Caveolin-3 is the muscle-enriched caveolin isoform and an oligomeric component of the caveolar coat at the sarcolemma. Together with cavins, it organizes membrane microdomains and coordinates recruitment and trafficking of selected proteins. Its interactions with dysferlin and MG53 connect caveolar organization to muscle membrane repair. Channel-specific assemblies regulate calcium currents and potassium-channel surface turnover, including recruitment of NEDD4-2 to hERG. Disruption of caveolin-3 abundance or trafficking can impair muscle membrane organization and cause caveolinopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi localization accompanies caveolin trafficking and is pronounced for several CAV3 mutants. Reason: The UniProt location mapping is compatible with passage through the Golgi. In the accessible study of human myopathy-associated constructs, wild-type CAV3 mainly reaches the cell surface whereas several mutants accumulate with GM130. Golgi accumulation is therefore retained as a trafficking or variant-dependent location, without making it the principal site of normal CAV3 function. Supporting Evidence: |
| GO:0001666 response to hypoxia | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat-derived hypoxia-response assignment requires its specific donor experiment. Reason: This automatic orthology transfer names rat CAV3. Cardiac ischemia/reperfusion protection is supported separately, but ischemia combines oxygen deprivation with other changes and does not by itself identify the hypoxia-specific experiment underlying this row. That primary donor assay has not been verified; the transfer is neither rejected nor treated as established human hypoxia regulation. |
| GO:0002027 regulation of heart rate | IMP PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | MARK AS OVER ANNOTATED | Summary: The cited study does not establish CAV3-dependent control of heart rate. Reason: The complete primary Results and Discussion distinguish mutant late sodium current in HEK293 cells from the proposed pacemaking mechanism. The heart-rate argument concerns bradycardia in T78M carriers, but T78M was not electrophysiologically tested in this paper; its proposed effect on sinus rate is extrapolated from a separate SCN5A mutation. The measured F97C/S141R channel effects do not establish that extrapolation. This source-specific physiological extension is excessive, without asserting that CAV3 can never influence heart rate or disputing the molecular current measurements. Supporting Evidence: |
| GO:0002931 response to ischemia | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAV3 contributes to a context-dependent cardiac response to ischemia. Reason: The conserved inference is supported by mouse cardiac-specific Cav3 overexpression and knockout comparisons, rat cardiomyocyte experiments, and infarct-size and signaling measurements after ischemia/reperfusion. These establish a protective response in the tested models, not a universal benefit of increased CAV3 dosage or a human therapeutic effect. Supporting Evidence: |
| GO:0005246 calcium channel regulator activity | IDA PMID:21084288 Caveolin-3 regulates protein kinase A modulation of the Ca(V... | ACCEPT | Summary: CAV3 regulates CaV3.2 channel activity and its PKA-dependent modulation. Reason: The primary study expresses human caveolin-3 with human CaV3.2 or CaV3.1 channels in HEK293 cells and also tests mouse cardiomyocytes. CAV3 associates with both channels but reduces CaV3.2 current without reducing its measured surface abundance; CaV3.1 current is not similarly suppressed. Knockdown removes cAMP-dependent augmentation without simply lowering basal T-type current. This supports channel regulator activity with channel- and signaling-context specificity. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:10988290 Caveolin-3 directly interacts with the C-terminal tail of be... | MODIFY | Summary: CAV3 binds the dystroglycan-containing protein assembly through beta-dystroglycan. Reason: The cited study identifies the beta-dystroglycan tail as the CAV3 interaction site within the dystrophin-associated assembly, using colocalization, cofractionation, coimmunoprecipitation and tail-binding experiments. The existing protein-containing complex binding annotation from the same source supplies a more informative description than generic binding. This refinement does not imply an obligatory stable dystrophin-complex subunit, a solved adaptor bridge, or a structurally verified WW domain in CAV3. Proposed replacements: protein-containing complex binding Supporting Evidence: PMID:10988290 directly interacts with beta-dystroglycan |
| GO:0005515 protein binding | IPI PMID:19726876 Human PTRF mutations cause secondary deficiency of caveolins... | KEEP AS NON CORE | Summary: CAV3 associates with CAVIN1/PTRF in caveolar membrane organization. Reason: Selected full primary Methods and Results from the authenticated fuller artifact describe sequence-verified tagged human CAV3 with wild-type or mutant PTRF, reciprocal immunoprecipitation, and membrane localization. The human disease in that paper is caused by PTRF variants and produces secondary caveolin deficiency; it must not be reassigned to CAV3. The canonical abstract-only cache remains unchanged. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:24567387 MURC/Cavin-4 facilitates recruitment of ERK to caveolae and ... | KEEP AS NON CORE | Summary: CAV3 associates with CAVIN1 and CAVIN2 in the cavin-containing membrane assembly. Reason: The exact two source partners are preserved. The paper reports bimolecular fluorescence complementation among CAV3 and the cavins in cardiomyocytes, while its coimmunoprecipitation and perturbation experiments distinguish individual interactions. This supports a qualified membrane-complex association, not a solved direct interface or transfer of the partners' enzymatic functions. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:24567387 MURC/Cavin-4 facilitates recruitment of ERK to caveolae and ... | KEEP AS NON CORE | Summary: CAV3 associates with CAVIN4/MURC. Reason: CAVIN4 and CAV3 coimmunoprecipitate in transfected COS cells, and the paper describes complementation in cardiomyocytes. CAV3 depletion also reduces membrane localization of CAVIN4. These are source-specific association and recruitment observations; they do not mean that all CAVIN4-dependent ERK effects are intrinsic CAV3 activities. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:25556234 New host factors important for respiratory syncytial virus (... | KEEP AS NON CORE | Summary: A reported interaction links CAV3 to respiratory syncytial virus matrix protein. Reason: The exact viral M partner P0DOE7 is independently present in the reviewed UniProt interaction record. The available primary Discussion explicitly reports interactions with all three caveolins, while the abstract and functional replication findings emphasize caveolin-2. The exact CAV3 assay controls were not independently reconstructed; the qualified interaction is retained without adding a viral assembly function for CAV3. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:26497963 The coiled-coil domain of MURC/cavin-4 is involved in membra... | KEEP AS NON CORE | Summary: CAVIN4 interaction influences CAV3 membrane trafficking. Reason: The complete abstract reports that a CAVIN4 coiled-coil deletion still binds CAV3 while altering its distribution and abundance. This supports the specific interaction, not the inference that the deleted domain is the binding interface or that CAV3 performs CAVIN4-dependent signaling. The full experiment remains unavailable in the canonical cache. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: BioPlex reports a CAV3–CAVIN1 association. Reason: The exact CAVIN1 partner agrees with reviewed UniProt and targeted reciprocal immunoprecipitation in the PTRF study. The BioPlex Methods describe tagged affinity-purification mass spectrometry and network filtering; those global controls are not claimed as individually inspected validation of this edge. Retain the corroborated association as non-core generic binding. