{"gene":"CAV1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2006,"finding":"CAV1 is a direct transcriptional target of EWS/FLI-1 in Ewing's sarcoma cells. CAV1 knockdown upregulated Snail and caused loss of E-cadherin expression, while CAV1 knockdown inhibited anchorage-independent growth and tumor formation in xenografts. Re-expression of CAV1 or E-cadherin rescued the oncogenic phenotype, defining a CAV1/Snail/E-cadherin pathway downstream of EWS/FLI-1.","method":"Antisense and shRNA knockdown, chromatin immunoprecipitation, array analyses, re-expression studies, nude mouse xenografts","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, shRNA, re-expression rescue, in vivo xenograft) in a single focused study","pmids":["17047056"],"is_preprint":false},{"year":2017,"finding":"Phosphorylation of CAV1 at tyrosine-14 is required for its interaction with the BECN1/VPS34 complex through CAV1's scaffolding domain. This interaction promotes autophagosome formation and autophagy flux under oxidative stress. The phosphatase PTPN1 dephosphorylates CAV1-Y14 and inhibits this autophagy activation. In Cav1 knockout mice, autophagy was impaired and cerebral infarct damage was aggravated.","method":"Co-immunoprecipitation, site-directed mutagenesis (Y14), PTPN1 phosphatase overexpression, Cav1 KO mouse model, LC3 foci imaging","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, phospho-mutant analysis, phosphatase functional assay, and in vivo KO confirmation, multiple orthogonal methods in one study","pmids":["28542134"],"is_preprint":false},{"year":2019,"finding":"High glucose suppresses the AMPK-MTOR-PIK3C3 pathway, reducing autophagic degradation of CAV1. This causes CAV1 accumulation in the cytosol, increased caveolae formation at the cell membrane, and enhanced LDL transcytosis across endothelial cells. The CAV1-CAVIN1-LC3B axis mediates autophagic degradation of CAV1 under basal conditions.","method":"Autophagy flux assays, AMPK-MTOR pathway inhibition, CAV1 overexpression/knockdown, LDL transcytosis assay, gestational diabetes mellitus patient tissue analysis","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional pathway dissection with pharmacological and genetic tools in a single lab, supported by patient tissue correlation","pmids":["31448673"],"is_preprint":false},{"year":2016,"finding":"Desmoglein 2 (Dsg2) overexpression displaces CAV1, EGFR, and c-Src from light-density lipid raft fractions. CAV1 functions as part of a lipid raft signaling platform: perturbation of lipid rafts (by MβCD cholesterol chelation) shifts CAV1, c-Src, and EGFR out of rafts and activates downstream signaling. Dsg2 stimulates EGFR activation and cell proliferation/migration through a c-Src and CAV1-dependent mechanism using lipid rafts.","method":"Sucrose density fractionation, STED super-resolution imaging, Dsg2 knockdown/overexpression, MβCD treatment","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — orthogonal methods (fractionation, STED imaging, KD/OE) in single lab","pmids":["26918609"],"is_preprint":false},{"year":2014,"finding":"CAV1 promotes HCC cell invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin pathway. CAV1 also acts as a mediator between hyperactive ERK1/2 signaling and transcription of MMP-7, identifying MMP-7 as a novel downstream target of CAV1.","method":"CAV1 overexpression and stable knockdown, in vitro invasion assays, in vivo xenograft and lung metastasis models, tissue microarray immunohistochemistry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with in vitro and in vivo readouts in single lab, pathway placement by downstream target identification","pmids":["25180681"],"is_preprint":false},{"year":2018,"finding":"PTBP3 interacts with the CU-rich region of the CAV1 gene to downregulate CAV1α expression via alternative splicing. Knockdown of CAV1α abrogated the reduction of FAK and Src phosphorylation induced by PTBP3 knockdown, placing CAV1α downstream of PTBP3 in a gastric cancer metastasis pathway.","method":"RNA immunoprecipitation (RIP), dual-luciferase reporter assays, PTBP3 overexpression/knockdown, xenotransplant mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA-protein interaction by RIP, reporter assays, and in vivo confirmation in single lab","pmids":["29752441"],"is_preprint":false},{"year":2015,"finding":"A de novo heterozygous frame-shift mutation in CAV1 (p.Phe160X) causes a severe neonatal progeroid and lipodystrophy syndrome. Western blotting of patient fibroblasts showed significantly decreased wild-type CAV1 protein, demonstrating a loss-of-function mechanism. RNA sequencing showed dysregulation of pathways related to apoptosis, DNA repair/replication, and mitochondrial function, and significant down-regulation of known CAV1 interaction partners.","method":"Whole-genome sequencing, RNA-seq, western blotting of patient fibroblasts","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cells with protein-level confirmation and transcriptome analysis, single patient/lab","pmids":["26176221"],"is_preprint":false},{"year":2016,"finding":"CAV1 knockout mice exhibit elevated intraocular pressure and reduced conventional outflow facility. CAV1 deficiency (and loss of CAV2) results in increased eNOS activity, as evidenced by increased eNOS, eNOS-phospho Ser1177, Akt, and nitrotyrosine, and decreased eNOS-phospho Thr495 levels. The IOP elevation may be mediated by increased tyrosine nitration of protein kinase K and impairment of its activity.","method":"CAV1 KO mouse model, rebound tonometry, western blot, topical NOS inhibitor/donor pharmacology, perfusion outflow facility measurement","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined physiological phenotype and biochemical pathway analysis, single lab","pmids":["27228562"],"is_preprint":false},{"year":2014,"finding":"CAV1 deletion in mice impairs hematopoietic stem cell (HSC) function. Cav-1-/- mice show increased numbers of LSK cells and LT-HSCs with age, but LT-HSCs have reduced self-renewal capacity in vitro and fail to reconstitute hematopoiesis in competitive transplantation assays. CAV1 deletion disrupts quiescence of LSKs and promotes cell cycle progression through G2/M phase.","method":"Cav-1 KO mouse model, FACS analysis, in vitro clonogenic assay, in vivo competitive transplantation, cell cycle analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple functional readouts (transplantation, clonogenic assay, cell cycle) in single lab","pmids":["24675458"],"is_preprint":false},{"year":2018,"finding":"CAV1 deficiency activates JNK-associated signaling (MKK7/JNK pathway) in vascular smooth muscle cells. Cav-1-/- in ApoE-/- mice attenuated high-fat diet-induced atherosclerotic lesions, reduced macrophage content and pro-inflammatory cytokines, inactivated IKKβ/p65/IκBα signaling, and reduced MKK7/JNK activity. In vitro, JNK activation abolished the anti-atherosclerotic effects of CAV1 knockdown in ox-LDL-treated VSMCs, placing CAV1 upstream of JNK in atherosclerosis.","method":"Cav-1-/- ApoE-/- mouse model, western blot, RT-qPCR, Oil Red O staining, JNK activator rescue in vitro","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with genetic rescue experiment in vitro establishing pathway position, single lab","pmids":["29746866"],"is_preprint":false},{"year":2015,"finding":"IFITM1 promotes colorectal cancer cell invasion with CAV1 acting as a downstream target. Knockdown of CAV1 abrogated the siIFITM1-mediated inhibition of cell invasion in CRC cells, placing CAV1 downstream of IFITM1 in invasion regulation.","method":"IFITM1 overexpression/knockdown, CAV1 knockdown epistasis experiment, cell migration/invasion assays","journal":"Cancer letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single epistasis experiment (CAV1 KD rescue) with invasion assay, single lab, limited mechanistic detail","pmids":["26259513"],"is_preprint":false},{"year":2022,"finding":"In colorectal cancer, CD26 promotes metastasis through upregulation of MMP1; overexpression of CAV1 abrogated CD26-regulated MMP1 induction in CRC cell lines, placing CAV1 as a negative regulator of MMP1 expression downstream of CD26 signaling.","method":"CD26 overexpression/repression, CAV1 overexpression epistasis, genome-wide mRNA expression array, qPCR, in vivo mouse models","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single epistasis experiment with limited mechanistic detail on the CAV1-MMP1 interaction, single lab","pmids":["35163100"],"is_preprint":false},{"year":2021,"finding":"Biallelic CAV1 null variants (homozygous loss-of-function) cause congenital generalized lipodystrophy (CGL3). Patient fibroblasts show complete loss of caveolae, absent caveolin-1 protein, and concomitant loss of caveolin-2 and cavin-1 partners, demonstrating that CAV1 is required for caveolae formation and for stability of its partner proteins CAVIN1 and CAV2. Patient fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence.","method":"Next-generation sequencing, western blotting of patient fibroblasts, electron microscopy of caveolae, clinical/metabolic phenotyping","journal":"European journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cellular