Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:B0FTZ7 (catenin)
 18,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cadherins are major cell-cell adhesion proteins whose cytoplasmic domains bind to catenin proteins. Strong intercellular adhesion depends on linkage of the cadherin/catenin complex to the actin cytoskeleton via alpha-catenin. To date, it is not clear how different cell types achieve the variable strength of cell-cell adhesion clearly needed in a multicellular organism. Here, we report the cloning and molecular characterization of alphaT(testis)-catenin, a novel human cDNA encoding a protein with homology to both human alphaE(epithelial)-catenin and alphaN(neural)-catenin. Although originally discovered in testis, alphaT-catenin is expressed in other tissues, the highest levels being observed in heart. Immunohistochemical analysis showed human alphaT-catenin localization at intercalated discs of cardiomyocytes and in peritubular myoid cells of testis. In cells transfected with alphaT-catenin cDNA, interaction with beta-catenin was demonstrated by co-immunoprecipitation. Transfection of alpha-catenin-deficient colon carcinoma cells recruited E-cadherin and beta-catenin to cell-cell contacts and functional cadherin-mediated cell-cell adhesion was restored in this way. Moreover, compaction of these cells was at least as prominent as in the case of cells expressing endogenous alphaE-catenin. We propose that alphaT-catenin is necessary for the formation of stretch-resistant cell-cell adhesion complexes, in particular, muscle cells.
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PMID:alphaT-catenin: a novel tissue-specific beta-catenin-binding protein mediating strong cell-cell adhesion. 1159 Feb 44

Alpha T-catenin is a novel member of the alpha-catenin family, which shows most abundant expression in cardiomyocytes and in peritubular myoid cells of the testis, pointing to a specific function for alpha T-catenin in particular muscle tissues. Like other alpha-catenins, alpha T-catenin provides an indispensable link between the cadherin-based cell-cell adhesion complex and the cytoskeleton, to mediate cell-cell adhesion. By isolating genomic clones, combined with database sequence analysis, we have been able to determine the structure of the CTNNA3 and Ctnna3 genes, encoding human and mouse alpha T-catenin, respectively. The positions of the exon-exon boundaries are completely conserved in CTNNA3, Ctnna3, and the alpha N-catenin encoding CTNNA2 gene. They overlap largely with the boundaries of the CTNNA1 and CTNNAL1 genes encoding alpha E-catenin and alpha-catulin, respectively. This emphasizes that these alpha-catenin genes evolved from the same ancestor gene. Nevertheless, the introns of CTNNA3 and Ctnna3 are remarkably large (often more than 100 kb) compared with introns of other CTNNA genes. The CTNNA3 gene was mapped to chromosome band 10q21 by both fluorescence in situ hybridization and polymerase-chain-reaction-based hybrid mapping. This region encodes a gene for autosomal dominant familial dilated cardiomyopathy (DCM), a common cause of morbidity and mortality. As alpha T-catenin is highly expressed in healthy heart tissue, we have considered CTNNA3 as a candidate disease gene in a family showing DCM linkage to the 10q21-q23 locus. Mutation screening of all 18 exons of the CTNNA3 gene in this family has, however, not detected any DCM-linked CTNNA3 mutations.
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PMID:Assessment of the CTNNA3 gene encoding human alpha T-catenin regarding its involvement in dilated cardiomyopathy. 1259 47

Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at approximately 80 cM on chromosome 10. Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Together, these two studies provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes alpha-T catenin, which is a binding partner of beta catenin. This makes VR22 an attractive candidate gene because beta catenin interacts with presenilin 1, which has many mutations that elevate Abeta42 and cause early onset familial AD. We identified two intronic VR22 SNPs (4360 and 4783) in strong linkage disequilibrium (LD) that showed highly significant association (P=0.0001 and 0.0006) with plasma Abeta42 in 10 extended LOAD families. This association clearly contributed to the linkage at approximately 80 cM because the lod scores decreased when linkage analysis was performed conditional upon the VR22 association. This association replicated in another independent set of 12 LOAD families (P=0.04 for 4783 and P=0.08 for 4360). Bounding of the association region using multiple SNPs showed VR22 to be the only confirmed gene within the region of association. These findings indicate that VR22 has variant(s) which influence Abeta42 and contribute to the previously reported linkage for plasma Abeta42 in LOAD families.
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PMID:Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. 1455 75