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: HuRI reports a CAV3–RBFA interaction. Reason: The exact RBFA accession is present in reviewed UniProt as well as the source annotation. The primary HuRI Methods describe multiple yeast two-hybrid configurations and repeated pair testing. The exact target pair table and a physiological RBFA–CAV3 mechanism were not independently verified; database corroboration supports a qualified non-core interaction, not mitochondrial or ribosome-related function for CAV3. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: HuRI reports a CAV3–PBX3 interaction. Reason: The exact PBX3 accession is corroborated in the reviewed UniProt interaction record. HuRI provides a binary interaction-screen context, but its global orthogonal validation statistics do not establish that this individual pair was independently validated. Retain the reported interaction without transferring PBX3 transcriptional activity to CAV3. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: The interaction map reports CAV3 binding to COL25A1. Reason: The exact COL25A1 accession also occurs in the reviewed UniProt interaction record. The available abstract describes an interaction-mapping study, not a demonstrated CAV3 role in neurodegeneration. The target table and assay configuration were not independently recovered, so the qualified association is non-core and makes no disease-mechanism claim. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: A second BioPlex map supports the CAV3–CAVIN1 association. Reason: This specific partner is corroborated by reviewed UniProt and targeted CAVIN1/CAV3 experiments. The cached article contains only partial HTML narrative despite its body-available flag; complete target controls were not read from this cache. Retain the association while distinguishing it from the paper's global cell-line comparisons. |
| GO:0005783 endoplasmic reticulum | IDA PMID:22792322 The E3-ubiquitin ligase TRIM50 interacts with HDAC6 and p62,... | UNDECIDED | Summary: CAV3 localization to endoplasmic reticulum is not resolved by the inspected TRIM50 evidence. Reason: The retrieved paper and selected proteomics and localization Methods focus on TRIM50, and the CAV3-specific experiment or supplemental observation behind this experimental annotation has not been located. This is an access/provenance limit, not proof of wrong-gene attribution; the curator may have assessed additional material. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | ACCEPT | Summary: Human CAV3 localizes at the cardiomyocyte plasma membrane. Reason: The original study stained human right-ventricular myocardial sections and reported sarcolemmal colocalization of CAV3 and Nav1.5. Independent imaging of human CAV3 constructs also distinguishes surface-localized wild type from intracellularly retained variants. This location is supported independently of the historical long-QT interpretation. |
| GO:0005886 plasma membrane | IDA PMID:20472890 Differential effects of myopathy-associated caveolin-3 mutan... | ACCEPT | Summary: Wild-type CAV3 reaches the plasma membrane. Reason: The primary imaging study distinguishes surface-localized wild-type CAV3 from several myopathy-associated variants retained in intracellular compartments. Plasma membrane localization is a central feature of the normal protein. Supporting Evidence: |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic plasma-membrane assignment is biologically supported. Reason: The mouse and rat orthology and location-vocabulary sources agree with direct human-construct imaging and caveolar membrane biology. No target-specific loss or divergent localization is indicated. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: The manually transferred rat plasma-membrane localization is conserved. Reason: This curator-reviewed orthology transfer agrees with direct localization of human CAV3 at the cell surface and the sarcolemma. It is not treated as unsupported merely because the originating experiment was in rat. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5263633 | ACCEPT | Summary: The membrane-repair assembly places CAV3 at the plasma membrane. Reason: The complete Reactome event identifies the human DYSF–CAV3–TRIM72 assembly at the plasma membrane. This location also has independent CAV3 imaging support. The pathway summary alone is not used to infer a new detailed repair process annotation. |
| GO:0005901 caveola | IBA GO_REF:0000033 | ACCEPT | Summary: Caveolar localization is a conserved core property of caveolins. Reason: The PAINT assertion represents inheritance from the curated ancestral node, not a vote among pairwise donors. CAV3-specific caveolar localization, cavin associations, and changes in caveola abundance support retention of the inherited location. |
| GO:0005901 caveola | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic caveolar localization agrees with CAV3 membrane organization. Reason: The combined orthology and vocabulary mapping is supported by CAV3-dependent caveola abundance and its association with caveolar cavins. The term is retained as a principal location. |
| GO:0005901 caveola | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse-derived caveolar localization is conserved in CAV3. Reason: The manually reviewed orthology transfer agrees with the human muscle/cavin evidence and experimental caveola measurements. No biological discrepancy justifies rejecting it. |
| GO:0005925 focal adhesion | IBA GO_REF:0000033 | UNDECIDED | Summary: The focal-adhesion PAINT assignment needs a CAV3-specific or ancestral-node assessment. Reason: The source is a curated phylogenetic inference, not a weak transfer merely because its listed experimental proteins include CAV1. The accessible CAV3 studies establish sarcolemmal and caveolar localization but do not resolve the focal-adhesion observation or exact ancestral-node scope. There is insufficient evidence either to reject the node placement or to identify this as a core CAV3 location. |
| GO:0006641 triglyceride metabolic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Raised circulating triglyceride does not establish a CAV3 triglyceride-metabolic step. Reason: The traced mouse knockout study measures fasting serum triglyceride concentrations and muscle insulin signaling. It does not identify triglyceride synthesis, breakdown or flux performed or organized by CAV3. GO:0006641 concerns triglyceride chemical reactions and pathways; assigning that process from the concentration phenotype is excessive. Supporting Evidence: |
| GO:0006897 endocytosis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CAV3 can regulate membrane internalization in particular cargo contexts. Reason: The manually transferred mouse endocytosis assignment is consistent with direct hERG surface-turnover experiments and CAV3-dependent receptor distribution. This does not establish that CAV3 promotes every endocytic route or that every caveola is constitutively internalized. |
| GO:0007009 plasma membrane organization | ISS GO_REF:0000024 | ACCEPT | Summary: CAV3 organizes specialized plasma-membrane domains. Reason: CAV3-dependent caveola abundance and recruitment of cavin-containing assemblies directly support the broader membrane-organization role. The core summary uses the more specific existing caveola-assembly process rather than adding a redundant new assertion. |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | IEA GO_REF:0000107 | UNDECIDED | Summary: The positive direction of the rat-derived cytosolic calcium response needs its donor context. Reason: CAV3 regulates calcium channels, but the directly inspected CaV3.2 work shows both inhibition of basal current under overexpression and a requirement for PKA-mediated enhancement. Those observations cannot substitute for the particular rat experiment supporting a positive cytosolic calcium-concentration effect. Supporting Evidence: |
| GO:0007204 positive regulation of cytosolic calcium ion concentration | ISS GO_REF:0000024 | UNDECIDED | Summary: The rat ISS calcium-concentration increase requires the original signaling experiment. Reason: This manual transfer is preserved, but the specific donor assay and stimulus have not been verified. Channel-specific and PKA-dependent CAV3 effects are compatible with either direction under different conditions; no direction is inferred solely from caveolar localization. Supporting Evidence: |
