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)

The Rho small GTPases, Cdc42, Rac1 and Rho, are implicated in regulation of integrin-mediated cell-substratum adhesion and cadherin-mediated cell-cell adhesion. Identification and characterization of effectors of these GTPases have provided insights into their modes of action. Rho-kinase, an effector of Rho, regulates integrin-mediated cell-substratum adhesion (focal adhesion) by regulating the phosphorylation state of myosin light chain (MLC): it directly phosphorylates MLC and also inactivates myosin phosphatase. IQGAP1, an effector of Cdc42 and Rac1, regulates cadherin-mediated cell-cell adhesion by interacting with (beta)-catenin and dissociating (alpha)-catenin from the cadherin-catenins complex. Activated Cdc42 and Rac1 inhibit IQGAP1, thereby stabilizing the cadherin-catenins complex. Cdc42/Rac1 and IQGAP1 thus appear to constitute a switch that regulates cadherin-mediated cell-cell adhesion.
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PMID:Cell adhesion and Rho small GTPases. 1057 99

Ca(2+)-dependent cell-cell adhesion is mediated by the cadherin family of transmembrane proteins. Adhesion is achieved by homophilic interaction of the extracellular domains of cadherins on adjacent cells, with the cytoplasmic regions serving to couple the complex to the cytoskeleton. IQGAP1, a novel RasGAP-related protein that interacts with the cytoskeleton, binds to actin, members of the Rho family, and E-cadherin. Calmodulin binds to IQGAP1 and regulates its association with Cdc42 and actin. Here we demonstrate competition between calmodulin and E-cadherin for binding to IQGAP1 both in vitro and in a normal cellular milieu. Immunocytochemical analysis in MCF-7 (E-cadherin positive) and MDA-MB-231 (E-cadherin negative) epithelial cells revealed that E-cadherin is required for accumulation of IQGAP1 at cell-cell junctions. The cell-permeable calmodulin antagonist CGS9343B significantly increased IQGAP1 at areas of MCF-7 cell-cell contact, with a concomitant decrease in the amount of E-cadherin at cell-cell junctions. Analysis of E-cadherin function revealed that CGS9343B significantly decreased homophilic E-cadherin adhesion. On the basis of these data, we propose that disruption of the binding of calmodulin to IQGAP1 enhances the association of IQGAP1 with components of the cadherin-catenin complex at cell-cell junctions, resulting in impaired E-cadherin function.
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PMID:IQGAP1 and calmodulin modulate E-cadherin function. 1060 54

Down-regulation of E-cadherin function is characteristic of cancer cells and might involve the small G-protein Rho family, including Rac1 and Cdc42. IQGAP1 has been reported to be one of the target proteins of Rac1 and Cdc42. To elucidate the role of IQGAP1 in cancer-cell adhesion, its expression was investigated in 47 cases of human gastric cancer by immunohistochemistry and Western blot upon protein fractionation, especially in comparison with E-cadherin and catenin expression. In the non-cancerous columnar epithelium of the stomach, IQGAP1, as well as E-cadherin/catenin, was expressed at the cell-cell boundary. IQGAP1 was frequently observed diffusely in the cytoplasm in intestinal-type tumors (20/22 cases) but was expressed at the cell membrane in diffuse-type tumors (19/25 cases), thus showing significant association with tumor differentiation (p < 0.01). Interestingly, membranous expression of IQGAP1 was inversely correlated with that of E-cadherin (p < 0.05) or alpha-catenin (p < 0.001). These observations were consistent with the Western blot results following protein fractionation. IQGAP1 was dominantly expressed in the soluble fraction in differentiated tumors; however, in undifferentiated tumors, it was mostly in the insoluble fraction. In contrast, both E-cadherin and alpha-catenin were detected only in the insoluble fraction. Thus, subcellular localization of IQGAP1 from the cytoplasm to the cell membrane was correlated with E-cadherin dysfunction and tumor dedifferentiation in gastric carcinogenesis.
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PMID:Localization of IQGAP1 is inversely correlated with intercellular adhesion mediated by e-cadherin in gastric cancers. 1127 80

