vcla

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0002102 podosome	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Podosome localization mapped from the UniProt subcellular location vocabulary (ARBA rule). Reason: Vinculin is a podosome component in mammalian cells, and the ARBA-derived location is a family-level transfer. There is no zebrafish evidence for podosomes containing this copy, and podosomes are not where the zebrafish mutant phenotypes lie; kept as a plausible non-core location.
GO:0003181 atrioventricular valve morphogenesis	IMP PMID:30635353 Focal adhesions are essential to drive zebrafish heart valve...	KEEP AS NON CORE	Summary: Endocardial overexpression of a dominant-negative vinculin head domain (cloned from vcla) blocks AV endocardial cell migration and valve leaflet formation. Reason: The experiment is sound and shows that vinculin engagement at focal adhesions is needed for AV valve morphogenesis. It is attributed to vcla only because the DN fragment was cloned from vcla; a head-domain DN competes for talin/alpha-catenin binding sites and therefore blocks vinculin function generally, not vcla specifically. In the heart, vcla is expressed at low levels and vclb predominates, and vclb single mutants had no strong valve delay. Kept, but as a non-core process whose endogenous paralog is not identified; it should not be read as evidence of a vcla-specific role. Supporting Evidence: PMID:30635353 We proceeded to analyze the functional consequences of blocking FA signaling and generated an upstream activating sequence (UAS)–driven DN Vinculin transgene, Tg(UAS:DN-Vcl-EGFP), which expresses a form of Vinculin containing only its head domain (Fig. 3 A). PMID:30635353 To generate the DN Vinculin transgene, the first 774 bp of the vcla coding sequence was amplified by PCR using the following primers PMID:30635353 The microarray data show that tln1 and apbb1ip are expressed at high levels in embryonic hearts (Fig. S1 A), but vcla is expressed at low levels (data not shown); no probe for vclb was included in the array. PMID:30635353 A recent report showed that vclb is the predominant vcl gene expressed in the embryonic heart (Cheng et al., 2016). PMID:30635353 However, we found that vclb mutants did not exhibit strong delays in AV EC migration and valve formation
GO:0003779 actin binding	IEA GO_REF:0000002	ACCEPT	Summary: Actin binding from the InterPro vinculin family signature. Reason: Vinculin binds F-actin through its tail domain, and the tail helices that mediate F-actin and paxillin binding are almost identical between the zebrafish copies and higher vertebrates. Correct, though less specific than the co-annotated actin filament binding (GO:0051015). Supporting Evidence: PMID:28767718 Especially Helices 3–5 which mediate paxillin and F-actin binding (Fig 1E) [52,53] are almost completely identical.
GO:0005198 structural molecule activity	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: Structural molecule activity from an InterPro vinculin conserved-site mapping. Reason: Vinculin is a mechanosensitive linker that couples talin and alpha-catenin to F-actin; it is not a structural constituent in the sense of a filament or matrix protein. The informative activities (actin filament binding, alpha-catenin binding) are already annotated, so this vague parent adds nothing and implies a role the protein does not have. Supporting Evidence: PMID:28767718 Vinculin binds the adherens junction component α-catenin, which interacts with cadherin-bound β-catenin through its N-terminal head domain, and links the cadherin complex to F-actin using its C-terminal tail.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Cytoplasmic protein (IBA). Reason: Vinculin is a cytoplasmic, membrane-associated cytoskeletal protein. Both TGD copies descend from the PANTHER PTN005285701 vinculin node, so the IBA is expected on vcla and vclb alike; nothing in the vcla sequence or phenotype argues for loss of the function. Supporting Evidence: PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin
GO:0005856 cytoskeleton	IBA GO_REF:0000033	ACCEPT	Summary: Cytoskeleton (IBA). Reason: Vinculin is an actin-cytoskeleton-associated protein at adhesion sites. Both TGD copies descend from the PANTHER PTN005285701 vinculin node, so the IBA is expected on vcla and vclb alike; nothing in the vcla sequence or phenotype argues for loss of the function. Supporting Evidence: PMID:28767718 Vinculin binds the adherens junction component α-catenin, which interacts with cadherin-bound β-catenin through its N-terminal head domain, and links the cadherin complex to F-actin using its C-terminal tail.
GO:0005856 cytoskeleton	IEA GO_REF:0000044	ACCEPT	Summary: Cytoskeleton from UniProt subcellular location mapping. Reason: Consistent with the IBA row and the known actin association of vinculin.