| GO:0007517 muscle organ development | TAS PMID:10988290 Caveolin-3 directly interacts with the C-terminal tail of be... | UNDECIDED | Summary: Muscle-organ development is not established by the accessible dystroglycan-binding evidence alone. Reason: The citation directly supports a CAV3–DAG1 interaction. Its full developmental evidence was not independently read, and a structural interaction or a muscular dystrophy phenotype does not automatically demonstrate work in organ development. The TAS assertion remains unresolved rather than being rejected on abstract-only evidence. Supporting Evidence: |
| GO:0008016 regulation of heart contraction | IMP PMID:17275750 Novel mechanism for sudden infant death syndrome: persistent... | UNDECIDED | Summary: The inference from altered late sodium current to regulation of heart contraction remains uncertain. Reason: The complete source supports mutant-dependent current modulation in a noncardiac expression system and reports an anonymous sudden-infant-death cohort. A contraction mechanism could follow from altered electrical activity, but the physiological connection and causal clinical interpretation remain unresolved. This is not an absolute requirement for a whole-heart assay: the limitation is that the specific contraction-regulatory step is not established by the inspected evidence. The molecular current result is retained independently. Supporting Evidence: |
| GO:0008104 intracellular protein localization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CAV3 influences the intracellular distribution of associated membrane proteins. Reason: The broad mouse transfer is supported by CAV3-dependent membrane recruitment of CAVIN4 and changes in surface hERG and receptor abundance. These are partner-specific localization effects, not general intracellular transport machinery. |
| GO:0008284 positive regulation of cell population proliferation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAV3 promotes laminin-dependent proliferation in a rat folliculostellate-cell model. Reason: The primary study tests CAV3-specific siRNA in anterior-pituitary folliculostellate cells from S100b-GFP rats on laminin. Proliferation falls with CAV3 depletion in an integrin/MAPK/cyclin-D1 context. Selected primary Methods include nonsilencing-siRNA controls. This supports the existing positive-regulation transfer as a context-dependent non-core process; it is not a direct human assay or a general proliferative activity of muscle CAV3. Supporting Evidence: PMID:21508095 the proliferation of FS cells was inhibited |
| GO:0009986 cell surface | IEA GO_REF:0000107 | ACCEPT | Summary: CAV3 is localized at the cell surface. Reason: The rat-derived location is consistent with direct surface localization of wild-type human CAV3 constructs and its principal sarcolemmal caveolar role. This does not imply an extracellularly secreted protein. |
| GO:0010614 negative regulation of cardiac muscle hypertrophy | IMP PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | KEEP AS NON CORE | Summary: CAV3 overexpression can restrain agonist-induced cardiomyocyte hypertrophy. Reason: The complete abstract specifies wild-type human CAV3 and a scaffolding-domain deletion expressed in rat neonatal cardiomyocytes. Cell size, protein synthesis, fetal-gene expression, and sarcomeric remodeling distinguish wild-type inhibition from the mutant response under phenylephrine or endothelin stimulation. Retain this experimental regulatory phenotype as contextual rather than a universal dosage effect. Supporting Evidence: |
| GO:0014704 intercalated disc | IEA GO_REF:0000107 | UNDECIDED | Summary: Intercalated-disc localization requires the precise rat localization evidence. Reason: CAV3 association with connexin43 does not by itself establish residence at an intercalated disc, since a binding interaction and an anatomical compartment are distinct assertions. The specific donor localization experiment has not been verified. Supporting Evidence: |
| GO:0014819 regulation of skeletal muscle contraction | IMP PMID:17524427 A novel in-frame deletion in the CAV3 gene in a Korean patie... | UNDECIDED | Summary: The human rippling-muscle report does not resolve a normal contraction-regulatory mechanism from the abstract alone. Reason: The available abstract describes a family and an in-frame CAV3 deletion associated with rippling muscle disease. Its full physiological observations and mechanistic interpretation are unavailable; the experimental annotation is retained as unresolved, without claiming misattribution or treating a clinical phenotype as a direct biochemical assay. Supporting Evidence: |
| GO:0016010 dystrophin-associated glycoprotein complex | IDA PMID:10988290 Caveolin-3 directly interacts with the C-terminal tail of be... | KEEP AS NON CORE | Summary: CAV3 can associate with dystrophin-glycoprotein-complex partners without being an obligatory stable core subunit. Reason: The official AmiGO definition of GO:0016010 explicitly includes "dystrophin, sarcoglycans, dystroglycan, dystrobrevins, syntrophins, sarcospan, caveolin-3, and NO synthase" among its components (https://amigo.geneontology.org/amigo/term/GO:0016010). The cited study supports beta-dystroglycan association. The separate purification study demonstrates separation from the stable purified complex and independent sarcolemmal localization; it does not test or exclude every transient association. Retain the broad ontology-defined localization non-core while distinguishing it from obligatory stable integral membership. This judgment concerns the biology and the verified term definition, not the inert relationship column. Supporting Evidence: PMID:9607328 not an integral component of the dystrophin-glycoprotein complex |
| GO:0016020 membrane | IEA GO_REF:0000107 | ACCEPT | Summary: CAV3 is a membrane-associated caveolin. Reason: The mouse orthology transfer agrees with direct human-construct membrane localization. The broad membrane location is correct, while the core summary identifies caveolae and sarcolemma more specifically. Supporting Evidence: |
| GO:0017080 sodium channel regulator activity | IDA PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | KEEP AS NON CORE | Summary: Human CAV3 variants alter late Nav1.5 current in a heterologous system. Reason: Human CAV3 and human Nav1.5 were coexpressed in HEK293 cells. F97C and S141R increased late current while retaining channel coassociation; wild-type CAV3 did not measurably change current relative to vector. Retain the curated molecular association and variant-dependent modulation non-core. These experiments do not establish normal CAV3 sodium-channel regulation as a core physiological activity, nor do they determine native pacemaking or contraction effects. Supporting Evidence: PMID:17060380 gain-of-function increase in late sodium current |
| GO:0017080 sodium channel regulator activity | IMP PMID:17275750 Novel mechanism for sudden infant death syndrome: persistent... | KEEP AS NON CORE | Summary: Human CAV3 variants modulate late SCN5A current. Reason: Human CAV3-V5-6His constructs and human SCN5A Q1077del were expressed in HEK293 cells. V14L, T78M and L79R significantly increased late current; the smaller wild-type increase was not significant, and peak-current/gating changes were not significant. Retain the curated variant-dependent regulator finding non-core without treating it as evidence for a general wild-type activation mechanism or a core cardiac function. Supporting Evidence: |
| GO:0019870 potassium channel inhibitor activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The transferred inhibitor activity overstates the resolved hERG turnover mechanism. Reason: GO:0019870 does not require pore occlusion, but its molecular-function regulator and inhibitor ancestors (GO:0098772 and GO:0140678) require noncovalent target regulation without resulting covalent target modification. The resolved CAV3 mechanism recruits NEDD4-2 and causes hERG ubiquitination, internalization and loss of mature surface channels; disrupting the hERG PY motif eliminates the effect. This covalent-modification-dependent turnover mechanism supports adaptor and trafficking regulation rather than this channel-inhibitor MF. The lower whole-cell current and unchanged measured gating are consistent context, not a universal test excluding every inhibitory mechanism. Supporting Evidence: PMID:22879586 through reducing the hERG channel density |