The mechanisms by which growth factors cooperate with cell adhesion molecules to modulate epithelial cell motility remain poorly understood. Here, we investigated the role of the E-cadherin/catenin complex in insulin-like growth factor (IGF-I)-dependent cell migration and invasion. We used variants of the HCT-8 colon cancer family that differ in their expression of alphaE-catenin, an intracellular molecule that links the E-cadherin/catenin complex to the actin cytoskeleton. Migration was determined using a monolayer wound model and cell invasion by the penetration of the cells into type-I collagen gels. We showed that alpha-catenin-deficient cells were not able to migrate in cohort upon IGF-I stimulation. Transfection of these cells with alpha-catenin isoforms (alphaN- or alphaT-catenin) restored migratory response IGF-I. These results suggest that alpha-catenins are involved in the signal issued from the E-cadherin/catenin complex to regulate IGF-I-stimulated migration. In contrast, IGF-I promoted invasion of both alpha-catenin-deficient and alpha-catenin-expressing cells, indicating that alpha-catenin did not participate in the regulation of IGF-I-induced invasion. Inhibition of E-cadherin function by treatment with MB-2 monoclonal antibodies inhibited both IGF-I-dependent cell migration and invasion. Taken together, our results indicate that functional alpha-catenin is essential for migration but not for invasion, while E-cadherin is involved in both phenomena.
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PMID:Alpha-catenin is required for IGF-I-induced cellular migration but not invasion in human colonic cancer cells. 1496 Oct 74

Linkage studies have implicated a broad region on chromosome 10q in Alzheimer's disease (AD). A recent genetic association study has provided evidence that polymorphism in the gene encoding alpha-3 catenin (CTNNA3, referred to previously as VR22 and also known as alpha-T catenin) may underlie linkage signals. Here, to investigate this finding, markers that previously exhibited maximum evidence of association have been tested in Swedish and Scottish AD case-control samples. Across models of disease risk and in relation to multiple quantitative indices of AD pathology (CSF A beta 42 and tau levels, age-at-onset, MMSE scores, and measures of senile plaque density) no evidence was found supporting a role for these particular variants in AD. More detailed studies of regional linkage disequilibrium structure around CTNNA3 will likely be required to determine whether sequence variation in this region impacts AD.
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PMID:Genetic variation in CTNNA3 encoding alpha-3 catenin and Alzheimer's disease. 1503 20

AlphaT-catenin is a recently identified member of the alpha-catenin family of cell-cell adhesion molecules. Its expression is restricted mainly to cardiomyocytes, although it is also expressed in skeletal muscle, testis and brain. Like other alpha-catenins, alphaT-catenin provides an indispensable link between a cadherin-based adhesion complex and the actin cytoskeleton, resulting in strong cell-cell adhesion. We show here that the tissue-specificity of alphaT-catenin expression is controlled by its promoter region. By in silico analysis, we found that the alphaT-catenin promoter contains several binding sites for cardiac and muscle-specific transcription factors. By co-transfection studies in P19 embryonal carcinoma cells, we demonstrated that MEF2C and GATA-4 each have an activating effect on the alphaT-catenin promoter. Transfections with wild-type and mutant promoter constructs in cardiac HL-1 cells indicated that one GATA box is absolutely required for high alphaT-catenin promoter activity in these cells. Furthermore, we showed that the GATA-4 transcription factor specifically binds and activates the alphaT-catenin promoter in vivo in cardiac HL-1 cells. In vivo promoter analysis in transgenic mice revealed that the isolated alphaT-catenin promoter region could direct the tissue-specific expression of a LacZ reporter gene in concordance with endogenous alphaT-catenin expression.
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PMID:GATA-4 and MEF2C transcription factors control the tissue-specific expression of the alphaT-catenin gene CTNNA3. 1530 15

Alpha-catenins anchor the transmembrane cell-cell adhesion molecule E-cadherin indirectly to the actin cytoskeleton through interaction with beta-catenin or plakoglobin. Three different alpha-catenins are known at present: alphaE-, alphaT-, and alphaN-catenin. Despite their different expression patterns, no functional differences between the alpha-catenins are known. In a yeast two-hybrid screening with alphaN-catenin as bait, we identified the Cys(2)-His2 zinc finger protein ZASC1. The mRNA and protein of ZASC1 were ubiquitously expressed in various cell lines and human tissues. Our results suggest an association of the ZASC1 protein with DNA, and luciferase reporter assays revealed that ZASC1 is a transcriptional repressor. Upon transient overexpression, the ZASC1 protein localized in the nucleus, to where it was able to recruit cytoplasmic alphaN-catenin. Neither the highly related alphaE-catenin nor alphaT-catenin interacted with ZASC1. By interchanging parts of alphaN-catenin and alphaE-catenin cDNAs, we were able to narrow down the interaction region of alphaN-catenin to two limited amino-terminal regions. On the other hand, the interaction of ZASC1 with alphaN-catenin can be mediated by the domain comprising zinc fingers six to eight of ZASC1. The interaction and nuclear cotranslocation of a neural alpha-catenin with a putative proto-oncogene product as reported here provides novel insights into the signaling functions of alpha-catenins.
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PMID:Nuclear translocation of alphaN-catenin by the novel zinc finger transcriptional repressor ZASC1. 1618 84

