Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using normal MDCK cells, and MDCK cells stably transfected with a temperature-sensitive viral src allele (pp60 ts-v-src), we have examined the composition and tyrosine phosphorylation of the E-cadherin complex. E-cadherin is a transmembrane calcium-dependent cell-cell adhesion molecule that is complexed with cytoplasmic proteins including alpha-catenin, beta-catenin, plakoglobin (gamma-catenin), and actin. We have identified two heterodimeric complexes which demonstrate that alpha-catenin interacts directly with beta-catenin, or with plakoglobin, in the absence of E-cadherin. beta-Catenin has previously been shown to bind directly to E-cadherin. We propose that E-cadherin associates with alpha-catenin, and thereby the actin cytoskeleton, via either beta-catenin or plakoglobin. We have further identified three new but related protein components of the E-cadherin complex, which are each cross-reactive by Western blot analysis to antibodies directed against p120, a phosphotyrosine substrate of src, and a phosphotyrosine, phosphoserine, and phosphothreonine substrate of growth factor-stimulated signaling pathways. Greater quantities of the p120-related proteins were found present in the E-cadherin immunoprecipitates of ts-src MDCK cells compared to normal MDCK cells, while two of the p120 cross-reactive species were significantly tyrosine phosphorylated in both normal and ts-src MDCK cells. The association of p120-related species with the E-cadherin complex adds them to our consideration of possible modulators of cadherin function. Likewise, the newly identified alpha-catenin-beta-catenin and alpha-catenin-plakoglobin dimers may have interesting biological properties, conceivably including the titration of catenins between cadherin and APC complexes.
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PMID:The E-cadherin complex contains the src substrate p120. 753 97

beta-Catenin is involved in the formation of adherens junctions of mammalian epithelia. It interacts with the cell adhesion molecule E-cadherin and also with the tumor suppressor gene product APC, and the Drosophila homologue of beta-catenin, armadillo, mediates morphogenetic signals. We demonstrate here that E-cadherin and APC directly compete for binding to the internal, armadillo-like repeats of beta-catenin; the NH2-terminal domain of beta-catenin mediates the interaction of the alternative E-cadherin and APC complexes to the cytoskeleton by binding to alpha-catenin. Plakoglobin (gamma-catenin), which is structurally related to beta-catenin, mediates identical interactions. We thus show that the APC tumor suppressor gene product forms strikingly similar associations as found in cell junctions and suggest that beta-catenin and plakoglobin are central regulators of cell adhesion, cytoskeletal interaction, and tumor suppression.
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PMID:E-cadherin and APC compete for the interaction with beta-catenin and the cytoskeleton. 780 82

The tumor suppressor APC protein associates with the cadherin-binding proteins alpha- and beta-catenin. To examine the relationship between cadherin, catenins, and APC, we have tested combinatorial protein-protein interactions in vivo, using a yeast two-hybrid system, and in vitro, using purified proteins. beta-Catenin directly binds to APC at high and low affinity sites. alpha-Catenin cannot directly bind APC but associates with it by binding to beta-catenin. Plakoglobin, also known as gamma-catenin, directly binds to both APC and alpha-catenin and also to the APC-beta-catenin complex, but not directly to beta-catenin. beta-Catenin binds to multiple independent regions of APC, some of which include a previously identified consensus motif and others which contain the centrally located 20 amino acid repeat sequences. The APC binding site on beta-catenin may be discontinuous since neither the carboxyl- nor amino-terminal halves of beta-catenin will independently associate with APC, although the amino-terminal half independently binds alpha-catenin. The catenins bind to APC and E-cadherin in a similar fashion, but APC and E-cadherin do not associate with each other either in the presence or absence of catenins. Thus, APC forms distinct heteromeric complexes containing combinations of alpha-catenin, beta-catenin, and plakoglobin which are independent from the cadherin-catenin complexes.
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PMID:The APC protein and E-cadherin form similar but independent complexes with alpha-catenin, beta-catenin, and plakoglobin. 789 Jun 74

Plakoglobin is a cytoplasmic protein localized in both adherens junctions and desmosomes. Little is known about its function, but it may play a role in maintaining cell junction integrity. A partly homologous protein, beta catenin, is localized mainly in adherens junctions and plays a key role in cell adhesion by associating with cadherins, a family of Ca2+ dependent cell-to-cell adhesion molecules. Recently the product of APC, a tumor suppressor gene, was found to associate with beta catenin. In this study we demonstrated that plakoglobin also associates with APC and that tyrosine phosphorylated plakoglobin associates with cadherins but not with APC. These results suggest that plakoglobin could play a role in mediating the signals of APC by mutual interaction and that this may be regulated by tyrosine phosphorylation.
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PMID:Association of plakoglobin with APC, a tumor suppressor gene product, and its regulation by tyrosine phosphorylation. 807 97