GO:0005886 plasma membrane	IBA GO_REF:0000033	ACCEPT	Summary: Plasma membrane (IBA); vinculin sits on the cytoplasmic face of adhesion sites. Reason: Vinculin is a peripheral protein at the cytoplasmic face of integrin and cadherin adhesions. Both TGD copies descend from the PANTHER PTN005285701 vinculin node, so the IBA is expected on vcla and vclb alike; nothing in the vcla sequence or phenotype argues for loss of the function. Supporting Evidence: PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin
GO:0005911 cell-cell junction	IEA GO_REF:0000117	ACCEPT	Summary: Cell-cell junction (ARBA). Reason: Correct but general; the more specific adherens junction term is supported experimentally for both copies in the same cell assay. Supporting Evidence: PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin
GO:0005912 adherens junction	IBA GO_REF:0000033	ACCEPT	Summary: Adherens junction (IBA). Reason: Both zebrafish copies are among the descendant evidences (ZFIN:ZDB-GENE-050506-61 = vcla, ZFIN:ZDB-GENE-131017-1 = vclb) used for this node, which is expected: each has its own IDA from PMID:28767718. Recruitment to adherens junctions depends on the alpha-catenin vinculin-binding site for both copies. Both TGD copies descend from the PANTHER PTN005285701 vinculin node, so the IBA is expected on vcla and vclb alike; nothing in the vcla sequence or phenotype argues for loss of the function. Supporting Evidence: PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin PMID:28767718 Here it is apparent that both vinculin A and vinculin B are now excluded from Focal Adherens Junctions and Linear Adherens Junctions (arrows), but are still present in Focal Adhesions (arrows).
GO:0005912 adherens junction	IDA PMID:28767718 Zygotic vinculin is not essential for embryonic development ...	ACCEPT	Summary: GFP-tagged zebrafish vcla localizes to focal and linear adherens junctions in MDCK cells, dependent on the alpha-catenin vinculin-binding site. Reason: Direct localization assay of the zebrafish protein in epithelial cells; junctional recruitment is lost when alpha-catenin lacks its vinculin-binding site, showing the canonical recruitment mechanism. Both copies behave the same in this assay. Supporting Evidence: PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin PMID:28767718 Here it is apparent that both vinculin A and vinculin B are now excluded from Focal Adherens Junctions and Linear Adherens Junctions (arrows), but are still present in Focal Adhesions (arrows).
GO:0005912 adherens junction	IEA GO_REF:0000044	ACCEPT	Summary: Adherens junction from UniProt subcellular location mapping. Reason: Consistent with the IDA and IBA rows for the same term.
GO:0005925 focal adhesion	IBA GO_REF:0000033	ACCEPT	Summary: Focal adhesion (IBA). Reason: Both copies localize to integrin-based focal adhesions independently of alpha-catenin. Both TGD copies descend from the PANTHER PTN005285701 vinculin node, so the IBA is expected on vcla and vclb alike; nothing in the vcla sequence or phenotype argues for loss of the function. Supporting Evidence: PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin PMID:28767718 Here it is apparent that both vinculin A and vinculin B are now excluded from Focal Adherens Junctions and Linear Adherens Junctions (arrows), but are still present in Focal Adhesions (arrows).