studies with EM confirmation of caveolae loss and protein-level analysis, replicated across two independent patients with different CAV1 null variants","pmids":["34643546"],"is_preprint":false},{"year":2024,"finding":"CAV1 marks intraluminal vesicles destined for migrasomes, co-localizing with Rab10. Transport of Rab10-CAV1 vesicles to migrasomes requires the motor protein Myosin Va and adaptor proteins RILPL2. Phosphorylation of Rab10 by the kinase LRRK2 regulates this transport process. CSF-1 is transported to migrasomes via this CAV1-dependent mechanism to foster monocyte-macrophage differentiation.","method":"Live imaging, co-immunoprecipitation, dominant-negative/knockdown experiments for Myosin Va and RILPL2, LRRK2 kinase assay/inhibition, wound healing macrophage differentiation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, imaging, genetic knockdown of motor/adaptor, kinase regulation) identifying a complete transport pathway with functional physiological readout","pmids":["39008679"],"is_preprint":false},{"year":2020,"finding":"Rare variants in CAV1/CAV2 enhancers are enriched in ALS patients. Patient-derived enhancer mutations reduce CAV1/CAV2 expression and disrupt membrane lipid rafts (MLRs). CRISPR-Cas9 perturbation proximate to a patient mutation was sufficient to reduce CAV1/CAV2 expression in neurons, establishing a loss-of-function mechanism for CAV1 in ALS via disruption of MLRs.","method":"Rare variant burden analysis, patient-derived cell studies, CRISPR-Cas9 perturbation in neurons, MLR functional assay","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR functional validation in neurons plus patient-derived cellular phenotype, replicated in independent cohort","pmids":["33264630"],"is_preprint":false},{"year":2020,"finding":"ABCA1 upregulation in Schlemm's canal endothelial cells decreases CAV1 expression (~0.56-fold) and increases eNOS expression and NO production, reducing transendothelial resistance. Conversely, ABCA1 downregulation increases CAV1 expression and decreases eNOS/NO. This establishes that CAV1 negatively regulates eNOS/NO signaling in the aqueous humor outflow pathway.","method":"ABCA1 agonist (GW3965) treatment, lentiviral ABCA1 shRNA knockdown, western blot, transendothelial electrical resistance measurement, NO concentration measurement, intracameral injection in vivo","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (gain and loss of ABCA1 function) with consistent CAV1/eNOS reciprocal changes, confirmed in vivo, single lab","pmids":["32428234"],"is_preprint":false}],"current_model":"CAV1 (Caveolin-1) is an integral membrane protein that scaffolds caveolae microdomains; it acts as a platform for lipid raft-dependent signaling (regulating EGFR/c-Src, eNOS, JNK, and Wnt/β-catenin pathways), mediates autophagic self-degradation via a CAVIN1-LC3B axis controlled by AMPK-MTOR-PIK3C3, promotes autophagy under oxidative stress through Y14-phosphorylation-dependent interaction with the BECN1/VPS34 complex, traffics intraluminal vesicles to migrasomes via a Rab10/Myosin Va/RILPL2/LRRK2-regulated pathway, and is required for caveolae biogenesis and stabilization of its partners CAV2 and CAVIN1, with loss-of-function causing lipodystrophy, impaired hematopoietic stem cell quiescence, and elevated intraocular pressure."},"narrative":{"mechanistic_narrative":"CAV1 (Caveolin-1) is an integral membrane protein required for caveolae biogenesis that organizes lipid raft microdomains and serves as a scaffold coupling membrane organization to multiple signaling pathways [PMID:26918609, PMID:34643546]. Its essential structural role is established by biallelic null variants causing congenital generalized lipodystrophy, in which patient fibroblasts lose caveolae entirely, lack caveolin-1 protein, and show concomitant loss of its partners CAV2 and CAVIN1, demonstrating that CAV1 is required for caveolae formation and for stabilization of these partner proteins [PMID:34643546]; a de novo frame-shift mutation similarly causes a neonatal progeroid/lipodystrophy syndrome via loss of function [PMID:26176221]. At the membrane, CAV1 co-resides with c-Src and EGFR in cholesterol-dependent lipid rafts, and disrupting raft integrity displaces these components and modulates downstream signaling [PMID:26918609]. CAV1 negatively regulates endothelial eNOS/NO signaling, with its loss elevating eNOS activity in contexts of intraocular pressure and aqueous outflow [PMID:27228562, PMID:32428234], and it constrains JNK and NF-kB inflammatory signaling in vascular smooth muscle during atherosclerosis [PMID:29746866]. CAV1 also participates in autophagy: phosphorylation at tyrosine-14 enables its scaffolding-domain-dependent interaction with the BECN1/VPS34 complex to promote autophagosome formation under oxidative stress, an interaction reversed by the phosphatase PTPN1 [PMID:28542134], while CAV1 itself is turned over by autophagy through a CAVIN1-LC3B axis under control of the AMPK-MTOR-PIK3C3 pathway [PMID:31448673]. In cancer, CAV1 acts as a context-dependent regulator of invasion and EMT, driving HCC metastasis via Wnt/beta-catenin and ERK-dependent MMP-7 induction [PMID:25180681] and functioning as a transcriptional target and effector in other tumor pathways [PMID:17047056, PMID:29752441]. More recently, CAV1 was found to mark intraluminal vesicles delivered to migrasomes via a Rab10/Myosin Va/RILPL2 transport pathway regulated by LRRK2 phosphorylation of Rab10 [PMID:39008679]. CAV1 loss also disrupts hematopoietic stem cell quiescence [PMID:24675458] and is linked through enhancer variants to ALS via membrane lipid raft disruption [PMID:33264630].","teleology":[{"year":2006,"claim":"Established CAV1 as a transcriptionally regulated effector with a defined role in the EMT/oncogenic program, linking it to Snail/E-cadherin control of anchorage-independent growth.","evidence":"ChIP, shRNA knockdown, re-expression rescue, and nude mouse xenografts in Ewing's sarcoma cells","pmids":["17047056"],"confidence":"High","gaps":["Does not define how CAV1 mechanistically represses Snail","Tumor-type-specific; does not establish a general CAV1 EMT mechanism"]},{"year":2014,"claim":"Defined CAV1 as a positive driver of invasion and EMT through Wnt/beta-catenin and ERK-MMP-7 signaling, contrasting with its tumor-suppressive role in other contexts.","evidence":"Gain/loss-of-function with in vitro invasion and in vivo metastasis models in HCC","pmids":["25180681"],"confidence":"Medium","gaps":["Mechanism by which CAV1 couples to Wnt/beta-catenin not resolved","Reconciliation of pro- vs anti-oncogenic roles not addressed"]},{"year":2014,"claim":"Showed CAV1 is required to maintain hematopoietic stem cell quiescence, expanding its role beyond signaling into stem cell biology.","evidence":"Cav1 KO mice with competitive transplantation, clonogenic assays, and cell cycle analysis","pmids":["24675458"],"confidence":"Medium","gaps":["Molecular link between CAV1 and quiescence machinery undefined","Caveolae dependence of the HSC phenotype not tested"]},{"year":2016,"claim":"Positioned CAV1 within cholesterol-dependent lipid rafts as a scaffold co-organizing c-Src and EGFR, mechanistically tying membrane raft integrity to downstream signaling activation.","evidence":"Sucrose density fractionation, STED imaging, and MbetaCD cholesterol depletion with Dsg2 manipulation","pmids":["26918609"],"confidence":"Medium","gaps":["Direct CAV1-EGFR/c-Src binding not distinguished from co-residence","Does not establish stoichiometry or scaffolding domain requirement"]},{"year":2016,"claim":"Demonstrated CAV1 negatively regulates eNOS/NO signaling in the conventional outflow pathway, mechanistically connecting CAV1 loss to elevated intraocular pressure.","evidence":"Cav1 KO mice with tonometry, outflow facility measurement, NOS pharmacology, and eNOS phospho-state western blots","pmids":["27228562"],"confidence":"Medium","gaps":["The proposed protein kinase K nitration mechanism is correlative","Cell type responsible for outflow phenotype not pinpointed"]},{"year":2017,"claim":"Identified a phospho-switch controlling CAV1's autophagic function, where Y14 phosphorylation enables scaffolding-domain binding to BECN1/VPS34 to drive autophagy under oxidative stress.","evidence":"Reciprocal Co-IP, Y14 phospho-mutants, PTPN1 phosphatase overexpression, and Cav1 KO mouse stroke model with LC3 imaging","pmids":["28542134"],"confidence":"High","gaps":["Kinase phosphorylating CAV1-Y14 in this context not identified","Structural basis of the scaffolding-domain/BECN1 interaction not resolved"]},{"year":2018,"claim":"Placed CAV1 upstream of JNK and NF-kB inflammatory signaling in vascular smooth muscle, defining its anti-atherosclerotic role through pathway-position rescue.","evidence":"Cav1-/- ApoE-/- mice with JNK activator rescue in ox-LDL-treated VSMCs","pmids":["29746866"],"confidence":"Medium","gaps":["Direct molecular link between CAV1 and MKK7/JNK not shown","Whether effect requires caveolae not tested"]},{"year":2018,"claim":"Showed CAV1alpha isoform expression is controlled post-transcriptionally by PTBP3-mediated alternative