complex DNA-repair pathway, with CAVIN3-deficient cells showing PARP-inhibitor sensitivity reversed by 53BP1 co-depletion [#7]. It stabilizes p53 to drive p53-dependent G1 arrest and apoptosis [#4], and its transcription is directly activated by NF-\\u03baB downstream of TNF\\u03b1 [#5]. CAVIN3 additionally functions in a caveolae-independent context as a cytoplasmic PER2-interacting protein that modulates circadian period length in a PKC\\u03b4-binding-site-dependent manner [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established CAVIN3 as a growth-suppressive protein acting through p53, providing the first mechanistic link to tumor suppression.\",\n      \"evidence\": \"Stable/transient overexpression with p53 functional blockade and xenograft assays measuring p53 target gene induction\",\n      \"pmids\": [\"18059034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define how CAVIN3 physically stabilizes p53\", \"No endogenous loss-of-function tumor data\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified the molecular basis for CAVIN3's caveolar localization and its requirement for caveolar vesicle trafficking, establishing it as a caveolae adapter.\",\n      \"evidence\": \"Reciprocal Co-IP with caveolin-1, leucine-zipper mutagenesis, PKC\\u03b4 binding, and live-cell imaging of cavicle trafficking\",\n      \"pmids\": [\"19262564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how CAVIN3 controls cavicle motility on microtubules\", \"Functional role of PKC\\u03b4 binding left open\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed CAVIN3 is a direct NF-\\u03baB transcriptional target induced by TNF\\u03b1, linking its expression to inflammatory signaling and apoptotic sensitivity.\",\n      \"evidence\": \"Luciferase reporter, ChIP, \\u03baB-site mutagenesis, RelA transfection in tumor cells\",\n      \"pmids\": [\"21980136\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect transcriptional induction to a downstream CAVIN3 effector mechanism\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed a caveolae-independent role: CAVIN3 binds PER2 in the cytoplasm to set circadian period length, expanding its functional repertoire.\",\n      \"evidence\": \"Co-IP of PER2, RNAi/overexpression circadian period assays, PKC\\u03b4-binding-site mutagenesis in fibroblasts\",\n      \"pmids\": [\"23079727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The kinase mediating the PKC\\u03b4-site-dependent effect remains unidentified\", \"Direct vs indirect PER2 interaction not resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined CAVIN3 as a switch between ERK and Akt signaling by anchoring caveolae to the membrane skeleton through myosin-1c, connecting caveolar architecture to signaling outcomes and organismal metabolism.\",\n      \"evidence\": \"Knockout mice, gain/loss-of-function, Co-IP with myosin-1c, ERK/Akt phosphorylation and metabolic assays\",\n      \"pmids\": [\"24069528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CAVIN3 suppresses EGR1/PTEN not detailed\", \"Tissue specificity of the signaling balance unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Clarified that CAVIN3 is dispensable for caveolae formation and metabolic homeostasis in adipose and other tissues, distinguishing it from core caveolae structural cavins.\",\n      \"evidence\": \"Knockout mice with EM caveolae counting and metabolic phenotyping\",\n      \"pmids\": [\"25036884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative finding does not exclude tissue-specific roles tested elsewhere\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended CAVIN3's tumor-suppressive function to invasion control via an AKT/MMP-9 axis.\",\n      \"evidence\": \"Overexpression/knockdown with MMP-9 zymography, migration assays, AKT phosphorylation western blot\",\n      \"pmids\": [\"25520561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CAVIN3 prevents AKT dephosphorylation mechanistically unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped the structural logic of cavin subcomplex assembly, showing CAVIN3's N-terminus binds a cavin1 trimer competitively with cavin2 and biases caveolae toward dynamic short-lived states.\",\n      \"evidence\": \"Co-IP, truncation/domain mapping, live-cell TIRF imaging of caveolae dynamics, siRNA\",\n      \"pmids\": [\"25588833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of mixed cavin1/2/3 complexes not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a tissue-specific requirement for CAVIN3 in caveolae maintenance in smooth muscle and an effect on NO-dependent vascular relaxation.\",\n      \"evidence\": \"Knockout mice, EM caveolae quantification, vascular contraction/relaxation assays, cavin-1/sGC western blots\",\n      \"pmids\": [\"28285351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why dependence is restricted to smooth muscle unexplained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified ROR1 as a CAVIN3 partner required for its proper localization and caveolae-dependent endocytosis feeding pro-survival AKT signaling.\",\n      \"evidence\": \"Co-IP with site mapping, siRNA, endocytosis assays, fractionation, AKT readouts in lung adenocarcinoma\",\n      \"pmids\": [\"30894682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs scaffold-mediated ROR1 interaction not distinguished\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed CAVIN3 promotes adipogenesis by modulating TACE/ADAM17-mediated shedding of the inhibitor Pref-1.\",\n      \"evidence\": \"Stable knockdown/overexpression, qRT-PCR, western blot, TACE activity and adipogenesis assays\",\n      \"pmids\": [\"32679831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CAVIN3 regulates TACE activity mechanistically undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed CAVIN3 as a host factor hijacked by hPIV-2 V protein, which stabilizes CAVIN3 in lipid rafts to support viral assembly and budding.\",\n      \"evidence\": \"Co-IP with domain mapping, pulse-chase degradation, siRNA, viral growth assays, lipid raft fractionation\",\n      \"pmids\": [\"32425917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular function co-opted by V protein binding not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established CAVIN3 as a stress-released caveolar protein that directly engages BRCA1 to support the BRCA1 A-complex DNA-repair pathway, mechanistically unifying caveolae disassembly with genome maintenance.\",\n      \"evidence\": \"CRISPR KO, label-free proteomics, cell-free direct interaction assays, UV-apoptosis, PARP-inhibitor sensitivity, 53BP1/BRCA1 epistasis\",\n      \"pmids\": [\"34142659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise binding interface with BRCA1 not structurally defined\", \"Trigger signal linking caveolae disassembly to nuclear BRCA1 unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked CAVIN3 to NLRP3-dependent pyroptosis and identified a lncRNA/miRNA ceRNA axis controlling its expression in NSCLC.\",\n      \"evidence\": \"Pyroptosis assays (ASC specks, CASP1/IL-1\\u03b2/GSDMD), dual-luciferase, RNA immunoprecipitation\",\n      \"pmids\": [\"36696967\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CAVIN3 activates NLRP3 mechanistically unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed CAVIN3 in endothelial neovascularization control through an ERK/JAG1 axis regulated by hypoxic ZEB1.\",\n      \"evidence\": \"siRNA in endothelial cells, CNV/OIR mouse models, ERK/JAG1 assays, ZEB1 ChIP/reporter, pericyte-EC co-culture\",\n      \"pmids\": [\"40337864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection to caveolar function in endothelium not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CAVIN3's distinct caveolar, signaling, stress/DNA-repair, and circadian activities are coordinated within a single cell, and the structural basis for its multiple direct interactions, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model for CAVIN3's separable interaction modes\", \"Switch governing caveolar vs cytoplasmic vs nuclear pools undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 15]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"caveolae cavin coat (cavin1-cavin3 subcomplex)\"],\n    \"partners\": [\"CAV1\", \"CAVIN1\", \"PRKCD\", \"MYO1C\", \"BRCA1\", \"PER2\", \"ROR1\", \"TP53\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}