GO:0005925 focal adhesion	IDA PMID:26954676 Paxillin and Focal Adhesion Kinase (FAK) Regulate Cardiac Co...	ACCEPT	Summary: Vinculin immunostaining at focal adhesion sites (costameres) in 72 hpf zebrafish hearts. Reason: The antibody is not paralog-specific, so this row alone does not show that vcla (rather than vclb) is at cardiac focal adhesions. Focal adhesion localization of vcla itself is independently established with GFP-tagged vcla (PMID:28767718), so the term is correct for vcla. Supporting Evidence: PMID:26954676 Whereas in control morphant hearts Vinculin properly localized to focal adhesion sites, Vinculin was mislocalized and seems to get degraded in morphant hearts (Fig 5A–5C). PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin
GO:0005925 focal adhesion	IEA GO_REF:0000120	ACCEPT	Summary: Focal adhesion (combined IEA). Reason: Consistent with experimental localization of both copies to focal adhesions. Supporting Evidence: PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin
GO:0005925 focal adhesion	IMP PMID:26954676 Paxillin and Focal Adhesion Kinase (FAK) Regulate Cardiac Co...	ACCEPT	Summary: Location term supported by a morphant (paxillin/FAK knockdown) experiment in which vinculin mislocalizes. Reason: Using IMP for a location is unusual: the data show that paxillin and FAK are needed to keep vinculin at focal adhesions. The location itself is correct for vcla (GFP-vcla localizes to focal adhesions), so the term is accepted on the combined evidence. Supporting Evidence: PMID:26954676 Whereas in control morphant hearts Vinculin properly localized to focal adhesion sites, Vinculin was mislocalized and seems to get degraded in morphant hearts (Fig 5A–5C). PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin
GO:0007155 cell adhesion	IBA GO_REF:0000033	ACCEPT	Summary: Cell adhesion (IBA). Reason: Vinculin reinforces integrin- and cadherin-based adhesions by linking them to actin; this is the core process of the protein. Both TGD copies descend from the PANTHER PTN005285701 vinculin node, so the IBA is expected on vcla and vclb alike; nothing in the vcla sequence or phenotype argues for loss of the function. Supporting Evidence: PMID:28767718 Vinculin binds the adherens junction component α-catenin, which interacts with cadherin-bound β-catenin through its N-terminal head domain, and links the cadherin complex to F-actin using its C-terminal tail. PMID:36260739 Together, the data show that vinculin tightens endothelial junctions in blood vessels.
GO:0007155 cell adhesion	IEA GO_REF:0000002	ACCEPT	Summary: Cell adhesion from InterPro vinculin family signatures. Reason: Consistent with the IBA row and the conserved adhesion-linker function.
GO:0008013 beta-catenin binding	IBA GO_REF:0000033	ACCEPT	Summary: Beta-catenin binding (IBA). Reason: Vinculin binds beta-catenin at cadherin junctions in mammals, and vcla keeps Y822, the phosphotyrosine required for the beta-catenin interaction in mammalian cells. Both TGD copies descend from the PANTHER PTN005285701 vinculin node, so the IBA is expected on vcla and vclb alike; nothing in the vcla sequence or phenotype argues for loss of the function. Supporting Evidence: PMID:28767718 Notably, besides α-catenin- and talin-dependent tension-induced recruitment, vinculin also binds to other proteins at both integrin and cadherin adhesions such as paxillin and β-catenin [19].
GO:0015629 actin cytoskeleton	IEA GO_REF:0000002	ACCEPT	Summary: Actin cytoskeleton (InterPro). Reason: Vinculin binds F-actin at adhesion sites; correct location. Supporting Evidence: PMID:28767718 Vinculin binds the adherens junction component α-catenin, which interacts with cadherin-bound β-catenin through its N-terminal head domain, and links the cadherin complex to F-actin using its C-terminal tail.
GO:0016020 membrane	IEA GO_REF:0000117	ACCEPT	Summary: Membrane (ARBA). Reason: Correct but uninformative; plasma membrane and adhesion-site terms are more specific.
GO:0030016 myofibril	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Myofibril (ARBA). Reason: In the zebrafish heart vinculin immunoreactivity is found at sarcomeric Z-disks and costameres (antibody not paralog-specific), consistent with a muscle location, but this is a tissue-specific attachment site, not the core location. Supporting Evidence: PMID:26954676 We show here for the first time that an orchestrated interplay of Paxillin, Focal Adhesion Kinase (FAK) and Vinculin localizing to sarcomeric Z-disks and costameres in cardiomyocytes is essential for the regulation of cardiac contractility.
GO:0042383 sarcolemma	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Sarcolemma (UniProt subcellular location mapping). Reason: Costameric vinculin lies at the sarcolemma of cardiomyocytes; the zebrafish antibody data do not distinguish the paralogs. Plausible, muscle-specific, non-core. Supporting Evidence: PMID:26954676 We show here for the first time that an orchestrated interplay of Paxillin, Focal Adhesion Kinase (FAK) and Vinculin localizing to sarcomeric Z-disks and costameres in cardiomyocytes is essential for the regulation of cardiac contractility.