It has been confirmed that several genes are involved in each step of liver metastasis of colorectal cancer. This article reviews recent highlights in this field. The expression of c-erbB2 or Rho protein in colorectal cancer tissues correlates closely with liver metastasis. Suppressor genes such as nm23, DCC, and DPC4 may play a role in the suppression of liver metastasis. On the other hand, the E-cadherin-catenin system, carbohydrate chains, selectin, and variant CD44 are known to play an important role in cells migration from the primary lesion, the adhesion of tumor cells to endothelial cells, and cell motility. These adhesion molecules may be a biological marker of liver metastasis. In addition, treatment targeting these genes will be a potent therapy for liver metastasis in the future.
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PMID:[Genetic changes in liver metastasis of colorectal cancer and their clinical application]. 1139 98

The integrity of the endothelium is dependent on cell-cell adhesion, which is mediated by vascular-endothelial (VE)-cadherin. Proper VE-cadherin-mediated homotypic adhesion is, in turn, dependent on the connection between VE-cadherin and the cortical actin cytoskeleton. Rho-like small GTPases are key molecular switches that control cytoskeletal dynamics and cadherin function in epithelial as well as endothelial cells. We show here that a cell-penetrating, constitutively active form of Rac (Tat-RacV12) induces a rapid loss of VE-cadherin-mediated cell-cell adhesion in endothelial cells from primary human umbilical veins (pHUVEC). This effect is accompanied by the formation of actin stress fibers and is dependent on Rho activity. However, transduction of pHUVEC with Tat-RhoV14, which induces pronounced stress fiber and focal adhesion formation, did not result in a redistribution of VE-cadherin or an overall loss of cell-cell adhesion. In line with this observation, endothelial permeability was more efficiently increased by Tat-RacV12 than by Tat-RhoV14. The loss of cell-cell adhesion, which is induced by Tat-RacV12, occurred in parallel to and was dependent upon the intracellular production of reactive oxygen species (ROS). Moreover, Tat-RacV12 induced an increase in tyrosine phosphorylation of a component the VE-cadherin-catenin complex, which was identified as alpha-catenin. The functional relevance of this signaling pathway was further underscored by the observation that endothelial cell migration, which requires a transient reduction of cell-cell adhesion, was blocked when signaling through ROS was inhibited. In conclusion, Rac-mediated production of ROS represents a previously unrecognized means of regulating VE-cadherin function and may play an important role in the (patho)physiology associated with inflammation and endothelial damage as well as with endothelial cell migration and angiogenesis.
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PMID:Reactive oxygen species mediate Rac-induced loss of cell-cell adhesion in primary human endothelial cells. 1195 15

Rho GTPases are important regulators of cellular behavior through their effects on processes such as cytoskeletal organization. Here we show interactions between Drosophila Rho1 and the adherens junction components alpha-catenin and p120(ctn). We find that while Rho1 protein is present throughout the cell, it accumulates apically, particularly at sites of cadherin-based adherens junctions. Cadherin and catenin localization is disrupted in Rho1 mutants, implicating Rho1 in their regulation. p120(ctn) has recently been suggested to inhibit Rho activity through an unknown mechanism. We find that Rho1 accumulates in response to lowered p120(ctn) activity. Significantly, we find that Rho1 binds directly to alpha-catenin and p120(ctn) in vitro, and these interactions map to distinct surface-exposed regions of the protein not previously assigned functions. In addition, we find that both alpha-catenin and p120(ctn) co-immunoprecipitate with Rho1-containing complexes from embryo lysates. Our observations suggest that alpha-catenin and p120(ctn) are key players in a mechanism of recruiting Rho1 to its sites of action.
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PMID:Rho1 interacts with p120ctn and alpha-catenin, and regulates cadherin-based adherens junction components in Drosophila. 1213 16