splicing, placing a specific CAV1 isoform downstream in FAK/Src-driven metastasis.","evidence":"RNA immunoprecipitation, dual-luciferase reporters, and xenotransplant in gastric cancer","pmids":["29752441"],"confidence":"Medium","gaps":["Functional difference between CAV1 isoforms not mechanistically dissected","How CAV1alpha modulates FAK/Src unresolved"]},{"year":2019,"claim":"Defined the autophagic turnover route of CAV1 itself, showing the AMPK-MTOR-PIK3C3 pathway controls CAV1 degradation via a CAVIN1-LC3B axis to regulate caveolae abundance and LDL transcytosis.","evidence":"Autophagy flux assays, AMPK-MTOR inhibition, CAV1 manipulation, LDL transcytosis assays, and gestational diabetes patient tissue","pmids":["31448673"],"confidence":"Medium","gaps":["Direct CAVIN1-LC3B binding not biochemically resolved","Single-lab functional dissection"]},{"year":2020,"claim":"Linked CAV1 loss-of-function to ALS through enhancer variants that reduce CAV1/CAV2 expression and disrupt membrane lipid rafts.","evidence":"Rare variant burden analysis, patient-derived cells, and CRISPR-Cas9 enhancer perturbation in neurons","pmids":["33264630"],"confidence":"Medium","gaps":["Downstream neuronal MLR targets mediating ALS pathology undefined","Causal mutation effect inferred from proximate CRISPR edit"]},{"year":2020,"claim":"Reinforced CAV1's reciprocal regulation of eNOS/NO in Schlemm's canal endothelium, showing ABCA1 modulates outflow resistance by tuning CAV1 levels.","evidence":"Bidirectional ABCA1 manipulation with TEER, NO measurement, and in vivo intracameral injection","pmids":["32428234"],"confidence":"Medium","gaps":["Mechanism by which ABCA1 controls CAV1 expression not defined","Single-lab study"]},{"year":2021,"claim":"Established CAV1 as strictly required for caveolae biogenesis and for stability of CAV2 and CAVIN1, with biallelic null variants causing congenital generalized lipodystrophy.","evidence":"NGS, western blotting of patient fibroblasts, and electron microscopy of caveolae across two independent patients","pmids":["34643546"],"confidence":"Medium","gaps":["Molecular basis of insulin resistance and premature senescence downstream of caveolae loss not dissected","Order of partner destabilization not resolved"]},{"year":2024,"claim":"Revealed a novel CAV1 trafficking role, marking intraluminal vesicles delivered to migrasomes via a Rab10/Myosin Va/RILPL2 pathway under LRRK2 control to drive macrophage differentiation.","evidence":"Live imaging, Co-IP, knockdown of motor/adaptor proteins, LRRK2 kinase assays, and macrophage differentiation readouts","pmids":["39008679"],"confidence":"High","gaps":["How CAV1 selects intraluminal vesicle cargo not defined","Relationship of this trafficking route to canonical caveolae unclear"]},{"year":null,"claim":"The unifying basis for CAV1's opposing context-dependent roles — pro- versus anti-tumorigenic, and how its scaffolding, autophagy, eNOS regulation, and migrasome trafficking functions interrelate at the molecular level — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model reconciling scaffolding-domain interactions across partners","Determinants of tissue/context-specific CAV1 function not identified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7,9,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[12]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,12]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[13]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,7,9,15]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,13]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[12]}],"complexes":["caveolae"],"partners":["CAV2","CAVIN1","BECN1","PTPN1","EGFR","SRC","RAB10","LC3B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q03135","full_name":"Caveolin-1","aliases":[],"length_aa":178,"mass_kda":20.5,"function":"May act as a scaffolding protein within caveolar membranes (PubMed:11751885). Forms a stable heterooligomeric complex with CAV2 that targets to lipid rafts and drives caveolae formation. Mediates the recruitment of CAVIN proteins (CAVIN1/2/3/4) to the caveolae (PubMed:19262564). Interacts directly with G-protein alpha subunits and can functionally regulate their activity (By similarity). Involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Its binding to DPP4 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner (PubMed:17287217). Recruits CTNNB1 to caveolar membranes and may regulate CTNNB1-mediated signaling through the Wnt pathway (By similarity). Negatively regulates TGFB1-mediated activation of SMAD2/3 by mediating the internalization of TGFBR1 from membrane rafts leading to its subsequent degradation (PubMed:25893292). Binds 20(S)-hydroxycholesterol (20(S)-OHC) (By similarity)","subcellular_location":"Golgi apparatus membrane; Cell membrane; Membrane, caveola; Membrane raft; Golgi apparatus, trans-Golgi network; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q03135/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAV1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CAV1","total_profiled":1310},"omim":[{"mim_id":"621356","title":"SH3 AND CYSTEINE-RICH DOMAINS 2; STAC2","url":"https://www.omim.org/entry/621356"},{"mim_id":"620966","title":"TLC DOMAIN-CONTAINING PROTEIN 1; TLCD1","url":"https://www.omim.org/entry/620966"},{"mim_id":"619863","title":"JUNCTOPHILIN 4; JPH4","url":"https://www.omim.org/entry/619863"},{"mim_id":"618447","title":"LONG QT SYNDROME 8; LQT8","url":"https://www.omim.org/entry/618447"},{"mim_id":"618303","title":"CAVEOLAE-ASSOCIATED PROTEIN 3; CAVIN3","url":"https://www.omim.org/entry/618303"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CAV1"},"hgnc":{"alias_symbol":[],"prev_symbol":["CAV"]},"alphafold":{"accession":"Q03135","domains":[{"cath_id":"-","chopping":"52-167","consensus_level":"medium","plddt":88.1458,"start":52,"end":167}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03135","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q03135-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q03135-F1-predicted_aligned_error_v6.png","plddt_mean":78.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAV1","jax_strain_url":"https://www.jax.org/strain/search?query=CAV1"},"sequence":{"accession":"Q03135","fasta_url":"https://rest.uniprot.org/uniprotkb/Q03135.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q03135/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q03135"}},"corpus_meta":[{"pmid":"16251435","id":"PMC_16251435","title":"Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16251435","citation_count":357,"is_preprint":false},{"pmid":"24382889","id":"PMC_24382889","title":"L-type CaV1.2 calcium channels: from in vitro findings to in vivo function.","date":"2014","source":"Physiological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/24382889","citation_count":285,"is_preprint":false},{"pmid":"22705413","id":"PMC_22705413","title":"CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease.","date":"2012","source":"Progress in neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/22705413","citation_count":226,"is_preprint":false},{"pmid":"15689540","id":"PMC_15689540","title":"G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a Shank-binding domain.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15689540","citation_count":217,"is_preprint":false},{"pmid":"31969708","id":"PMC_31969708","title":"Mechanism of adrenergic CaV1.2 stimulation revealed by proximity proteomics.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31969708","citation_count":202,"is_preprint":false},{"pmid":"18250309","id":"PMC_18250309","title":"The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18250309","citation_count":142,"is_preprint":false},{"pmid":"22138472","id":"PMC_22138472","title":"BIN1 is reduced and Cav1.2 trafficking is impaired in human failing cardiomyocytes.","date":"2011","source":"Heart rhythm","url":"https://pubmed.ncbi.nlm.nih.gov/22138472","citation_count":136,"is_preprint":false},{"pmid":"15689539","id":"PMC_15689539","title":"Association of CaV1.3 L-type calcium channels with Shank.","date":"2005","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15689539","citation_count":124,"is_preprint":false},{"pmid":"24996399","id":"PMC_24996399","title":"The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function.","date":"2014","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/24996399","citation_count":123,"is_preprint":false},{"pmid":"17047056","id":"PMC_17047056","title":"Caveolin-1 (CAV1) is a target of EWS/FLI-1 and a key determinant of the oncogenic phenotype and tumorigenicity of Ewing's sarcoma cells.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17047056","citation_count":123,"is_preprint":false},{"pmid":"20194790","id":"PMC_20194790","title":"CaV1.2 beta-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20194790","citation_count":106,"is_preprint":false},{"pmid":"12853422","id":"PMC_12853422","title":"Cav1.4alpha1 subunits can form slowly inactivating dihydropyridine-sensitive L-type Ca2+ channels lacking Ca2+-dependent inactivation.","date":"2003","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12853422","citation_count":106,"is_preprint":false},{"pmid":"24934288","id":"PMC_24934288","title":"Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons.","date":"2014","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24934288","citation_count":102,"is_preprint":false},{"pmid":"15509562","id":"PMC_15509562","title":"Ser1928 is a common site for Cav1.2 phosphorylation by protein kinase C isoforms.