GO:0044291 cell-cell contact zone	IBA GO_REF:0000033	ACCEPT	Summary: Cell-cell contact zone (IBA). Reason: Vinculin is recruited to tensioned cadherin contacts; both copies reach cell-cell junctions in the same assay. Both TGD copies descend from the PANTHER PTN005285701 vinculin node, so the IBA is expected on vcla and vclb alike; nothing in the vcla sequence or phenotype argues for loss of the function. Supporting Evidence: PMID:28767718 In α-catenin rescued cells, both vinculin A and vinculin B localize to integrin-based Focal Adhesion structures, as well as to the punctate Focal Adherens Junctions as evidenced by colocalization with α-catenin
GO:0045214 sarcomere organization	IMP PMID:19800866 In-vivo characterization of human dilated cardiomyopathy gen...	UNDECIDED	Summary: vcla morpholino knockdown causes cardiac systolic dysfunction; sarcomere organization inferred from morphants. Reason: The only evidence is a zygotic vcla splice morpholino (ZDB-MRPHLNO-100114-3), and the cached paper is abstract-only. Maternal-zygotic vcla mutants are fully viable, and zygotic vcla;vclb double mutants have normal skeletal muscle and only mild, transient cardiac edema; the mutant authors consider the morpholino effects most likely non-specific. Against that, vinculin is reported to be essential for cardiomyocyte myofilament maturation in zebrafish (PMID:31495694, abstract only; paralog and alleles not stated), and vcla PTC alleles that decay trigger vclb upregulation, which could mask a single-mutant phenotype. A role for vinculin in cardiac sarcomere organization is plausible, but a vcla-specific IMP cannot be adjudicated from these data. Supporting Evidence: PMID:19800866 Consistently, knock-down of the here selected human DCM genes leads to severe heart failure with impairment of systolic cardiac function in zebrafish. PMID:28767718 While we cannot fully exclude the latter, the most likely explanation is that the reported effects of the used vinculin A morpholinos are non-specific. PMID:28767718 While we do see cardiac edemas in vinculin-null mutants, skeletal muscle tissue seems unaffected. PMID:31495694 Here, we first show that the forces of the contracting heart regulate the localization and activation of the cytoskeletal protein vinculin (VCL), which we find to be essential for myofilament maturation.
GO:0045294 alpha-catenin binding	IBA GO_REF:0000033	ACCEPT	Summary: Alpha-catenin binding (IBA). Reason: Junctional recruitment of both zebrafish copies requires the vinculin-binding site of alpha-catenin, and the D1 head residue A50 that mediates talin/alpha-catenin binding is conserved. Both TGD copies descend from the PANTHER PTN005285701 vinculin node, so the IBA is expected on vcla and vclb alike; nothing in the vcla sequence or phenotype argues for loss of the function. Supporting Evidence: PMID:28767718 Here it is apparent that both vinculin A and vinculin B are now excluded from Focal Adherens Junctions and Linear Adherens Junctions (arrows), but are still present in Focal Adhesions (arrows). PMID:28767718 The key residue of which mutation perturbs all of these interactions, A50, is fully conserved [47,48].
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: Perinuclear region of cytoplasm (UniProt subcellular location mapping). Reason: No zebrafish or functional basis for a perinuclear vinculin pool; the protein acts at adhesion sites. The mapped keyword adds no information about function.
GO:0051015 actin filament binding	IEA GO_REF:0000002	ACCEPT	Summary: Actin filament binding (InterPro). Reason: Core activity of the vinculin tail; the F-actin-binding tail helices are nearly identical to mammalian vinculin in both copies. Supporting Evidence: PMID:28767718 Especially Helices 3–5 which mediate paxillin and F-actin binding (Fig 1E) [52,53] are almost completely identical.