| GO:0019870 potassium channel inhibitor activity | ISS PMID:22879586 Cell surface expression of human ether-a-go-go-related gene ... | MARK AS OVER ANNOTATED | Summary: Rat CAV3 supports hERG turnover rather than a demonstrated channel-inhibitory activity. Reason: The manual transfer traces to native rat/rabbit association and neonatal rat depletion experiments as well as heterologous hERG assays. Cav3 depletion increases current and slows labeled surface-channel internalization; the PY-motif and NEDD4-2 experiments identify recruitment, ubiquitination and degradation as the mechanism. GO:0019870 inherits the noncovalent-regulation constraint of GO:0098772/GO:0140678, excluding regulation that results in covalent target modification. The supported turnover route therefore overstates this MF, without denying the potassium-current phenotype or imposing a pore-block requirement. Supporting Evidence: |
| GO:0019899 enzyme binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAV3 binds enzyme-containing signaling and trafficking assemblies. Reason: The broad rat-derived binding assignment is supported by coassociation with NEDD4-2 and its recruitment to the plasma membrane. It does not mean CAV3 itself is a ubiquitin ligase. A specific molecular adaptor role is summarized separately where recruitment and substrate turnover were tested. Supporting Evidence: |
| GO:0030018 Z disc | IEA GO_REF:0000107 | UNDECIDED | Summary: Z-disc localization is not resolved by the inspected caveolar and T-tubule observations. Reason: The specific rat donor image or localization assay has not been read. The cavin paper discusses registration of T tubules with Z lines, which is not sufficient by itself to identify CAV3 as a Z-disc component. Preserve the electronic source and leave the localization uncertain. Supporting Evidence: |
| GO:0030018 Z disc | ISS GO_REF:0000024 | UNDECIDED | Summary: The manually transferred rat Z-disc observation needs its primary localization context. Reason: A historical official donor graph links the location to a rat study, but its microscopy and structural interpretation were not inspected. Caveolar staining near a Z line is not automatically identical to Z-disc localization; no rejection is made without the underlying image and assay. |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited differentiation role is retained as a non-core process. Reason: PAINT records a curator's ancestral functional judgment across the caveolin family, rather than a transfer from the single rat expression experiment. CAV3's muscle developmental context is compatible with this broad role and no target-specific loss is established. Retain the inherited process with curator deference; the unreconstructed node analysis does not justify a narrower developmental mechanism. The separate rat IEA/ISS rows remain limited by their particular primary evidence. |
| GO:0030154 cell differentiation | IEA GO_REF:0000107 | UNDECIDED | Summary: The rat expression-based differentiation transfer remains unresolved. Reason: The historical official donor graph traces this assertion to PMID:16135403. Its complete abstract reports decreased CAV3 expression during dibutyryl-cAMP-induced astrocyte-like differentiation of rat C6 glioma cells. This is neither a muscle-differentiation assay nor evidence that expression annotations are inherently invalid. The complete experiments needed to assess CAV3's contribution to differentiation remain inaccessible; retain uncertainty for this specific transfer. Supporting Evidence: |
| GO:0030154 cell differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: The manual rat differentiation transfer remains limited by its specific donor source. Reason: The traced rat C6 glioma study measures caveolin expression during induced differentiation; it is distinct from the PAINT ancestral assertion. The accessible abstract establishes the experimental context but does not resolve a causal CAV3 differentiation mechanism, and the complete body is unavailable. Preserve this curator-assessed transfer without either rejecting it from an incomplete read or treating the PAINT row as verification of this particular experiment. Supporting Evidence: |
| GO:0030315 T-tubule | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: CAV3 is associated with the muscle T-tubule membrane system. Reason: The combined mouse/rat localization inference is consistent with the muscle caveolar literature and the cavin study's discussion of CAV3 staining registered with T tubules and Z lines. Retain the established muscle-membrane location without treating it as proof of a distinct T-tubule assembly mechanism or as the principal location in every muscle state. Supporting Evidence: |
| GO:0030315 T-tubule | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The rat T-tubule localization transfer is retained. Reason: The muscle-membrane localization is consistent with the accessible caveolar/cavin literature. The specific donor microscopy has not been reconstructed, so curator deference supports the established localization without extending it to a particular developmental or excitation-contraction mechanism. Supporting Evidence: |
| GO:0031116 positive regulation of microtubule polymerization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAV3 overexpression enhances the polymerized-tubulin fraction in rat vascular smooth muscle cells. Reason: The historical official graph identifies rat IMP evidence from PMID:16480946. Actual publisher Methods and Results describe adeno-Cav3 versus adeno-GFP in rat aortic vascular smooth muscle cells and an increased polymerized-tubulin fraction after overexpression. Retain the existing transfer as non-core with this gain-of-function context. The result does not establish intrinsic tubulin-polymerase activity, a direct human assay, or CAV3-specific attribution of every peptide/knockdown experiment in the abstract. Supporting Evidence: |
| GO:0031116 positive regulation of microtubule polymerization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The manual microtubule-polymerization transfer has a CAV3-specific rat experiment. Reason: The donor study explicitly tests adeno-Cav3 in rat vascular smooth muscle cells and reports increased polymerized tubulin relative to GFP control. It is not a CAV1-only experiment. Retain the curator's existing transfer non-core while limiting the conclusion to regulation in this overexpression model; the inaccessible remainder of the paper is not used to assign a CAV3-specific stathmin or knockdown mechanism. Supporting Evidence: |
| GO:0031579 membrane raft organization | ISS GO_REF:0000024 | ACCEPT | Summary: CAV3 organizes caveolar membrane domains. Reason: The mouse transfer agrees with the demonstrated CAV3 dependence of caveola abundance and cavin-containing membrane assemblies. Caveolae are specialized membrane domains; this broader organization annotation is retained while the core uses existing caveola assembly as its specific process. |
| GO:0031594 neuromuscular junction | IEA GO_REF:0000107 | UNDECIDED | Summary: Neuromuscular-junction localization requires its rat donor experiment. Reason: CAV3 is predominantly a muscle membrane protein, but muscle expression and association with signaling partners do not establish enrichment at the neuromuscular junction. The primary localization evidence behind this electronic transfer has not been verified. |
| GO:0031594 neuromuscular junction | ISS GO_REF:0000024 | UNDECIDED | Summary: The rat neuromuscular-junction localization transfer is unresolved. Reason: The curator-reviewed orthology source is preserved. Its specific junctional localization assay has not been read, and no absence of CAV3 from the junction is asserted from the available sarcolemmal studies. |