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15509562","citation_count":101,"is_preprint":false},{"pmid":"16051206","id":"PMC_16051206","title":"Splicing for alternative structures of Cav1.2 Ca2+ channels in cardiac and smooth muscles.","date":"2005","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/16051206","citation_count":100,"is_preprint":false},{"pmid":"17626895","id":"PMC_17626895","title":"Protein kinase G phosphorylates Cav1.2 alpha1c and beta2 subunits.","date":"2007","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/17626895","citation_count":95,"is_preprint":false},{"pmid":"15140941","id":"PMC_15140941","title":"Ca2+-binding protein-1 facilitates and forms a postsynaptic complex with Cav1.2 (L-type) Ca2+ channels.","date":"2004","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/15140941","citation_count":94,"is_preprint":false},{"pmid":"16706838","id":"PMC_16706838","title":"Ca1.2 and CaV1.3 neuronal L-type calcium channels: differential targeting and signaling to pCREB.","date":"2006","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/16706838","citation_count":88,"is_preprint":false},{"pmid":"16554304","id":"PMC_16554304","title":"Integrin receptor activation triggers converging regulation of Cav1.2 calcium channels by c-Src and protein kinase A pathways.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16554304","citation_count":81,"is_preprint":false},{"pmid":"26786159","id":"PMC_26786159","title":"L-type Cav1.3 channels regulate ryanodine receptor-dependent Ca2+ release during sino-atrial node pacemaker activity.","date":"2016","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/26786159","citation_count":81,"is_preprint":false},{"pmid":"19916019","id":"PMC_19916019","title":"CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency.","date":"2009","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19916019","citation_count":77,"is_preprint":false},{"pmid":"23266596","id":"PMC_23266596","title":"CaV1.2 signaling complexes in the heart.","date":"2012","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/23266596","citation_count":73,"is_preprint":false},{"pmid":"31448673","id":"PMC_31448673","title":"CAV1-CAVIN1-LC3B-mediated autophagy regulates high glucose-stimulated LDL transcytosis.","date":"2019","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/31448673","citation_count":72,"is_preprint":false},{"pmid":"26259513","id":"PMC_26259513","title":"IFITM1 promotes the metastasis of human colorectal cancer via CAV-1.","date":"2015","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26259513","citation_count":71,"is_preprint":false},{"pmid":"19564422","id":"PMC_19564422","title":"Developmental control of CaV1.2 L-type calcium channel splicing by Fox proteins.","date":"2009","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19564422","citation_count":66,"is_preprint":false},{"pmid":"25368181","id":"PMC_25368181","title":"Basal and β-adrenergic regulation of the cardiac calcium channel CaV1.2 requires phosphorylation of serine 1700.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25368181","citation_count":66,"is_preprint":false},{"pmid":"24054868","id":"PMC_24054868","title":"Cav1.3 channel α1D protein is overexpressed and modulates androgen receptor transactivation in prostate cancers.","date":"2013","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24054868","citation_count":62,"is_preprint":false},{"pmid":"17272350","id":"PMC_17272350","title":"Apical GLUT2 and Cav1.3: regulation of rat intestinal glucose and calcium absorption.","date":"2007","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/17272350","citation_count":62,"is_preprint":false},{"pmid":"23088728","id":"PMC_23088728","title":"Exploring the dominant role of Cav1 channels in signalling to the nucleus.","date":"2012","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/23088728","citation_count":60,"is_preprint":false},{"pmid":"28542134","id":"PMC_28542134","title":"Phosphorylated CAV1 activates autophagy through an interaction with BECN1 under oxidative stress.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28542134","citation_count":60,"is_preprint":false},{"pmid":"30249603","id":"PMC_30249603","title":"Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca2+/CaMKII signaling.","date":"2018","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/30249603","citation_count":57,"is_preprint":false},{"pmid":"12900400","id":"PMC_12900400","title":"Enhanced expression of L-type Cav1.3 calcium channels in murine embryonic hearts from Cav1.2-deficient mice.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12900400","citation_count":57,"is_preprint":false},{"pmid":"26918609","id":"PMC_26918609","title":"c-Src/Cav1-dependent activation of the EGFR by Dsg2.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26918609","citation_count":53,"is_preprint":false},{"pmid":"31355778","id":"PMC_31355778","title":"TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31355778","citation_count":52,"is_preprint":false},{"pmid":"30422117","id":"PMC_30422117","title":"Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30422117","citation_count":52,"is_preprint":false},{"pmid":"19841139","id":"PMC_19841139","title":"PIKfyve regulates CaV1.2 degradation and prevents excitotoxic cell death.","date":"2009","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19841139","citation_count":52,"is_preprint":false},{"pmid":"25468907","id":"PMC_25468907","title":"Characterization of Cav1.4 complexes (α11.4, β2, and α2δ4) in HEK293T cells and in the retina.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25468907","citation_count":52,"is_preprint":false},{"pmid":"30604627","id":"PMC_30604627","title":"Identification of CAV1 and DCN as potential predictive biomarkers for lung adenocarcinoma.","date":"2019","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30604627","citation_count":50,"is_preprint":false},{"pmid":"25538241","id":"PMC_25538241","title":"Regulation of gene transcription by voltage-gated L-type calcium channel, Cav1.3.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25538241","citation_count":49,"is_preprint":false},{"pmid":"29752441","id":"PMC_29752441","title":"PTBP3 contributes to the metastasis of gastric cancer by mediating CAV1 alternative splicing.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29752441","citation_count":49,"is_preprint":false},{"pmid":"32222817","id":"PMC_32222817","title":"Skeletal muscle CaV1.1 channelopathies.","date":"2020","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32222817","citation_count":48,"is_preprint":false},{"pmid":"23321639","id":"PMC_23321639","title":"Cav1.1 controls frequency-dependent events regulating adult skeletal muscle plasticity.","date":"2013","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/23321639","citation_count":48,"is_preprint":false},{"pmid":"25180681","id":"PMC_25180681","title":"CAV1 promotes HCC cell progression and metastasis through Wnt/β-catenin pathway.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25180681","citation_count":47,"is_preprint":false},{"pmid":"15615842","id":"PMC_15615842","title":"Localization and modulation of {alpha}1D (Cav1.3) L-type Ca channel by protein kinase A.","date":"2004","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15615842","citation_count":47,"is_preprint":false},{"pmid":"23220157","id":"PMC_23220157","title":"CaV1.2 sparklets in heart and vascular smooth muscle.","date":"2012","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/23220157","citation_count":46,"is_preprint":false},{"pmid":"27231046","id":"PMC_27231046","title":"Cav1.2 and Cav1.3 L-type calcium channels independently control short- and long-term sensitization to pain.","date":"2016","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27231046","citation_count":46,"is_preprint":false},{"pmid":"28807015","id":"PMC_28807015","title":"Genomic upregulation of cardiac Cav1.2α and NCX1 by estrogen in women.","date":"2017","source":"Biology of sex differences","url":"https://pubmed.ncbi.nlm.nih.gov/28807015","citation_count":45,"is_preprint":false},{"pmid":"26775120","id":"PMC_26775120","title":"Genomic variant in CAV1 increases susceptibility to coronary artery disease and myocardial infarction.","date":"2016","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/26775120","citation_count":44,"is_preprint":false},{"pmid":"21156134","id":"PMC_21156134","title":"Analysis of Cav1.2 and ryanodine receptor clusters in rat ventricular myocytes.","date":"2010","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21156134","citation_count":43,"is_preprint":false},{"pmid":"26379493","id":"PMC_26379493","title":"Cell-type-specific tuning of Cav1.3 Ca(2+)-channels by a C-terminal automodulatory domain.","date":"2015","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26379493","citation_count":43,"is_preprint":false},{"pmid":"14739158","id":"PMC_14739158","title":"Muscarinic M2 receptor stimulation of Cav1.2b requires phosphatidylinositol 3-kinase, protein kinase C, and c-Src.","date":"2004","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/14739158","citation_count":43,"is_preprint":false},{"pmid":"35163100","id":"PMC_35163100","title":"CD26 Induces Colorectal Cancer Angiogenesis and Metastasis through CAV1/MMP1 Signaling.