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

In C. elegans, lin-7 as well as lin-2/lin-10 is involved in the proper localization of the LET-23 receptor tyrosine kinase that regulates vulval induction. The mammalian homologue, mLin-7, forms a ternary complex with the mammalian homologues of LIN-2 and LIN-10 and localizes at cell-cell junctions in epithelial cells, but the mechanism of this localization of mLin-7 is unknown. Nectin is an immunoglobulin-like cell-cell adhesion molecule that is involved in organization of adherens and tight junctions in epithelial cells. Nectin is indirectly associated with the cadherin-catenin system and the actin cytoskeleton through afadin, an actin filament-binding protein. We showed here that mLin-7 localized at the nectin-based cell-cell junctions. This localization of mLin-7 required the interaction of nectin with afadin, but not the cadherin-catenin system or the actin cytoskeleton. mLin-7 did not directly interact with nectin or afadin. The results indicate that mLin-7 localizes at cell-cell junctions through the nectin-afadin system.
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PMID:Localization of mLin-7 at nectin-based cell-cell junctions. 1197 Nov 89

During embryonic limb development, cartilage formation is presaged by a crucial mesenchymal cell condensation phase. N-Cadherin, a Ca2+ -dependent cell-cell adhesion molecule, is expressed in embryonic chick limb buds in a spatiotemporal pattern suggestive of its involvement during cellular condensation; functional blocking of N-cadherin homotypic binding, by using a neutralizing monoclonal antibody, results in perturbed chondrogenesis in vitro and in vivo. In high-density micromass cultures of embryonic limb mesenchymal cells, N-cadherin expression level is high during days 1 and 2, coincident with active cellular condensation, and decreases upon overt chondrogenic differentiation from day 3 on. In this study, we have used a transfection approach to evaluate the effects of gain- and loss-of-function expression of N-cadherin constructs on mesenchymal condensation and chondrogenesis in vitro. Chick limb mesenchymal cells were transfected by electroporation with recombinant expression plasmids encoding wild-type or two mutant extracellular/cytoplasmic deletion forms of N-cadherin. Expression of the transfected N-cadherin forms showed a transient profile, being high on days 1-2 of culture, and decreasing by day 3, fortuitously coincident with the temporal profile of endogenous N-cadherin gene expression. Examined by means of peanut agglutinin (PNA) staining for condensing precartilage mesenchymal cells, cultures overexpressing wild-type N-cadherin showed enhanced cellular condensation on culture days 2 and 3, whereas expression of the deletion mutant forms (extracellular/cytoplasmic) of N-cadherin resulted in a decrease in PNA staining, suggesting that a complete N-cadherin protein is required for normal cellular condensation to occur. Subsequent chondrogenesis was also affected. Cultures overexpressing the wild-type N-cadherin protein showed enhanced chondrogenesis, indicated by increased production of cartilage matrix (sulfated proteoglycans, collagen type II, and cartilage proteoglycan link protein), as well as increased cartilage nodule number and size of individual nodules, compared with control cultures and cultures transfected with either of the two mutant N-cadherin constructs. These results demonstrate that complete N-cadherin function, at the levels of both extracellular homotypic binding and cytoplasmic linkage to the cytoskeleton by means of the catenin complex, is required for chondrogenesis by mediating functional mesenchymal cell condensation.
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PMID:Analysis of N-cadherin function in limb mesenchymal chondrogenesis in vitro. 1224 19

Afadin is an actin filament (F-actin)-binding protein that is associated with the cytoplasmic tail of nectin, a Ca(2+)-independent immunoglobulin-like cell-cell adhesion molecule. Nectin and afadin strictly localize at cell-cell adherens junctions (AJs) undercoated with F-actin bundles and are involved in the formation of AJs in cooperation with E-cadherin in epithelial cells. In epithelial cells of afadin (-/-) mice and (-/-) embryoid bodies, the proper organization of AJs is markedly impaired. However, the molecular mechanism of how the nectin-afadin system is associated with the E-cadherin-catenin system or functions in the formation of AJs has not yet been fully understood. Here we identified a novel afadin-binding protein, named ADIP (afadin DIL domain-interacting protein). ADIP consists of 615 amino acids with a calculated M(r) of 70,954 and has three coiled-coil domains. Northern and Western blot analyses in mouse tissues indicated that ADIP was widely distributed. Immunofluorescence and immunoelectron microscopy revealed that ADIP strictly localized at cell-cell AJs undercoated with F-actin bundles in small intestine absorptive epithelial cells. This localization pattern was the same as those of afadin and nectin. ADIP was undetectable at cell-matrix AJs. ADIP furthermore bound alpha-actinin, an F-actin-bundling protein known to be indirectly associated with E-cadherin through its direct binding to alpha-catenin. These results indicate that ADIP is an afadin- and alpha-actinin-binding protein that localizes at cell-cell AJs and may have two functions. ADIP may connect the nectin-afadin and E-cadherin-catenin systems through alpha-actinin, and ADIP may be involved in organization of the actin cytoskeleton at AJs through afadin and alpha-actinin.
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PMID:ADIP, a novel Afadin- and alpha-actinin-binding protein localized at cell-cell adherens junctions. 1244 11