| GO:0031982 vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAV3 occurs in membrane-trafficking compartments. Reason: The broad vesicle location is compatible with CAV3-dependent internalization and intracellular redistribution in the receptor and hERG studies. It is retained as a trafficking-associated location, without equating every internal vesicle with a caveola. |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAV3 participates in protein assemblies. Reason: The broad rat-derived complex assignment agrees with cavin and channel-containing assemblies. It is correct but does not identify a single stoichiometrically defined complex or an additional molecular function. |
| GO:0033292 T-tubule organization | TAS PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | UNDECIDED | Summary: T-tubule organization is not verified by the accessible hypertrophy abstract. Reason: The cited study measures agonist-induced hypertrophic responses in rat cardiomyocytes expressing human CAV3 constructs. Its complete T-tubule evidence, if present, was not available for inspection. T-tubule localization and caveola abundance cannot substitute for a T-tubule-organization experiment. Supporting Evidence: |
| GO:0035995 detection of muscle stretch | IEA GO_REF:0000107 | UNDECIDED | Summary: The mouse-derived detection-of-stretch role needs the original mechanosensory assay. Reason: Caveolar membrane organization and membrane repair are compatible with mechanical-stress responses but do not alone identify the entity or step that detects stretch. The donor experiment behind this automatic transfer has not been verified. |
| GO:0035995 detection of muscle stretch | ISS GO_REF:0000024 | UNDECIDED | Summary: The manually transferred muscle-stretch detection assertion remains source-limited. Reason: The official mouse annotation graph provides a provenance lead, not a read primary assay. A structural contribution to membrane mechanics can be relevant, but the particular evidence for detection rather than downstream protection is needed before resolving this term. |
| GO:0038009 regulation of signal transduction by receptor internalization | IMP PMID:20472890 Differential effects of myopathy-associated caveolin-3 mutan... | KEEP AS NON CORE | Summary: CAV3-dependent receptor distribution modulates growth-factor signaling. Reason: The complete accessible primary narrative measures surface TrkA and EGF receptor abundance and downstream signaling with wild-type and mutant CAV3 constructs. Effects differ by variant and receptor. The term is retained for this trafficking/signaling context, without claiming CAV3 universally accelerates receptor internalization. Supporting Evidence: |
| GO:0042383 sarcolemma | IBA GO_REF:0000033 | ACCEPT | Summary: Sarcolemmal localization is a conserved core feature of CAV3. Reason: The PAINT inference is independently consistent with human muscle and human-construct localization. Inclusion of human CAV3 among the descendant evidence sources is expected in an IBA and is not circular support. |
| GO:0042383 sarcolemma | IDA PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | ACCEPT | Summary: CAV3 is a sarcolemmal membrane protein. Reason: The experimental annotation agrees with independent human muscle localization in the PTRF study and with the accepted muscle caveolar role. The accessible hypertrophy abstract does not reproduce the complete localization experiment, so the location is retained with curator deference and independent corroboration. |
| GO:0042383 sarcolemma | IDA PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | ACCEPT | Summary: CAV3 is a sarcolemmal protein in human muscle. Reason: Human right-ventricular sections in the sodium-channel study show sarcolemmal CAV3, and human muscle/cavin studies independently support this location. The human observations are separated from prior rat localization cited in the sodium paper. Frozen Limited long-QT validity does not undermine the cellular localization. |
| GO:0042383 sarcolemma | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic sarcolemmal location is correct. Reason: Mouse/rat orthology and UniProt location mapping agree with human muscle CAV3 staining. This is a principal physiological location rather than a default inferred from sequence alone. Supporting Evidence: |
| GO:0042391 regulation of membrane potential | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CAV3 regulates ion-channel behavior relevant to membrane potential. Reason: The curated ancestral assignment is consistent with CAV3 effects on sodium, calcium and hERG potassium channels. It does not claim that CAV3 conducts ions, and target inclusion among PAINT evidence is not circular. The broad electrical process is retained as a consequence of channel-regulatory activity. |
| GO:0042391 regulation of membrane potential | IDA PMID:21084288 Caveolin-3 regulates protein kinase A modulation of the Ca(V... | KEEP AS NON CORE | Summary: CAV3-dependent CaV3.2 current changes affect membrane excitability. Reason: Direct voltage-clamp experiments support regulation of a membrane conductance, with channel and signaling-context dependence. Retain the broad membrane-potential process without claiming a whole-animal action-potential phenotype or universal inhibition of calcium entry. Supporting Evidence: |
| GO:0042593 glucose homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse CAV3 supports insulin-dependent glucose homeostasis. Reason: Cav3-null mice show reduced insulin-stimulated muscle glucose uptake and impaired glucose tolerance. Re-expression restores muscle insulin signaling. These organismal and muscle endpoints support the existing glucose-homeostasis transfer as non-core, without assigning CAV3 glucose transport or insulin-receptor catalysis or claiming a direct human experiment. Supporting Evidence: PMID:15314230 decreased glucose uptake in skeletal muscles |
| GO:0042632 cholesterol homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The mouse knockout supports a non-core cholesterol-homeostasis phenotype. Reason: The donor study finds increased fasting total cholesterol in Cav3-null mice relative to controls. GO:0042632 concerns maintenance of cholesterol levels, so this supports the existing broad homeostasis transfer with curator deference. It does not identify a CAV3 cholesterol transporter, synthetic reaction or direct lipid-processing mechanism. Supporting Evidence: |
| GO:0043014 alpha-tubulin binding | IEA GO_REF:0000107 | UNDECIDED | Summary: The alpha-tubulin interaction needs its mouse donor binding assay. Reason: An official mouse annotation provides a provenance lead, but the underlying biochemical interaction has not been read. The PTRF mutant's colocalization with beta-tubulin in another study cannot validate CAV3 binding to alpha-tubulin. Supporting Evidence: |
| GO:0043409 negative regulation of MAPK cascade | IMP PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | KEEP AS NON CORE | Summary: Human CAV3 expression suppresses agonist-induced ERK signaling in rat cardiomyocytes. Reason: The complete abstract reports selective inhibition of ERK activation with wild-type human CAV3 compared with the scaffolding-domain deletion, without the same effect on JNK or p38. This supports a contextual negative MAPK regulation phenotype rather than intrinsic kinase or phosphatase activity. Supporting Evidence: |
| GO:0043409 negative regulation of MAPK cascade | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The mouse negative-MAPK transfer agrees with direct CAV3 perturbation evidence. Reason: The conserved direction is supported by the human-construct cardiomyocyte experiment and by the cavin paper's distinction between CAV3-dependent membrane organization and CAVIN4-driven agonist signaling. MAPK control is context dependent, so the process is retained as non-core. |
| GO:0044325 transmembrane transporter binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: CAV3 binds transmembrane ion channels. Reason: The PAINT molecular-function inference agrees with target-specific sodium-channel association and calcium-channel coimmunoprecipitation. The current human target in the ancestral evidence is valid descendant support, not circularity. Binding is retained separately from the more informative channel-regulation mechanisms. |