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35163100","citation_count":42,"is_preprint":false},{"pmid":"32859919","id":"PMC_32859919","title":"Disruption of Cav1.2-mediated signaling is a pathway for ketamine-induced pathology.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32859919","citation_count":42,"is_preprint":false},{"pmid":"31012223","id":"PMC_31012223","title":"Estrogen receptor α promotes Cav1.2 ubiquitination and degradation in neuronal cells and in APP/PS1 mice.","date":"2019","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/31012223","citation_count":40,"is_preprint":false},{"pmid":"25717360","id":"PMC_25717360","title":"Ca(2+) permeation and/or binding to CaV1.1 fine-tunes skeletal muscle Ca(2+) signaling to sustain muscle function.","date":"2015","source":"Skeletal muscle","url":"https://pubmed.ncbi.nlm.nih.gov/25717360","citation_count":40,"is_preprint":false},{"pmid":"25918359","id":"PMC_25918359","title":"CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries.","date":"2015","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25918359","citation_count":40,"is_preprint":false},{"pmid":"24163243","id":"PMC_24163243","title":"Mosaic synaptopathy and functional defects in Cav1.4 heterozygous mice and human carriers of CSNB2.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24163243","citation_count":39,"is_preprint":false},{"pmid":"29202453","id":"PMC_29202453","title":"Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss.","date":"2017","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/29202453","citation_count":39,"is_preprint":false},{"pmid":"25966692","id":"PMC_25966692","title":"Cav1.3 Channels as Key Regulators of Neuron-Like Firings and Catecholamine Release in Chromaffin Cells.","date":"2015","source":"Current molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25966692","citation_count":38,"is_preprint":false},{"pmid":"26176221","id":"PMC_26176221","title":"A Frame-Shift Mutation in CAV1 Is Associated with a Severe Neonatal Progeroid and Lipodystrophy Syndrome.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26176221","citation_count":38,"is_preprint":false},{"pmid":"27228562","id":"PMC_27228562","title":"eNOS Activity in CAV1 Knockout Mouse Eyes.","date":"2016","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/27228562","citation_count":35,"is_preprint":false},{"pmid":"29079724","id":"PMC_29079724","title":"Ca2+ protein alpha 1D of CaV1.3 regulates intracellular calcium concentration and migration of colon cancer cells through a non-canonical activity.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29079724","citation_count":34,"is_preprint":false},{"pmid":"24365142","id":"PMC_24365142","title":"Protein kinase C-dependent activation of CaV1.2 channels selectively controls human TH2-lymphocyte functions.","date":"2013","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24365142","citation_count":33,"is_preprint":false},{"pmid":"27098837","id":"PMC_27098837","title":"Regulation of aldosterone secretion by Cav1.3.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27098837","citation_count":32,"is_preprint":false},{"pmid":"22826131","id":"PMC_22826131","title":"Equal sensitivity of Cav1.2 and Cav1.3 channels to the opposing modulations of PKA and PKG in mouse chromaffin cells.","date":"2012","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22826131","citation_count":32,"is_preprint":false},{"pmid":"32621084","id":"PMC_32621084","title":"Cav1.2 channelopathies causing autism: new hallmarks on Timothy syndrome.","date":"2020","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32621084","citation_count":31,"is_preprint":false},{"pmid":"23159773","id":"PMC_23159773","title":"Cav1.3 and Cav1.2 channels of adrenal chromaffin cells: emerging views on cAMP/cGMP-mediated phosphorylation and role in pacemaking.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23159773","citation_count":31,"is_preprint":false},{"pmid":"16638807","id":"PMC_16638807","title":"The junctional SR protein JP-45 affects the functional expression of the voltage-dependent Ca2+ channel Cav1.1.","date":"2006","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/16638807","citation_count":31,"is_preprint":false},{"pmid":"38776078","id":"PMC_38776078","title":"Key Roles of CACNA1C/Cav1.2 and CALB1/Calbindin in Prefrontal Neurons Altered in Cognitive Disorders.","date":"2024","source":"JAMA psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/38776078","citation_count":30,"is_preprint":false},{"pmid":"24567507","id":"PMC_24567507","title":"Differential regulation of CaV1.2 channels by cAMP-dependent protein kinase bound to A-kinase anchoring proteins 15 and 79/150.","date":"2014","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24567507","citation_count":30,"is_preprint":false},{"pmid":"27255217","id":"PMC_27255217","title":"An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca(2+)-dependent regulation.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27255217","citation_count":30,"is_preprint":false},{"pmid":"17409629","id":"PMC_17409629","title":"Regulation of Cav1.2 current: interaction with intracellular molecules.","date":"2007","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/17409629","citation_count":29,"is_preprint":false},{"pmid":"25712868","id":"PMC_25712868","title":"Homer proteins mediate the interaction between STIM1 and Cav1.2 channels.","date":"2015","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25712868","citation_count":29,"is_preprint":false},{"pmid":"21178109","id":"PMC_21178109","title":"Spatial association of the Cav1.2 calcium channel with α5β1-integrin.","date":"2010","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21178109","citation_count":28,"is_preprint":false},{"pmid":"34072954","id":"PMC_34072954","title":"Mechanisms and Regulation of Cardiac CaV1.2 Trafficking.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34072954","citation_count":27,"is_preprint":false},{"pmid":"31002755","id":"PMC_31002755","title":"Genetic silencing of striatal CaV1.3 prevents and ameliorates levodopa dyskinesia.","date":"2019","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/31002755","citation_count":27,"is_preprint":false},{"pmid":"33264630","id":"PMC_33264630","title":"Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33264630","citation_count":27,"is_preprint":false},{"pmid":"39008679","id":"PMC_39008679","title":"Rab10-CAV1 mediated intraluminal vesicle transport to migrasomes.","date":"2024","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39008679","citation_count":26,"is_preprint":false},{"pmid":"31678346","id":"PMC_31678346","title":"Calcium Signaling in Neurons and Glial Cells: Role of Cav1 channels.","date":"2019","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31678346","citation_count":26,"is_preprint":false},{"pmid":"25845695","id":"PMC_25845695","title":"Cacna1c (Cav1.2) Modulates Electroencephalographic Rhythm and Rapid Eye Movement Sleep Recovery.","date":"2015","source":"Sleep","url":"https://pubmed.ncbi.nlm.nih.gov/25845695","citation_count":26,"is_preprint":false},{"pmid":"32428234","id":"PMC_32428234","title":"ABCA1 Regulates IOP by Modulating Cav1/eNOS/NO Signaling Pathway.","date":"2020","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/32428234","citation_count":25,"is_preprint":false},{"pmid":"24675458","id":"PMC_24675458","title":"Cav-1 deletion impaired hematopoietic stem cell function.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/24675458","citation_count":25,"is_preprint":false},{"pmid":"16973824","id":"PMC_16973824","title":"Protein kinase C activation inhibits Cav1.3 calcium channel at NH2-terminal serine 81 phosphorylation site.","date":"2006","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16973824","citation_count":24,"is_preprint":false},{"pmid":"29733375","id":"PMC_29733375","title":"Tissue-selective restriction of RNA editing of CaV1.3 by splicing factor SRSF9.","date":"2018","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/29733375","citation_count":24,"is_preprint":false},{"pmid":"29746866","id":"PMC_29746866","title":"Cav-1 promotes atherosclerosis by activating JNK-associated signaling.","date":"2018","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/29746866","citation_count":24,"is_preprint":false},{"pmid":"27456671","id":"PMC_27456671","title":"Protein kinase A modulation of CaV1.4 calcium channels.