Loss of the cell adhesion molecule E-cadherin is suggested to promote tumor invasion and distant metastasis in tumor development. Recently, it has been proposed that E-cadherin function requires its linkage to the cytoskeleton through catenins. We evaluated the expression of E-cadherin and alpha-, beta-, gamma-catenins in tissues of human endometrial carcinoma, analyzed the patterns of cell adhesion molecules' expression in endometrial carcinoma and investigated the relationship between the statuses of cell adhesion molecules and various clinicopathological factors. This study investigated the immunohistochemical expression of E-cadherin and alpha-, beta-, gamma-catenins in 33 paraffin embedded formalin fixed tissues of endometrial carcinomas. Aberrant E-cadherin, and alpha-, beta-, gamma-catenin expression was observed in 33.3 (11 of 33), 27.3 (9 of 33), 18.2 (6 of 33), and 51.5 (17 of 33) % of the specimens, respectively. Statistically significant correlation was found between aberrant expression of E-cadherin and lymph node metastasis and cell types other than endometrioid adenocarcinoma. Aberrant pattern of gamma-catenin expression was also correlated with deep myometrial invasion. However, alpha-, and beta-catenin expression was not correlated with any clinicopathological parameters. Using the Kaplan-Meier method and log-rank comparison test, abnormal expression of E-cadherin was correlated closely with poor survival (p < 0.05), but cases with loss of both E-cadherin and catenin expression predicted even poorer survival than cases with only one or no aberrant expression in E-cadherin and catenins. We revealed aberrant expression of these cell adhesion molecules among patients with endometrial carcinoma. Aberrant expression of E-cadherin was correlated with lymph node metastasis and cell types other than endometrioid adenocarcinoma, while aberrant expression of gamma-catenin was related with deep myometrial invasion. The expression of E-cadherin might be a possible prognostic factor for endometrial cancer while the expression of catenins may help predict patient's survival.
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PMID:Expression of E-cadherin and alpha-, beta-, gamma-catenin proteins in endometrial carcinoma. 1249 52

E-cadherin is a Ca(2+)-dependent cell-cell adhesion molecule at adherens junctions (AJs) of epithelial cells. A fragment of N-cadherin lacking its extracellular region serves as a dominant negative mutant (DN) and inhibits cell-cell adhesion activity of E-cadherin, but its mode of action remains to be elucidated. Nectin is a Ca(2+)-independent immunoglobulin-like cell-cell adhesion molecule at AJs and is associated with E-cadherin through their respective peripheral membrane proteins, afadin and catenins, which connect nectin and cadherin to the actin cytoskeleton, respectively. We showed here that overexpression of nectin capable of binding afadin, but not a mutant incapable of binding afadin, reduced the inhibitory effect of N-cadherin DN on the cell-cell adhesion activity of E-cadherin in keratinocytes. Overexpressed nectin recruited N-cadherin DN to the nectin-based cell-cell adhesion sites in an afadin-dependent manner. Moreover, overexpression of nectin enhanced the E-cadherin-based cell-cell adhesion activity. These results suggest that N-cadherin DN competitively inhibits the association of the endogenous nectin-afadin system with the endogenous E-cadherin-catenin system and thereby reduces the cell-cell adhesion activity of E-cadherin. Thus, nectin plays a role in the formation of E-cadherin-based AJs in keratinocytes.
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PMID:Role of nectin in formation of E-cadherin-based adherens junctions in keratinocytes: analysis with the N-cadherin dominant negative mutant. 1268 12

Loss of E-cadherin/catenin mediated cell-cell adhesion and overexpression of matrix metalloproteinases (MMPs) are largely involved in tumor invasion. It has been recently shown that high levels of a soluble 80 kDa fragment of E-cadherin, resulting from a cleavage by MMPs, are found in serum and in urine from cancer patients. Additionally, this soluble E-cadherin (sE-CAD) promotes cell invasion into chick heart and into collagen type I gels. The aim of our study was to examine the mechanism of sE-CAD-induced cell invasion. Since MMPs play a crucial role in invasion, we looked for induction of MMPs by sE-CAD in noninvasive human lung tumor cells 16HBE. An induction of MMP-2, MMP-9 and MT1-MMP expression was observed both at the mRNA and at the protein level in the presence of sE-CAD (in conditioned medium form or in E-cadherin HAV peptide form). No induction of MMP-1, -3 and -7 or variation of the levels of their inhibitors, TIMP-1 and TIMP-2, were detected. The biologic relevance of the sE-CAD-induced MMP upregulation was tested by demonstrating that sE-CAD promotes in vitro cell invasion in a modified Boyden chamber assay. These data provide new insight into mechanisms of tumor invasion by ectodomain shedding of the cell-cell adhesion molecule E-cadherin.
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PMID:Upregulation of MMPs by soluble E-cadherin in human lung tumor cells. 1276 64