Plakoglobin is a member of a protein family with a repeating amino acid motif called the armadillo repeat, and is a cytoplasmic protein found in both adherens junctions and desmosomes. Little is known about its function, but it has been shown to form distinct complexes with cadherins or desmosomal cadherins. Also, plakoglobin has been shown to form a complex with APC, a tumor suppressor gene product. We have isolated a cDNA clone encoding plakoglobin by means of the polymerase chain reaction (PCR) from a human transitional carcinoma cell line. The cDNA has the same nucleotide sequence as the previously published one [Franke et al. (1989) Proc. Natl. Acad. Sci. USA 86, 4027-4031], except that it has a deletion of 120 bp. The deleted sequence encodes the fourth armadillo repeat. Southern blot analysis of genomic DNA revealed that there is a single copy of the plakoglobin gene per haploid genome. Cloning and sequencing of a genomic DNA fragment containing the 120-bp deletion and the surrounding sequences revealed that these sequences are encoded by a single exon sequence. PCR amplification of the genomic DNA fragment of the corresponding region excluded the possible presence of the 120-bp deletion in the gene. Therefore the variant form is most likely derived through alternative splicing of precursor RNA transcripts in an exon sequence.
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PMID:Cloning of an alternative form of plakoglobin (gamma-catenin) lacking the fourth armadillo repeat. 857 1

Plakoglobin is a major component of the submembranal plaque of adherens junctions and desmosomes in mammalian cells. It is closely related to the Drosophila segment polarity gene armadillo which has a role in the transduction of transmembrane signals that regulate cell fate. Like its close homologue beta-catenin, plakoglobin can associate with the product of the tumor suppressor gene APC that is linked to human colon cancer. We have studied the effect of plakoglobin overexpression, and the cooperation between plakoglobin and N-cadherin, on the morphology and tumorigenic ability of cells either lacking, or expressing cadherin and alpha- and beta-catenin. Overexpression of plakoglobin in SV40-transformed 3T3 (SVT2) cells suppressed the tumorigenicity of the cells in syngeneic mice. Transfection with N-cadherin conferred an epithelial phenotype on the cell culture, but had no significant effect on the tumorigenicity of the cells. Cotransfection of plakoglobin and N-cadherin into SVT2 cells, however, was considerably more effective in tumor suppression than plakoglobin overexpression alone. Finally, transfection of plakoglobin into a human renal carcinoma cell line that expresses neither cadherins nor plakoglobin, or alpha-and beta-catenin, resulted in a dose-dependent suppression of tumor formation by these cells in nude mice. Plakoglobin, in these cells, did not exhibit junctional localization and was diffusely distributed in the cytoplasm, with a significant amount of the protein also localized in the nucleus. The results suggest that plakoglobin can efficiently suppress the tumorigenicity of cells in the presence of, or independently of the cadherin-catenin complex.
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PMID:Suppression of tumorigenicity by plakoglobin: an augmenting effect of N-cadherin. 860 8

The Wnt-1 proto-oncogene induces the accumulation of beta-catenin and plakoglobin, two related proteins that associate with and functionally modulate the cadherin cell adhesion proteins. Here we have investigated the effects of Wnt-1 expression on the tumor suppressor protein APC, which also associates with catenins. Expression of Wnt-1 in two different cell lines greatly increased the stability of APC-catenin complexes. The steady-state levels of both catenins and APC were elevated by Wnt-1, and the half-lives of both beta-catenin and plakoglobin associated with APC were also markedly increased. The stabilization of catenins by Wnt-1 was primarily the result of a selective increase in the amount of uncomplexed, monomeric beta-catenin and plakoglobin, detected both by affinity precipitation and size-exclusion chromatography of cell extracts. Exogenous expression of beta-catenin was possible in cells already responding to Wnt-1 but not in the parental cells, suggesting that Wnt-1 inhibits an essential regulatory mechanism for beta-catenin turnover. APC has the capacity to oppose this Wnt-1 effect in experiments in which overexpression of the central region of APC significantly reduced the size of the monomeric pool of beta-catenin induced by Wnt-1. Thus, the Wnt-1 signal transduction pathway leads to the accumulation of monomeric catenins and stabilization of catenin complex formation with both APC and cadherins.
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PMID:Wnt-1 regulates free pools of catenins and stabilizes APC-catenin complexes. 862 79