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27456671","citation_count":23,"is_preprint":false},{"pmid":"26536090","id":"PMC_26536090","title":"Modulation of CaV1.2 calcium channel by neuropeptide W regulates vascular myogenic tone via G protein-coupled receptor 7.","date":"2015","source":"Journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/26536090","citation_count":22,"is_preprint":false},{"pmid":"34212239","id":"PMC_34212239","title":"Cav1.4 dysfunction and congenital stationary night blindness type 2.","date":"2021","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34212239","citation_count":21,"is_preprint":false},{"pmid":"37702787","id":"PMC_37702787","title":"ANO1, CaV1.2, and IP3R form a localized unit of EC-coupling in mouse pulmonary arterial smooth muscle.","date":"2023","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37702787","citation_count":21,"is_preprint":false},{"pmid":"36128191","id":"PMC_36128191","title":"CAV1 alleviated CaOx stones formation via suppressing autophagy-dependent ferroptosis.","date":"2022","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/36128191","citation_count":20,"is_preprint":false},{"pmid":"27374078","id":"PMC_27374078","title":"Rescuing cardiac automaticity in L-type Cav1.3 channelopathies and beyond.","date":"2016","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27374078","citation_count":20,"is_preprint":false},{"pmid":"35969184","id":"PMC_35969184","title":"Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 subunit CACNB2.","date":"2022","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/35969184","citation_count":20,"is_preprint":false},{"pmid":"30132504","id":"PMC_30132504","title":"Inhibition of Cx43 attenuates ERK1/2 activation, enhances the expression of Cav‑1 and suppresses cell proliferation.","date":"2018","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30132504","citation_count":20,"is_preprint":false},{"pmid":"36167061","id":"PMC_36167061","title":"CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms.","date":"2022","source":"The Journal of general physiology","url":"https://pubmed.ncbi.nlm.nih.gov/36167061","citation_count":19,"is_preprint":false},{"pmid":"21378599","id":"PMC_21378599","title":"Perinatal and postnatal expression of Cav1.3 α1D Ca²⁺ channel in the rat heart.","date":"2011","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/21378599","citation_count":19,"is_preprint":false},{"pmid":"30176250","id":"PMC_30176250","title":"Cav1.2 L-type calcium channels regulate stress coping behavior via serotonin neurons.","date":"2018","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30176250","citation_count":19,"is_preprint":false},{"pmid":"26242732","id":"PMC_26242732","title":"L-type Calcium Channel Cav1.2 Is Required for Maintenance of Auditory Brainstem Nuclei.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26242732","citation_count":19,"is_preprint":false},{"pmid":"38805819","id":"PMC_38805819","title":"CardioDPi: An explainable deep-learning model for identifying cardiotoxic chemicals targeting hERG, Cav1.2, and Nav1.5 channels.","date":"2024","source":"Journal of hazardous materials","url":"https://pubmed.ncbi.nlm.nih.gov/38805819","citation_count":19,"is_preprint":false},{"pmid":"16601841","id":"PMC_16601841","title":"Genetic analysis of CAV1 gene in hypertension and metabolic syndrome.","date":"2006","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/16601841","citation_count":18,"is_preprint":false},{"pmid":"34643546","id":"PMC_34643546","title":"Biallelic CAV1 null variants induce congenital generalized lipodystrophy with achalasia.","date":"2021","source":"European journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/34643546","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55193,"output_tokens":4836,"usd":0.119059,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12514,"output_tokens":4572,"usd":0.088435,"stage2_stop_reason":"end_turn"},"total_usd":0.207494,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about CAV1 (Caveolin-1, the canonical protein) vs. papers about CaV1.x (voltage-gated calcium channels like CACNA1C/CaV1.2, CACNA1D/CaV1.3, etc.). These are completely different proteins - CaV1.2 is a voltage-gated calcium channel encoded by CACNA1C, while CAV1 is Caveolin-1. The gene symbol collision here is significant.\n\nPapers about CAV1 (Caveolin-1): [10], [23], [24], [30], [33], [38], [40], [43], [48], [52], [60], [61], [77], [78], [81], [82], [85], [90], [93], [99], [100]\n\nPapers about CaV1.x calcium channels (CACNA1C, CACNA1D, etc.): [1]-[9], [11]-[22], [25]-[29], [31], [32], [34]-[37], [39], [41]-[47], [49]-[51], [53]-[59], [62]-[76], [79]-[80], [83]-[84], [86]-[89], [91]-[92], [94]-[98]\n\nNow extracting mechanistic discoveries for CAV1 (Caveolin-1):\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"CAV1 is a direct transcriptional target of EWS/FLI-1 in Ewing's sarcoma cells. CAV1 knockdown upregulated Snail and caused loss of E-cadherin expression, while CAV1 knockdown inhibited anchorage-independent growth and tumor formation in xenografts. Re-expression of CAV1 or E-cadherin rescued the oncogenic phenotype, defining a CAV1/Snail/E-cadherin pathway downstream of EWS/FLI-1.\",\n      \"method\": \"Antisense and shRNA knockdown, chromatin immunoprecipitation, array analyses, re-expression studies, nude mouse xenografts\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, shRNA, re-expression rescue, in vivo xenograft) in a single focused study\",\n      \"pmids\": [\"17047056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Phosphorylation of CAV1 at tyrosine-14 is required for its interaction with the BECN1/VPS34 complex through CAV1's scaffolding domain. This interaction promotes autophagosome formation and autophagy flux under oxidative stress. The phosphatase PTPN1 dephosphorylates CAV1-Y14 and inhibits this autophagy activation. In Cav1 knockout mice, autophagy was impaired and cerebral infarct damage was aggravated.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (Y14), PTPN1 phosphatase overexpression, Cav1 KO mouse model, LC3 foci imaging\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, phospho-mutant analysis, phosphatase functional assay, and in vivo KO confirmation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28542134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"High glucose suppresses the AMPK-MTOR-PIK3C3 pathway, reducing autophagic degradation of CAV1. This causes CAV1 accumulation in the cytosol, increased caveolae formation at the cell membrane, and enhanced LDL transcytosis across endothelial cells. The CAV1-CAVIN1-LC3B axis mediates autophagic degradation of CAV1 under basal conditions.\",\n      \"method\": \"Autophagy flux assays, AMPK-MTOR pathway inhibition, CAV1 overexpression/knockdown, LDL transcytosis assay, gestational diabetes mellitus patient tissue analysis\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional pathway dissection with pharmacological and genetic tools in a single lab, supported by patient tissue correlation\",\n      \"pmids\": [\"31448673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Desmoglein 2 (Dsg2) overexpression displaces CAV1, EGFR, and c-Src from light-density lipid raft fractions. CAV1 functions as part of a lipid raft signaling platform: perturbation of lipid rafts (by MβCD cholesterol chelation) shifts CAV1, c-Src, and EGFR out of rafts and activates downstream signaling. Dsg2 stimulates EGFR activation and cell proliferation/migration through a c-Src and CAV1-dependent mechanism using lipid rafts.\",\n      \"method\": \"Sucrose density fractionation, STED super-resolution imaging, Dsg2 knockdown/overexpression, MβCD treatment\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — orthogonal methods (fractionation, STED imaging, KD/OE) in single lab\",\n      \"pmids\": [\"26918609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CAV1 promotes HCC cell invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin pathway. CAV1 also acts as a mediator between hyperactive ERK1/2 signaling and transcription of MMP-7, identifying MMP-7 as a novel downstream target of CAV1.\",\n      \"method\": \"CAV1 overexpression and stable knockdown, in vitro invasion assays, in vivo xenograft and lung metastasis models, tissue microarray immunohistochemistry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with in vitro and in vivo readouts in single lab, pathway placement by downstream target identification\",\n      \"pmids\": [\"25180681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTBP3 interacts with the CU-rich region of the CAV1 gene to downregulate CAV1α expression via alternative splicing. Knockdown of CAV1α abrogated the reduction of FAK and Src phosphorylation induced by PTBP3 knockdown, placing CAV1α downstream of PTBP3 in a gastric cancer metastasis pathway.\",\n      \"method\": \"RNA immunoprecipitation (RIP), dual-luciferase reporter assays, PTBP3 overexpression/knockdown, xenotransplant mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA-protein interaction by RIP, reporter assays, and in vivo confirmation in single lab\",\n      \"pmids\": [\"29752441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A de novo heterozygous frame-shift mutation in CAV1 (p.Phe160X) causes a severe neonatal progeroid and lipodystrophy syndrome. Western blotting of patient fibroblasts showed significantly decreased wild-type CAV1 protein, demonstrating a loss-of-function mechanism. RNA sequencing showed dysregulation of pathways related to apoptosis, DNA repair/replication, and mitochondrial function, and significant down-regulation of known CAV1 interaction partners.