| GO:0044325 transmembrane transporter binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: The combined orthology assignment for transporter binding is supported. Reason: CAV3 associates with SCN5A and with CaV3.1/CaV3.2 channels. The term identifies the binding partner class; it does not imply every bound channel is regulated in the same direction. |
| GO:0044325 transmembrane transporter binding | IPI PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | KEEP AS NON CORE | Summary: CAV3 coassociates with the exact sodium-channel partner SCN5A. Reason: The original human-construct experiment recovered Nav1.5 with wild-type and mutant CAV3 using anti-CAV3 immunoprecipitation, with control IgG negative. Human ventricular sections also showed colocalization. This supports association, not a purified direct-binding interface; the mutant late-current effects were not explained by complete loss of coassociation. Supporting Evidence: |
| GO:0044325 transmembrane transporter binding | IPI PMID:21084288 Caveolin-3 regulates protein kinase A modulation of the Ca(V... | KEEP AS NON CORE | Summary: CAV3 binds CaV3.1 without the CaV3.2-like inhibitory phenotype. Reason: Coimmunoprecipitation in the primary study supports association with the exact CACNA1G partner. The same paper finds no comparable reduction in CaV3.1 current, demonstrating why binding should not be equated with inhibition. Supporting Evidence: |
| GO:0044325 transmembrane transporter binding | IPI PMID:21084288 Caveolin-3 regulates protein kinase A modulation of the Ca(V... | KEEP AS NON CORE | Summary: CAV3 associates with CaV3.2 through its N-terminal region. Reason: The source combines specific coimmunoprecipitation and GST-fragment binding with human constructs and functional current measurements. This supports the exact CACNA1H interaction. The separate calcium-channel regulator annotation captures the functional consequence. Supporting Evidence: |
| GO:0044877 protein-containing complex binding | IDA PMID:10988290 Caveolin-3 directly interacts with the C-terminal tail of be... | KEEP AS NON CORE | Summary: CAV3 binds a partner of the dystrophin-associated protein complex. Reason: The original experiment concerns beta-dystroglycan binding, membrane cofractionation and competition with dystrophin. This supports association with a protein-containing complex while the separate purification study limits interpretation as an obligatory stable core subunit. The existing broad binding term is retained non-core rather than inferring a particular complex-recruitment mechanism or a verified WW domain from the historical motif model. |
| GO:0045121 membrane raft | IEA GO_REF:0000107 | ACCEPT | Summary: CAV3 localizes to specialized membrane rafts. Reason: The mouse-derived location is consistent with caveolar membrane localization and detergent-resistant membrane fractionation in the receptor study. The more specific caveolar location is used in the core summary. |
| GO:0045121 membrane raft | ISS GO_REF:0000024 | ACCEPT | Summary: The mouse raft-localization transfer is retained. Reason: Caveolar CAV3 localization and membrane-domain fractionation provide independent support. This does not imply that every raft is a morphologically defined caveola. |
| GO:0045792 negative regulation of cell size | IMP PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | KEEP AS NON CORE | Summary: CAV3 can limit agonist-induced cardiomyocyte enlargement. Reason: The abstract explicitly reports reduced cell-size responses with human wild-type CAV3 in rat neonatal cardiomyocytes. This is a contextual hypertrophic-growth phenotype rather than a general negative regulator of cell size in all cell types. Supporting Evidence: |
| GO:0050998 nitric-oxide synthase binding | IEA GO_REF:0000107 | UNDECIDED | Summary: The NOS-binding transfer needs its rat donor interaction assay. Reason: The specific direct or complex-mediated association underlying the rat annotation has not been inspected. Lack of altered NOS activity in a separate cardiac overexpression experiment does not refute binding, so neither rejection nor a direct inhibitory mechanism is inferred. Supporting Evidence: |
| GO:0051394 regulation of nerve growth factor receptor activity | IMP PMID:20472890 Differential effects of myopathy-associated caveolin-3 mutan... | KEEP AS NON CORE | Summary: CAV3-dependent TrkA distribution changes nerve-growth-factor signaling. Reason: The accessible primary study measures PC12 TrkA surface abundance and Akt/ERK responses with wild-type and myopathy-associated CAV3 constructs. These are model- and variant-specific effects on receptor signaling, not a claim that CAV3 is the ligand or receptor. Supporting Evidence: |
| GO:0051480 regulation of cytosolic calcium ion concentration | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Inherited regulation of cytosolic calcium is consistent with CAV3 channel modulation. Reason: The PAINT row reflects a curated ancestral placement rather than pairwise transfer solely from the listed CAV1 protein. Target-specific calcium-channel experiments support a conserved regulatory role, while direction and stimulus depend on channel subtype and PKA state. No argument against the ancestral node is established. Supporting Evidence: |
| GO:0051926 negative regulation of calcium ion transport | IDA PMID:21084288 Caveolin-3 regulates protein kinase A modulation of the Ca(V... | KEEP AS NON CORE | Summary: CAV3 can reduce CaV3.2-mediated calcium transport. Reason: Human-construct electrophysiology and mouse cardiomyocyte overexpression support reduced T-type current in the tested context. Unchanged surface CaV3.2 abundance and lack of equivalent CaV3.1 inhibition delimit the mechanism. This is not generalized suppression of all calcium transport. Supporting Evidence: |
| GO:0055117 regulation of cardiac muscle contraction | IMP PMID:17275750 Novel mechanism for sudden infant death syndrome: persistent... | UNDECIDED | Summary: Cardiac muscle contraction is a plausible downstream consequence, with unresolved source-specific support. Reason: Human CAV3 variants increased late SCN5A current in HEK293 cells, but the paper explicitly limits extrapolation to native cardiac complexes and lacks segregation information for the anonymous cases. The link from that perturbation to CAV3 participation in the contraction-regulatory process remains uncertain. Neither lack of a particular assay alone nor the frozen Limited disease classification is used as a negative result. Supporting Evidence: |
| GO:0060090 molecular adaptor activity | IBA GO_REF:0000033 | MODIFY | Summary: The supported coordinated protein-recruitment mechanism is protein-macromolecule adaptor activity. Reason: The inherited adaptor role is supported by channel/ligase recruitment and cavin-dependent assemblies. In particular, CAV3 associates with hERG and NEDD4-2, recruits the ligase to the membrane, and enhances channel turnover in a motif-dependent manner. This fits the broad adaptor definition without assigning ligase or protease catalysis to CAV3; target inclusion among PAINT sources is expected. The more specific replacement describes recruitment of protein partners into coordinated contact. It is distinct from an integral structural scaffold holding a stable coat together and does not imply that every CAV3 interaction is an adaptor mechanism. Proposed replacements: protein-macromolecule adaptor activity |
| GO:0060090 molecular adaptor activity | IEA GO_REF:0000107 | MODIFY | Summary: The supported coordinated protein-recruitment mechanism is protein-macromolecule adaptor activity. Reason: CAV3-dependent recruitment of NEDD4-2 and control of hERG surface turnover provide a coordinated binding mechanism consistent with the orthology transfer. Cavin associations further support organization of membrane assemblies. The function is not inferred from an isolated coimmunoprecipitation alone. The more specific replacement describes recruitment of protein partners into coordinated contact. It is distinct from an integral structural scaffold holding a stable coat together and does not imply that every CAV3 interaction is an adaptor mechanism. Proposed replacements: protein-macromolecule adaptor activity |