Plakoglobin is a member of a protein family with a repeated amino acid motif, the armadillo repeat, and is a cytoplasmic protein found in both adherens junctions and desmosomes. Plakoglobin has been shown to form distinct complexes with cadherins or desmosomal cadherins. Also, plakoglobin has been shown to complex with APC, the tumor suppressor gene product. Recently we isolated a cDNA clone encoding plakoglobin lacking the fourth armadillo repeat of the original 13-repeat protein [Ozawa et al. (1995) J. Biochem. 118, 836-840]. In this study, we established an in vitro assay system to study the molecular interaction of plakoglobin with cadherins, the APC gene product, and alpha-catenin. Establishment of the system and cloning of an alternate form of plakoglobin cDNA allowed us to examine the biological activity of plakoglobin lacking the fourth armadillo repeat. Experiments with the bacterially expressed 12-repeat plakoglobin revealed that the protein binds to E-cadherin, desmoglein (Dsg2), and APC with lower affinity than the 13-repeat form does. Consistent with the observation that the affinity of alpha-catenin for these two alternate forms was similar, we found amino acid residues 104 to 145 of plakoglobin, the residues present in both isoforms, are sufficient for its binding to alpha-catenin.
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PMID:The fourth armadillo repeat of plakoglobin (gamma-catenin) is required for its high affinity binding to the cytoplasmic domains of E-cadherin and desmosomal cadherin Dsg2, and the tumor suppressor APC protein. 874 29

Cadherins comprise a family of calcium-dependent glycoproteins that function in mediating cell-cell adhesion in virtually all solid tissues of multicellular organisms. In epithelial cells, E-cadherin represents a key molecule in the establishment and stabilization of cellular junctions. On the cellular level, E-cadherin is concentrated at the adherens junction and interacts homophilically with E-cadherin molecules of adjacent cells. Significant progress has been made in understanding the extra- and intracellular interactions of E-cadherin. Recent success in solving the three-dimensional structure of an extracellular cadherin domain provides a structural basis for understanding the homophilic interaction mechanism and the calcium requirement of cadherins. According to the crystal structure, individual cadherin molecules cooperate to form a linear cell adhesion zipper. The intracellular anchorage of cadherins is regulated by the dynamic association with cytoplasmic proteins, termed catenins. The cytoplasmic domain of E-cadherin is complexed with either beta-catenin or plakoglobin (gamma-catenin). Beta-catenin and plakoglobin bind directly to alpha-catenin, giving rise to two distinct cadherin-catenin complexes (CCC). Alpha-catenin is thought to link both CCC's to actin filaments. The anchorage of cadherins to the cytoskeleton appears to be regulated by tyrosine phosphorylation. Phosphorylation-induced junctional disassembly targets the catenins, indicating that catenins are components of signal transduction pathways. The unexpected association of catenins with the product of the tumor suppressor gene APC has led to the discovery of a second, cadherin-independent catenin complex. Two separate catenin complexes are therefore involved in the cross-talk between cell adhesion and signal transduction. In this review we focus on protein interactions regulating the molecular architecture and function of the CCC. In the light of a fundamental role of the CCC during mammalian development and tissue morphogenesis, we also discuss the phenotypes of embryos lacking E-cadherin or beta-catenin.
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PMID:Cadherin-catenin complex: protein interactions and their implications for cadherin function. 880 74

Catenins (alpha-, beta- and gamma- or plakoglobin) are cytoplasmic cadherin-associated proteins. Studies on cultured cells have suggested that both alpha-catenin and plakoglobin are important for the adhesive function of cadherins. alpha-catenin binds to both beta-catenin and plakoglobin and may link the cadherin/catenin complex to actin filaments. Separate domains of plakoglobin bind to cadherin and alpha-catenin, suggesting it may act as a bridge between these molecules. However, plakoglobin may have other activities: it is expressed in both desmosomal junctions in association with desmogleins and the cytoplasm in conjunction with APC, and previous work suggests it may act in a dorsal signalling pathway when overexpressed in Xenopus embryos. Here, we have studied the roles of alpha-catenin and plakoglobin directly, by depleting the maternal mRNAs coding for each of them in developing Xenopus embryos. We find that depletion of maternal alpha-catenin causes the loss of intercellular adhesion at the blastula stage, similar to that reported previously for EP cadherin. Depletion of plakoglobin results in a partial loss of adhesion, and a loss of embryonic shape, but does not affect dorsal signalling.
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PMID:The roles of maternal alpha-catenin and plakoglobin in the early Xenopus embryo. 910 71


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