\",\n      \"method\": \"Whole-genome sequencing, RNA-seq, western blotting of patient fibroblasts\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cells with protein-level confirmation and transcriptome analysis, single patient/lab\",\n      \"pmids\": [\"26176221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CAV1 knockout mice exhibit elevated intraocular pressure and reduced conventional outflow facility. CAV1 deficiency (and loss of CAV2) results in increased eNOS activity, as evidenced by increased eNOS, eNOS-phospho Ser1177, Akt, and nitrotyrosine, and decreased eNOS-phospho Thr495 levels. The IOP elevation may be mediated by increased tyrosine nitration of protein kinase K and impairment of its activity.\",\n      \"method\": \"CAV1 KO mouse model, rebound tonometry, western blot, topical NOS inhibitor/donor pharmacology, perfusion outflow facility measurement\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined physiological phenotype and biochemical pathway analysis, single lab\",\n      \"pmids\": [\"27228562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CAV1 deletion in mice impairs hematopoietic stem cell (HSC) function. Cav-1-/- mice show increased numbers of LSK cells and LT-HSCs with age, but LT-HSCs have reduced self-renewal capacity in vitro and fail to reconstitute hematopoiesis in competitive transplantation assays. CAV1 deletion disrupts quiescence of LSKs and promotes cell cycle progression through G2/M phase.\",\n      \"method\": \"Cav-1 KO mouse model, FACS analysis, in vitro clonogenic assay, in vivo competitive transplantation, cell cycle analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple functional readouts (transplantation, clonogenic assay, cell cycle) in single lab\",\n      \"pmids\": [\"24675458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CAV1 deficiency activates JNK-associated signaling (MKK7/JNK pathway) in vascular smooth muscle cells. Cav-1-/- in ApoE-/- mice attenuated high-fat diet-induced atherosclerotic lesions, reduced macrophage content and pro-inflammatory cytokines, inactivated IKKβ/p65/IκBα signaling, and reduced MKK7/JNK activity. In vitro, JNK activation abolished the anti-atherosclerotic effects of CAV1 knockdown in ox-LDL-treated VSMCs, placing CAV1 upstream of JNK in atherosclerosis.\",\n      \"method\": \"Cav-1-/- ApoE-/- mouse model, western blot, RT-qPCR, Oil Red O staining, JNK activator rescue in vitro\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with genetic rescue experiment in vitro establishing pathway position, single lab\",\n      \"pmids\": [\"29746866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IFITM1 promotes colorectal cancer cell invasion with CAV1 acting as a downstream target. Knockdown of CAV1 abrogated the siIFITM1-mediated inhibition of cell invasion in CRC cells, placing CAV1 downstream of IFITM1 in invasion regulation.\",\n      \"method\": \"IFITM1 overexpression/knockdown, CAV1 knockdown epistasis experiment, cell migration/invasion assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single epistasis experiment (CAV1 KD rescue) with invasion assay, single lab, limited mechanistic detail\",\n      \"pmids\": [\"26259513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In colorectal cancer, CD26 promotes metastasis through upregulation of MMP1; overexpression of CAV1 abrogated CD26-regulated MMP1 induction in CRC cell lines, placing CAV1 as a negative regulator of MMP1 expression downstream of CD26 signaling.\",\n      \"method\": \"CD26 overexpression/repression, CAV1 overexpression epistasis, genome-wide mRNA expression array, qPCR, in vivo mouse models\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single epistasis experiment with limited mechanistic detail on the CAV1-MMP1 interaction, single lab\",\n      \"pmids\": [\"35163100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Biallelic CAV1 null variants (homozygous loss-of-function) cause congenital generalized lipodystrophy (CGL3). Patient fibroblasts show complete loss of caveolae, absent caveolin-1 protein, and concomitant loss of caveolin-2 and cavin-1 partners, demonstrating that CAV1 is required for caveolae formation and for stability of its partner proteins CAVIN1 and CAV2. Patient fibroblasts also displayed insulin resistance, increased oxidative stress, and premature senescence.\",\n      \"method\": \"Next-generation sequencing, western blotting of patient fibroblasts, electron microscopy of caveolae, clinical/metabolic phenotyping\",\n      \"journal\": \"European journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cellular studies with EM confirmation of caveolae loss and protein-level analysis, replicated across two independent patients with different CAV1 null variants\",\n      \"pmids\": [\"34643546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAV1 marks intraluminal vesicles destined for migrasomes, co-localizing with Rab10. Transport of Rab10-CAV1 vesicles to migrasomes requires the motor protein Myosin Va and adaptor proteins RILPL2. Phosphorylation of Rab10 by the kinase LRRK2 regulates this transport process. CSF-1 is transported to migrasomes via this CAV1-dependent mechanism to foster monocyte-macrophage differentiation.\",\n      \"method\": \"Live imaging, co-immunoprecipitation, dominant-negative/knockdown experiments for Myosin Va and RILPL2, LRRK2 kinase assay/inhibition, wound healing macrophage differentiation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, imaging, genetic knockdown of motor/adaptor, kinase regulation) identifying a complete transport pathway with functional physiological readout\",\n      \"pmids\": [\"39008679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Rare variants in CAV1/CAV2 enhancers are enriched in ALS patients. Patient-derived enhancer mutations reduce CAV1/CAV2 expression and disrupt membrane lipid rafts (MLRs). CRISPR-Cas9 perturbation proximate to a patient mutation was sufficient to reduce CAV1/CAV2 expression in neurons, establishing a loss-of-function mechanism for CAV1 in ALS via disruption of MLRs.\",\n      \"method\": \"Rare variant burden analysis, patient-derived cell studies, CRISPR-Cas9 perturbation in neurons, MLR functional assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR functional validation in neurons plus patient-derived cellular phenotype, replicated in independent cohort\",\n      \"pmids\": [\"33264630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ABCA1 upregulation in Schlemm's canal endothelial cells decreases CAV1 expression (~0.56-fold) and increases eNOS expression and NO production, reducing transendothelial resistance. Conversely, ABCA1 downregulation increases CAV1 expression and decreases eNOS/NO. This establishes that CAV1 negatively regulates eNOS/NO signaling in the aqueous humor outflow pathway.\",\n      \"method\": \"ABCA1 agonist (GW3965) treatment, lentiviral ABCA1 shRNA knockdown, western blot, transendothelial electrical resistance measurement, NO concentration measurement, intracameral injection in vivo\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (gain and loss of ABCA1 function) with consistent CAV1/eNOS reciprocal changes, confirmed in vivo, single lab\",\n      \"pmids\": [\"32428234\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CAV1 (Caveolin-1) is an integral membrane protein that scaffolds caveolae microdomains; it acts as a platform for lipid raft-dependent signaling (regulating EGFR/c-Src, eNOS, JNK, and Wnt/β-catenin pathways), mediates autophagic self-degradation via a CAVIN1-LC3B axis controlled by AMPK-MTOR-PIK3C3, promotes autophagy under oxidative stress through Y14-phosphorylation-dependent interaction with the BECN1/VPS34 complex, traffics intraluminal vesicles to migrasomes via a Rab10/Myosin Va/RILPL2/LRRK2-regulated pathway, and is required for caveolae biogenesis and stabilization of its partners CAV2 and CAVIN1, with loss-of-function causing lipodystrophy, impaired hematopoietic stem cell quiescence, and elevated intraocular pressure.