GO:0060047 heart contraction	IMP PMID:19800866 In-vivo characterization of human dilated cardiomyopathy gen...	UNDECIDED	Summary: vcla morpholino knockdown impairs systolic function (heart contraction). Reason: Morpholino-only evidence (abstract-only cache). MZvcla mutants show no cardiac phenotype, and the mutant study found no rise in vinculin protein from vclb, while noting the morpholino targeted zygotic vcla only and judging its effects most likely non-specific. vcla PTC alleles do trigger transcriptional adaptation of vclb mRNA, so masking cannot be excluded. Vinculin is required for cardiomyocyte maturation (PMID:31495694) and for heart function in mammals, so the process is plausible for vinculin in general, but whether vcla contributes is unresolved. Supporting Evidence: PMID:19800866 Consistently, knock-down of the here selected human DCM genes leads to severe heart failure with impairment of systolic cardiac function in zebrafish. PMID:28767718 Moreover, the splice-site morpholino that was used, only targeted the zygotic vinculin A isoform, keeping maternally supplied mRNA and vinculin B intact. PMID:28767718 This result strongly indicates that mutation of the vcla gene leads to loss of most of the functional vinculin protein in zebrafish embryos and that this is not compensated for by increased expression of vinculin B. PMID:30944477 hbegfa, vcla, hif1ab, vegfaa, egfl7 and alcama zebrafish mutants exhibit increased mRNA levels of a paralogue or family member (hereafter referred to as ‘adapting gene’), namely hbegfb, vclb, epas1a and epas1b, vegfab, emilin3a and alcamb, respectively
GO:0060047 heart contraction	IMP PMID:26954676 Paxillin and Focal Adhesion Kinase (FAK) Regulate Cardiac Co...	UNDECIDED	Summary: The same vcla morpholino reduces ventricular fractional shortening (supplementary data). Reason: Same morpholino (ZDB-MRPHLNO-100114-3) as PMID:19800866, re-tested as a supplementary control; the paper is about paxillin/FAK. The mutant data (MZvcla viable; double zygotic mutants with mild transient edema only) conflict with the severe morphant contractility defect. Undecided for the same reasons as the PMID:19800866 row. Supporting Evidence: PMID:26954676 Finally, we found that targeted gene knock-down of vinculin, similar to Paxillin and FAK ablation, results in severe ventricular contractile dysfunction in zebrafish embryos [5] (S4A–S4D Fig). PMID:28767718 Taken together, the results show that vcla is not essential for zebrafish development or adult life. PMID:28767718 While we cannot fully exclude the latter, the most likely explanation is that the reported effects of the used vinculin A morpholinos are non-specific.
GO:0086013 membrane repolarization during cardiac muscle cell action potential	IMP PMID:24952909 Annotation of loci from genome-wide association studies usin...	MARK AS OVER ANNOTATED	Summary: vcl morpholino knockdown alters cardiac action potential repolarization (supplementary figure of a proteomics/GWAS paper). Reason: Vinculin is a cytoskeletal adaptor, not a channel or channel subunit; the paper places it in a CAV3/SNTA1 interaction network. A morphant change in action potential duration is a downstream physiological readout (morpholino only, disputed by mutant data), not evidence that vinculin does work in membrane repolarization. The participation bar for this specific electrophysiological process is not met. Supporting Evidence: PMID:24952909 We furthermore confirmed the involvement of VCL in cardiac repolarization by knockdown experiments of the ortholog, vcl, in zebrafish, which had a direct effect on cardiac repolarization in vivo (Supplementary Figure 13). PMID:24952909 Second, VCL encodes a cytoskeletal protein, vinculin, which we show interacts with CAV3 and SNTA1. PMID:28767718 While we cannot fully exclude the latter, the most likely explanation is that the reported effects of the used vinculin A morpholinos are non-specific.
GO:0061028 establishment of endothelial barrier	IGI PMID:36260739 Vinculin strengthens the endothelial barrier during vascular...	NEW	Summary: Vinculin strengthens endothelial adherens junctions; vcla;vclb double and vcla-/-;vclb+/- embryos leak 10 kDa dextran from intersegmental vessels. Reason: Participation: vinculin is recruited to tensioned VE-cadherin junctions through alpha-catenin and reinforces their link to actin, so it contributes structure that barrier formation depends on (junctional vinculin, not a downstream signal). The in vivo evidence is genetic and involves both copies (vcla-/-;vclb+/- and vcla-/-;vclb-/- both leak), so the annotation is made to both copies as IGI rather than to one. vclb is the copy most prominently expressed in endothelium (PMID:36314606), so the relative contribution of each copy is not resolved. Supporting Evidence: PMID:36260739 Our analysis shows that vcla−/−;vclb+/−and vcl full-KO embryos exhibited increased perivascular dextran levels PMID:36260739 we observed vascular leakage specifically for small molecules, 10 kDa, in vinculin knockout zebrafish, whereas the vasculature still acted as a barrier for larger molecules PMID:36260739 Together, the data show that vinculin tightens endothelial junctions in blood vessels.

Gene Description

Existing Annotations Review

Core Functions

Actin-binding adaptor at integrin-based focal adhesions and cadherin-based adherens junctions, recruited via talin and alpha-catenin and linking them to F-actin; molecular function equivalent to vclb and to mammalian vinculin.

Alpha-catenin binding at tensioned cell-cell junctions; with vclb, strengthens endothelial junctions so embryonic vessels retain small molecules.

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