| GO:0060090 molecular adaptor activity | IPI PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | MODIFY | Summary: The supported coordinated protein-recruitment mechanism is protein-macromolecule adaptor activity. Reason: The original exact SCN5A interaction is preserved. An isolated channel pair does not by itself prove a bridge, but independent hERG/NEDD4-2 recruitment and cavin experiments substantiate the broader adaptor function of CAV3. Retain with that explicit distinction rather than claiming the sodium paper alone establishes a complete ternary mechanism. The more specific replacement describes recruitment of protein partners into coordinated contact. It is distinct from an integral structural scaffold holding a stable coat together and does not imply that every CAV3 interaction is an adaptor mechanism. Proposed replacements: protein-macromolecule adaptor activity Supporting Evidence: PMID:22879586 enhances the hERG-Nedd4-2 interaction |
| GO:0060299 negative regulation of sarcomere organization | IMP PMID:12847114 Adenovirus-mediated overexpression of caveolin-3 inhibits ra... | KEEP AS NON CORE | Summary: CAV3 limits agonist-induced sarcomeric remodeling in the tested hypertrophy model. Reason: The complete abstract reports suppression of phenylephrine- or endothelin-induced sarcomeric reorganization with wild-type human CAV3 in rat neonatal cardiomyocytes. This supports the existing contextual negative-regulation assertion without claiming that normal CAV3 generally prevents developmental sarcomere assembly. Supporting Evidence: |
| GO:0060307 regulation of ventricular cardiac muscle cell membrane repolarization | IMP PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | UNDECIDED | Summary: The ventricular-repolarization interpretation remains a qualified physiological inference. Reason: Persistent inward sodium current can delay repolarization, and the paper combines human ventricular localization with variant-dependent late-current measurements. However, the current measurements were made in HEK293 cells, wild type did not change current versus vector, and the proposed native causal mechanism was not resolved. The GO term concerns regulation of the ventricular cardiomyocyte membrane potential towards rest. Retain uncertainty about this precise source-level assignment rather than converting channel effects or historical QT association into a settled native process. Supporting Evidence: |
| GO:0060373 regulation of ventricular cardiac muscle cell membrane depolarization | IDA PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | UNDECIDED | Summary: The specific ventricular-depolarization process is not resolved by the source. Reason: The functional finding is increased persistent late inward current for CAV3 variants, not a significant change in peak current or activation in the tested HEK293 system. Human myocardial localization makes a cardiac role plausible, but does not resolve how CAV3 regulates ventricular depolarization in the native complex. This is uncertainty about the physiological interpretation, not a claim that the current experiment or curator attribution is erroneous. Supporting Evidence: |
| GO:0061052 negative regulation of cell growth involved in cardiac muscle cell development | IEA GO_REF:0000107 | UNDECIDED | Summary: The developmental qualifier in the rat cardiac-growth transfer needs the donor experiment. Reason: Agonist-induced neonatal cardiomyocyte hypertrophy supports contextual growth control, but does not by itself identify a role during cardiac-muscle-cell development. The original donor experiment behind this more specific electronic process has not been verified. Supporting Evidence: |
| GO:0070836 caveola assembly | IBA GO_REF:0000033 | ACCEPT | Summary: CAV3 contributes to the assembly of muscle caveolae. Reason: The PAINT ancestral assertion is consistent with CAV3-dependent caveola abundance, human muscle caveolar defects accompanying caveolin depletion, and cavin assembly experiments. Human CAV3 among the descendant evidence sources is not circularity. |
| GO:0070836 caveola assembly | IDA PMID:18936328 Cardiac-specific overexpression of caveolin-3 induces endoge... | ACCEPT | Summary: CAV3 expression controls caveola abundance in cardiac membrane. Reason: The primary study measures caveolae by blinded electron microscopy after cardiac-specific Cav3 overexpression in mice and tests rodent cardiomyocytes. Its morphology supports a direct structural assembly contribution, not merely a downstream survival phenotype. The machine-sourced human IDA row remains unchanged, with the rodent experimental context stated explicitly. Supporting Evidence: PMID:18936328 showed enhanced formation of caveolae on the sarcolemma |
| GO:0070836 caveola assembly | IEA GO_REF:0000002 | ACCEPT | Summary: The caveolin-domain mapping to caveola assembly is supported for CAV3. Reason: This InterPro inference agrees with direct CAV3-dependent caveolar morphology and membrane-assembly evidence. It is not accepted solely because a family name resembles the process. |
| GO:0071253 connexin binding | IDA PMID:19544087 Connexin43 interacts with Caveolin-3 in the heart. | KEEP AS NON CORE | Summary: CAV3 associates with connexin43. Reason: The complete abstract reports yeast two-hybrid identification confirmed by coimmunoprecipitation and colocalization. This supports connexin binding while leaving exact species and construct details to the full paper, which is not in the cache. It does not by itself establish gap-junction gating or intercalated-disc residency. Supporting Evidence: |
| GO:0071253 connexin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The mouse-derived connexin-binding assignment is corroborated by the targeted interaction study. Reason: The source-specific abstract identifies connexin43–CAV3 association using multiple assays. Retain the conserved binding function without asserting a mechanism for electrical coupling that was not inspected. Supporting Evidence: |
| GO:0072659 protein localization to plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CAV3 controls membrane delivery or retention of selected partners. Reason: CAV3 depletion reduces CAVIN4 membrane localization, and channel/receptor studies identify additional partner-specific changes in surface abundance. This supports the broader mouse-derived localization process without making CAV3 a universal trafficking factor. |
| GO:0086005 ventricular cardiac muscle cell action potential | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAV3 influences potassium conductance relevant to ventricular action potentials. Reason: The rat-derived process is supported by native cardiac hERG association and neonatal rat current/internalization experiments. CAV3 performs channel-regulatory work, but the primary study does not directly record a human ventricular action potential; the process is retained as a non-core physiological inference from the conductance mechanism. Supporting Evidence: |
| GO:0086005 ventricular cardiac muscle cell action potential | ISS PMID:22879586 Cell surface expression of human ether-a-go-go-related gene ... | KEEP AS NON CORE | Summary: CAV3-dependent hERG regulation contributes to the ventricular electrical context. Reason: The cited study shows changes in hERG current and surface abundance, including rat cardiomyocyte depletion experiments. This mechanistic contribution is relevant to action potentials without requiring CAV3 to be a channel. The annotation is retained as contextual and does not claim a directly measured human action-potential waveform. Supporting Evidence: |
| GO:0090279 regulation of calcium ion import | IDA PMID:21084288 Caveolin-3 regulates protein kinase A modulation of the Ca(V... | KEEP AS NON CORE | Summary: CAV3 regulates calcium entry through CaV3.2 in the tested systems. Reason: The human-channel and mouse-cardiomyocyte experiments directly test calcium-channel current. Regulation is channel- and signaling-state dependent, so the annotation is retained without asserting the same direction for all calcium-entry pathways. Supporting Evidence: |