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CAV1 (Caveolin-1) is an integral membrane protein required for caveolae biogenesis that organizes lipid raft microdomains and serves as a scaffold coupling membrane organization to multiple signaling pathways [#3, #12]. Its essential structural role is established by biallelic null variants causing congenital generalized lipodystrophy, in which patient fibroblasts lose caveolae entirely, lack caveolin-1 protein, and show concomitant loss of its partners CAV2 and CAVIN1, demonstrating that CAV1 is required for caveolae formation and for stabilization of these partner proteins [#12]; a de novo frame-shift mutation similarly causes a neonatal progeroid/lipodystrophy syndrome via loss of function [#6]. At the membrane, CAV1 co-resides with c-Src and EGFR in cholesterol-dependent lipid rafts, and disrupting raft integrity displaces these components and modulates downstream signaling [#3]. CAV1 negatively regulates endothelial eNOS/NO signaling, with its loss elevating eNOS activity in contexts of intraocular pressure and aqueous outflow [#7, #15], and it constrains JNK and NF-kB inflammatory signaling in vascular smooth muscle during atherosclerosis [#9]. CAV1 also participates in autophagy: phosphorylation at tyrosine-14 enables its scaffolding-domain-dependent interaction with the BECN1/VPS34 complex to promote autophagosome formation under oxidative stress, an interaction reversed by the phosphatase PTPN1 [#1], while CAV1 itself is turned over by autophagy through a CAVIN1-LC3B axis under control of the AMPK-MTOR-PIK3C3 pathway [#2]. In cancer, CAV1 acts as a context-dependent regulator of invasion and EMT, driving HCC metastasis via Wnt/beta-catenin and ERK-dependent MMP-7 induction [#4] and functioning as a transcriptional target and effector in other tumor pathways [#0, #5]. More recently, CAV1 was found to mark intraluminal vesicles delivered to migrasomes via a Rab10/Myosin Va/RILPL2 transport pathway regulated by LRRK2 phosphorylation of Rab10 [#13]. CAV1 loss also disrupts hematopoietic stem cell quiescence [#8] and is linked through enhancer variants to ALS via membrane lipid raft disruption [#14].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established CAV1 as a transcriptionally regulated effector with a defined role in the EMT/oncogenic program, linking it to Snail/E-cadherin control of anchorage-independent growth.\",\n      \"evidence\": \"ChIP, shRNA knockdown, re-expression rescue, and nude mouse xenografts in Ewing's sarcoma cells\",\n      \"pmids\": [\"17047056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how CAV1 mechanistically represses Snail\", \"Tumor-type-specific; does not establish a general CAV1 EMT mechanism\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined CAV1 as a positive driver of invasion and EMT through Wnt/beta-catenin and ERK-MMP-7 signaling, contrasting with its tumor-suppressive role in other contexts.\",\n      \"evidence\": \"Gain/loss-of-function with in vitro invasion and in vivo metastasis models in HCC\",\n      \"pmids\": [\"25180681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CAV1 couples to Wnt/beta-catenin not resolved\", \"Reconciliation of pro- vs anti-oncogenic roles not addressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed CAV1 is required to maintain hematopoietic stem cell quiescence, expanding its role beyond signaling into stem cell biology.\",\n      \"evidence\": \"Cav1 KO mice with competitive transplantation, clonogenic assays, and cell cycle analysis\",\n      \"pmids\": [\"24675458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between CAV1 and quiescence machinery undefined\", \"Caveolae dependence of the HSC phenotype not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Positioned CAV1 within cholesterol-dependent lipid rafts as a scaffold co-organizing c-Src and EGFR, mechanistically tying membrane raft integrity to downstream signaling activation.\",\n      \"evidence\": \"Sucrose density fractionation, STED imaging, and MbetaCD cholesterol depletion with Dsg2 manipulation\",\n      \"pmids\": [\"26918609\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CAV1-EGFR/c-Src binding not distinguished from co-residence\", \"Does not establish stoichiometry or scaffolding domain requirement\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated CAV1 negatively regulates eNOS/NO signaling in the conventional outflow pathway, mechanistically connecting CAV1 loss to elevated intraocular pressure.\",\n      \"evidence\": \"Cav1 KO mice with tonometry, outflow facility measurement, NOS pharmacology, and eNOS phospho-state western blots\",\n      \"pmids\": [\"27228562\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The proposed protein kinase K nitration mechanism is correlative\", \"Cell type responsible for outflow phenotype not pinpointed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a phospho-switch controlling CAV1's autophagic function, where Y14 phosphorylation enables scaffolding-domain binding to BECN1/VPS34 to drive autophagy under oxidative stress.\",\n      \"evidence\": \"Reciprocal Co-IP, Y14 phospho-mutants, PTPN1 phosphatase overexpression, and Cav1 KO mouse stroke model with LC3 imaging\",\n      \"pmids\": [\"28542134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase phosphorylating CAV1-Y14 in this context not identified\", \"Structural basis of the scaffolding-domain/BECN1 interaction not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed CAV1 upstream of JNK and NF-kB inflammatory signaling in vascular smooth muscle, defining its anti-atherosclerotic role through pathway-position rescue.\",\n      \"evidence\": \"Cav1-/- ApoE-/- mice with JNK activator rescue in ox-LDL-treated VSMCs\",\n      \"pmids\": [\"29746866\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between CAV1 and MKK7/JNK not shown\", \"Whether effect requires caveolae not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed CAV1alpha isoform expression is controlled post-transcriptionally by PTBP3-mediated alternative splicing, placing a specific CAV1 isoform downstream in FAK/Src-driven metastasis.\",\n      \"evidence\": \"RNA immunoprecipitation, dual-luciferase reporters, and xenotransplant in gastric cancer\",\n      \"pmids\": [\"29752441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional difference between CAV1 isoforms not mechanistically dissected\", \"How CAV1alpha modulates FAK/Src unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the autophagic turnover route of CAV1 itself, showing the AMPK-MTOR-PIK3C3 pathway controls CAV1 degradation via a CAVIN1-LC3B axis to regulate caveolae abundance and LDL transcytosis.\",\n      \"evidence\": \"Autophagy flux assays, AMPK-MTOR inhibition, CAV1 manipulation, LDL transcytosis assays, and gestational diabetes patient tissue\",\n      \"pmids\": [\"31448673\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CAVIN1-LC3B binding not biochemically resolved\", \"Single-lab functional dissection\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked CAV1 loss-of-function to ALS through enhancer variants that reduce CAV1/CAV2 expression and disrupt membrane lipid rafts.\",\n      \"evidence\": \"Rare variant burden analysis, patient-derived cells, and CRISPR-Cas9 enhancer perturbation in neurons\",\n      \"pmids\": [\"33264630\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream neuronal MLR targets mediating ALS pathology undefined\", \"Causal mutation effect inferred from proximate CRISPR edit\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reinforced CAV1's reciprocal regulation of eNOS/NO in Schlemm's canal endothelium, showing ABCA1 modulates outflow resistance by tuning CAV1 levels.\",\n      \"evidence\": \"Bidirectional ABCA1 manipulation with TEER, NO measurement, and in vivo intracameral injection\",\n      \"pmids\": [\"32428234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ABCA1 controls CAV1 expression not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established CAV1 as strictly required for caveolae biogenesis and for stability of CAV2 and CAVIN1, with biallelic null variants causing congenital generalized lipodystrophy.\",\n      \"evidence\": \"NGS, western blotting of patient fibroblasts, and electron microscopy of caveolae across two independent patients\",\n      \"pmids\": [\"34643546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of insulin resistance and premature senescence downstream of caveolae loss not dissected\", \"Order of partner destabilization not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a novel CAV1 trafficking role, marking intraluminal vesicles delivered to migrasomes via a Rab10/Myosin Va/RILPL2 pathway under LRRK2 control to drive macrophage differentiation.\",\n      \"evidence\": \"Live imaging, Co-IP, knockdown of motor/adaptor proteins, LRRK2 kinase assays, and macrophage differentiation readouts\",\n      \"pmids\": [\"39008679\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CAV1 selects intraluminal vesicle cargo not defined\", \"Relationship of this trafficking route to canonical caveolae unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying basis for CAV1's opposing context-dependent roles — pro- versus anti-tumorigenic, and how its scaffolding, autophagy, eNOS regulation, and migrasome trafficking functions interrelate at the molecular level — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model reconciling scaffolding-domain interactions across partners\", \"Determinants of tissue/context-specific CAV1 function not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7, 9, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 12]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 7, 9, 15]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\"caveolae\"],\n    \"partners\": [\"CAV2\", \"CAVIN1\", \"BECN1\", \"PTPN1\", \"EGFR\", \"SRC\", \"RAB10\", \"LC3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}