Phenotypic and genotypic analyses of cutaneous melanoma have identified the endothelin B receptor (ET(B)R) as tumor progression marker, thus representing a potential therapeutic target. Here, we demonstrate that activation of ET(B)R by endothelin-1 (ET-1) and ET-3 leads to loss of expression of the cell adhesion molecule E-cadherin and associated catenin proteins and gain of N-cadherin expression. Exposure of melanoma cells to ET-1 leads to a 60% inhibition in intercellular communication by inducing phosphorylation of gap junctional protein connexin 43. Additionally, activation of the ET(B)R pathway increases alpha(v)beta(3) and alpha(2)beta(1) integrin expression and matrix metalloproteinase (MMP)-2 and MMP-9, membrane type-1-MMP activation, and tissue inhibitor MMP-2 secretion. The ET(B)R pathway results into the downstream activation of focal adhesion kinase and extracellular signal-regulated kinase 1/2 signaling pathways, which lead to enhanced cell proliferation, adhesion, migration, and MMP-dependent invasion. The small molecule A-192621, an orally bioavailable nonpeptide ET(B)R antagonist, significantly inhibits melanoma growth in nude mice. These findings demonstrate that ET-1 and ET-3 through ET(B)R activation trigger signaling pathways involved in events associated with disruption of normal host-tumor interactions and progression of cutaneous melanoma. Pharmacological interruption of ET(B)R signaling may represent a novel therapeutic strategy in the treatment of this malignancy.
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PMID:Endothelin B receptor blockade inhibits dynamics of cell interactions and communications in melanoma cell progression. 1497 17

Vascular stabilization, a process by which nascent vessels are invested with mural cells, is important in angiogenesis. Here we describe the molecular basis of vascular stabilization regulated by sphingosine 1-phosphate (S1P), a platelet-derived lipid mediator. S1P1 receptor-dependent cell-surface trafficking and activation of the cell-cell adhesion molecule N-cadherin is essential for interactions between endothelial and mural cells. Endothelial cell S1P1/Gi/Rac pathway induces microtubule polymerization, resulting in trafficking of N-cadherin to polarized plasma membrane domains. S1P treatment modulated the phosphorylation of N-cadherin as well as p120-catenin and induced the formation of cadherin/catenin/actin complexes containing novel regulatory and trafficking factors. The net result of endothelial cell S1P1 receptor activation is the proper trafficking and strengthening of N-cadherin-dependent cell-cell adhesion with mural cells. Perturbation of N-cadherin expression with small interfering RNA profoundly attenuated vascular stabilization in vitro and in vivo. S1P-induced trafficking and activation of N-cadherin provides a novel mechanism for the stabilization of nascent blood vessels by mural cells and may be exploited to control angiogenesis and vascular diseases.
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PMID:Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. 1537 28

Gamma-catenin is a cell adhesion molecule and a candidate mediator of Wnt signal transduction. We hypothesized that impaired regulation of gamma-catenin through genetic and epigenetic pathways is associated with the pathogenesis of prostate cancer. To test this hypothesis, cytosine-phosphate-guanine methylation, loss of heterozygosity (LOH), and mutation status of the gamma-catenin gene were analyzed in cultured prostate cancer cell lines, 180 localized prostate cancers, 69 benign prostatic hyperplasias, and 11 hormone refractory prostate cancers (HRPC). In prostate cancer cell lines (DuPro, LNCaP, ND-1, and PC3), gamma-catenin mRNA transcripts were increased after 5-aza-2'-deoxycytidine treatment. In localized prostate cancer, gamma-catenin expression was lower but prevalence of gamma-catenin methylation was higher compared with benign prostatic hyperplasia. However, gamma-catenin methylation did not correlate with Gleason sum, pT category, or capsular penetration. Among localized prostate cancers with positive gamma-catenin methylation, the presence of LOH at chromosome 17q21 was closely related to down-regulation of gamma-catenin mRNA expression. The gamma-catenin mutations were not found in localized prostate cancers, whereas six mutations were found in five HRPCs within or close to the GSK-3beta consensus motif phosphorylation site, among which four HRPCs showed strong nuclear gamma-catenin accumulation. In these four HRPCs, Bcl-2 expression was increased, whereas the target of the Wnt signal, c-myc, was only expressed in one HRPC. Therefore, although epigenetic gamma-catenin methylation is an early event in the development of prostate cancer, simultaneous events of epigenetic cytosine-phosphate-guanine methylation and genetic LOH may be responsible for functional loss of gamma-catenin. The gamma-catenin mutation related to Bcl-2 overexpression has a significant effect on the pathogenesis of HRPC. This is the first report to characterize the epigenetic and genetic regulation of gamma-catenin in human prostate cancer.
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PMID:Functional Loss of the gamma-catenin gene through epigenetic and genetic pathways in human prostate cancer. 1578 23

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


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