| GO:0098909 regulation of cardiac muscle cell action potential involved in regulation of contraction | IMP PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | UNDECIDED | Summary: The contraction-linked cardiac action-potential assignment remains uncertain. Reason: The primary study establishes human myocardial localization, channel coassociation and mutant late-current effects in HEK293 cells. Its proposed connection to cardiac action potentials and contraction remains a physiological inference, with wild-type regulation and the mechanism unresolved. The specific process is retained as undecided without rejecting the directly supported sodium-regulator molecular function. Supporting Evidence: |
| GO:1900825 regulation of membrane depolarization during cardiac muscle cell action potential | IMP PMID:17275750 Novel mechanism for sudden infant death syndrome: persistent... | UNDECIDED | Summary: The cardiac-action-potential depolarization interpretation remains unresolved. Reason: The original study reports variant-dependent persistent sodium current in human-construct HEK293 experiments, with no significant peak-current or tested gating change and an explicit noncardiac-model limitation. The precise relationship of these effects to CAV3 regulation of depolarization during a native cardiac action potential is uncertain. The action does not imply a universal requirement for a cardiomyocyte assay or a contradiction of the measured channel phenotype. Supporting Evidence: |
| GO:1900826 negative regulation of membrane depolarization during cardiac muscle cell action potential | IEA GO_REF:0000107 | UNDECIDED | Summary: The negative direction of the mouse cardiac-depolarization transfer requires its donor assay. Reason: CAV3 has multiple channel-specific effects, so a negative depolarization direction cannot be inferred from the generic presence of channel regulation. The precise mouse experiment and physiological endpoint behind this transfer have not been verified. |
| GO:1901380 negative regulation of potassium ion transmembrane transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAV3 reduces hERG-mediated potassium transport in a trafficking-dependent context. Reason: The rat-derived annotation agrees with CAV3-dependent loss of surface hERG and reduced potassium current. The effect depends on NEDD4-2 recruitment and the channel interaction motif rather than universal inhibition of potassium channels. Supporting Evidence: |
| GO:1901380 negative regulation of potassium ion transmembrane transport | ISS PMID:22879586 Cell surface expression of human ether-a-go-go-related gene ... | KEEP AS NON CORE | Summary: CAV3 promotes hERG internalization and lowers its potassium current. Reason: The manually transferred rat result is supported by the cited current, surface-abundance and depletion experiments. Retain this negative transport regulation as a contextual downstream process, without assigning catalytic ubiquitination to CAV3. Supporting Evidence: |
| GO:1902305 regulation of sodium ion transmembrane transport | IDA PMID:17060380 Mutant caveolin-3 induces persistent late sodium current and... | KEEP AS NON CORE | Summary: CAV3 variants regulate late sodium transport through SCN5A. Reason: Human CAV3 F97C/S141R altered persistent inward current relative to wild type and vector in the primary expression experiments. Wild-type CAV3 alone had no measurable effect in this context. The transport-regulatory consequence is supported with this variant dependence and remains distinct from heart-rate, contraction and disease-validity conclusions. Supporting Evidence: |
| GO:1902305 regulation of sodium ion transmembrane transport | IDA PMID:17275750 Novel mechanism for sudden infant death syndrome: persistent... | KEEP AS NON CORE | Summary: Variant-dependent CAV3 effects alter persistent late sodium current. Reason: The human CAV3/SCN5A experiment shows significant late-current increases for the tested CAV3 variants; the smaller wild-type increase was not significant. Retain sodium-transport regulation within that experimental scope, without claiming a universal effect of wild-type CAV3 or a proven sudden-death mechanism. Supporting Evidence: |
| GO:1904637 cellular response to ionomycin | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: CAV3 expression and caveolae increase after ionomycin treatment in rat cardiomyocytes. Reason: PMID:15725944 reports that ionomycin induces caveolin-3 expression and increases caveolae in neonatal rat cardiomyocytes. The official response term includes changes in gene expression, so this is a relevant stimulus-response endpoint rather than an inference from generic calcium signaling. Retain the existing transfer non-core, with its pharmacological rat-cell context; no CAV3 ionomycin binding, calcium-sensing activity or direct human response is asserted. Supporting Evidence: PMID:15725944 ionomycin increased the number of caveolae |
| GO:2000009 negative regulation of protein localization to cell surface | NAS PMID:22879586 Cell surface expression of human ether-a-go-go-related gene ... | KEEP AS NON CORE | Summary: CAV3 lowers surface hERG abundance through enhanced turnover. Reason: Although the source row is NAS, the accessible cited experiments directly measure surface mature hERG, internalization, and current, with NEDD4-2 and channel-motif perturbations. These substantiate a protein-specific negative localization process, not a general suppression of all cell-surface proteins. Supporting Evidence: |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | NAS PMID:22879586 Cell surface expression of human ether-a-go-go-related gene ... | KEEP AS NON CORE | Summary: CAV3 promotes NEDD4-2-dependent turnover of hERG. Reason: CAV3 recruits the ubiquitin ligase to the membrane and enhances loss of mature hERG in a PY-motif-dependent pathway. CAV3 therefore contributes adaptor work to this existing regulatory process; NEDD4-2 performs ubiquitination and the degradation machinery performs proteolysis. No catalytic activity is transferred to CAV3. Supporting Evidence: |
| GO:2001288 positive regulation of caveolin-mediated endocytosis | IEA GO_REF:0000107 | UNDECIDED | Summary: Positive regulation of caveolin-mediated endocytosis requires the original rat experiment. Reason: CAV3 can promote hERG internalization and can alter other receptor distributions in different directions. Those observations do not identify the precise caveolin-mediated route or the positive regulatory step underlying this donor annotation. The specific source mechanism remains unresolved. |
Loading supporting content…
Download this section (compressed HTML)Q: Which native CAV3-dependent mechanisms regulate SCN5A independently of variant overexpression, and how do they affect ventricular repolarization, depolarization or pacemaking?
Suggested experts: Cardiac electrophysiology and channel-complex specialists
Q: Does the target-specific structural evidence justify a protein-complex scaffold molecular-function annotation for CAV3, distinct from its experimentally supported adaptor role? Compare muscle caveolar components in the same structural role before proposing NEW.
Q: How should broad dystrophin-complex membership represent transient beta-dystroglycan association versus the biochemical separation of CAV3 from the stable purified complex?
Q: Which source-specific donor assays resolve the remaining developmental, focal-adhesion, T-tubule and stretch-response transfers, and which observations demonstrate work performed by CAV3 rather than a downstream phenotype?
Q: Where is the CAV3-specific endoplasmic-reticulum observation supporting PMID:22792322, and do the exact screen records distinguish stable interactions from assay-context associations?
Experiment: Compare endogenous-level wild-type CAV3 and selected variants in isogenic human cardiomyocytes, with matched surface expression and sodium-current, action-potential and calcium measurements, to separate channel-complex regulation from overexpression and secondary injury.
Experiment: Measure caveolar assembly and repair-protein recruitment after matched CAV3 perturbations, separating oligomer/coat stability, DYSF/TRIM72 localization and membrane repair instead of treating one phenotype as proof of every mechanism.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)