AlphaT-catenin is a recently identified member of the alpha-catenin family of cell-cell adhesion molecules. For decades it was thought that alpha-catenins mediate solid cell-cell adhesion by linking the cadherin-mediated cell-cell adhesion complex with the actin cytoskeleton. However, the roles of alpha-catenins in this classical adhesion model have been questioned recently. AlphaT-catenin has a restricted expression pattern, in contrast to the ubiquitously expressed alphaE-catenin. High levels of alphaT-catenin were detected in heart and testis. Northern and Western blot experiments indicated that besides the standard full-length alphaT-catenin transcript, smaller alternative transcripts are expressed in testis. We report the cloning of two alternative transcripts of the mouse alphaT-catenin gene (transcript-B and -X), both of which are expressed in a testis-restricted manner from two putative alternative promoters. Alternative transcript-X encodes a smaller protein, isoform-X, which lacks the amino-terminal beta-catenin binding domain of the standard mouse alphaT-catenin protein, and is therefore unable to restore cell-cell adhesion in an alpha-catenin-negative colon carcinoma cell line. Immunohistochemical analysis showed specific localization of the alphaT-catenin isoform-X in the differentiating germ cells. In contrast to the standard full-length alphaT-catenin protein, this shortened isoform-X can bind to l-afadin, an important component of the nectin/afadin/ponsin adhesion complex that reportedly is essential for spermatogenesis.
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PMID:Truncated isoform of mouse alphaT-catenin is testis-restricted in expression and function. 1718 52

Alpha-catenins play key functional roles in cadherin-catenin cell-cell adhesion complexes. We previously reported on alphaT-catenin, a novel member of the alpha-catenin protein family. alphaT-catenin is expressed predominantly in cardiomyocytes, where it colocalizes with alphaE-catenin at the intercalated discs. Whether alphaT- and alphaE-catenin have specific or synergistic functions remains unknown. In this study we used the yeast two-hybrid approach to identify specific functions of alphaT-catenin. An interaction between alphaT-catenin and plakophilins was observed and subsequently confirmed by co-immunoprecipitation and colocalization. Interaction with the amino-terminal part of plakophilins appeared to be specific for the central ;adhesion-modulation' domain of alphaT-catenin. In addition, we showed, by immuno-electron microscopy, that desmosomal proteins in the heart localize not only to the desmosomes in the intercalated discs but also at adhering junctions with hybrid composition. We found that in the latter junctions, endogenous plakophilin-2 colocalizes with alphaT-catenin. By providing an extra link between the cadherin-catenin complex and intermediate filaments, the binding of alphaT-catenin to plakophilin-2 is proposed to be a means of modulating and strengthening cell-cell adhesion between cardiac muscle cells. This could explain the devastating effect of plakophilin-2 mutations on cell junction stability in intercalated discs, which lead to cardiac muscle malfunction.
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PMID:A unique and specific interaction between alphaT-catenin and plakophilin-2 in the area composita, the mixed-type junctional structure of cardiac intercalated discs. 1753 49

Adherens junctions and desmosomes are intercellular adhesive junctions and essential for the morphogenesis, differentiation, and maintenance of tissues that are subjected to high mechanical stress, including heart and skin. The different junction complexes are organized at the termini of the cardiomyocyte called the intercalated disc. Disruption of adhesive integrity via mutations in genes encoding desmosomal proteins causes an inherited heart disease, arrhythmogenic right ventricular cardiomyopathy (ARVC). Besides plakoglobin, which is shared by adherens junctions and desmosomes, other desmosomal components, desmoglein-2, desmocollin-2, plakophilin-2, and desmoplakin are also present in ultrastructurally defined fascia adherens junctions of heart muscle, but not other tissues. This mixed-type of junctional structure is termed hybrid adhering junction or area composita. Desmosomal plakophilin-2 directly interacts with adherens junction protein alphaT-catenin, providing a new molecular link between the cadherin-catenin complex and desmosome. The area composita only exists in the cardiac intercalated disc of mammalian species suggesting that it evolved to strengthen mechanical coupling in the heart of higher vertebrates. The cross-talk among different junctions and their implication in the pathogenesis of ARVC are discussed in this review.
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PMID:A new perspective on intercalated disc organization: implications for heart disease. 2058 98


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