Several lines of evidence support an important role for the insulin-like growth factor system in breast cancer. Alterations in insulin-like growth factor I receptor (IGF-IR) have been associated with breast cancer metastasis; however, the specific role played by the IGF-IR in this process remains unclear. To address this issue, we evaluated MCF-7 breast cancer cells stably transfected either with an antisense construct to the IGF-IR, which reduced the expression of the IGF-IRs by approximately 50% (SX13 cells), or with the empty vector as control (NEO cells). Using functional assays for motility, attachment, and aggregation, we found a 3-fold increase in migration using both the wounding assay and the Boyden chamber migration assay. In addition, the SX13 cells attached less, and there was a reduction in cellular aggregation. These functional changes were accompanied by approximately 50% decrease in expression of E-cadherin and approximately 80% increase in p120 protein levels. Moreover, there was a significant reduction in p120 present in the E-cadherin-catenin-p120 complex. There was a 2-fold increase in active Rac1 and Cdc42 and a 35% decrease in active Rho in the SX13 cells. Our findings strongly suggest that the IGF-IR plays a role in the stabilization of the E-cadherin-catenin complex, thereby providing one possible explanation for the association between low levels of IGF-IR and a higher risk of mammary tumor metastasis.
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PMID:Reduced expression of insulin-like growth factor I receptors in MCF-7 breast cancer cells leads to a more metastatic phenotype. 1243 47

Cadherin-catenin complexes, localized to adherens junctions, are essential for cell-cell adhesion. One means of regulating adhesion is through the juxtamembrane domain of the cadherin cytoplasmic tail. This region is the binding site for p120, leading to the hypothesis that p120 is a key regulator of cell adhesion. p120 has also been suggested to regulate the GTPase Rho and to regulate transcription via its binding partner Kaiso. To test these hypothesized functions, we turned to Drosophila, which has only a single p120 family member. It localizes to adherens junctions and binds the juxtamembrane region of DE-cadherin (DE-cad). We generated null alleles of p120 and found that mutants are viable and fertile and have no substantial changes in junction structure or function. However, p120 mutations strongly enhance mutations in the genes encoding DE-cadherin or Armadillo, the beta-catenin homologue. Finally, we examined the localization of p120 during embryogenesis. p120 localizes to adherens junctions, but its localization there is less universal than that of core adherens junction proteins. Together, these data suggest that p120 is an important positive modulator of adhesion but that it is not an essential core component of adherens junctions.
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PMID:Drosophila p120catenin plays a supporting role in cell adhesion but is not an essential adherens junction component. 1255 51

Invasion causes cancer malignancy. We review recent data about cellular and molecular mechanisms of invasion, focusing on cross-talk between the invaders and the host. Cancer disturbs these cellular activities that maintain multicellular organisms, namely, growth, differentiation, apoptosis, and tissue integrity. Multiple alterations in the genome of cancer cells underlie tumor development. These genetic alterations occur in varying orders; many of them concomitantly influence invasion as well as the other cancer-related cellular activities. Examples discussed are genes encoding elements of the cadherin/catenin complex, the nonreceptor tyrosine kinase Src, the receptor tyrosine kinases c-Met and FGFR, the small GTPase Ras, and the dual phosphatase PTEN. In microorganisms, invasion genes belong to the class of virulence genes. There are numerous clinical and experimental observations showing that invasion results from the cross-talk between cancer cells and host cells, comprising myofibroblasts, endothelial cells, and leukocytes, all of which are themselves invasive. In bone metastases, host osteoclasts serve as targets for therapy. The molecular analysis of invasion-associated cellular activities, namely, homotypic and heterotypic cell-cell adhesion, cell-matrix interactions and ectopic survival, migration, and proteolysis, reveal branching signal transduction pathways with extensive networks between individual pathways. Cellular responses to invasion-stimulatory molecules such as scatter factor, chemokines, leptin, trefoil factors, and bile acids or inhibitory factors such as platelet activating factor and thrombin depend on activation of trimeric G proteins, phosphoinositide 3-kinase, and the Rac and Rho family of small GTPases. The role of proteolysis in invasion is not limited to breakdown of extracellular matrix but also causes cleavage of proinvasive fragments from cell surface glycoproteins.
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PMID:Clinical, cellular, and molecular aspects of cancer invasion. 1266 62

Several signaling pathways that regulate tight junction and adherens junction assembly are being characterized. Calpeptin activates stress fiber assembly in fibroblasts by inhibiting SH2-containing phosphatase-2 (SHP-2), thereby activating Rho-GTPase signaling. Here, we have examined the effects of calpeptin on stress fiber and junctional complex assembly in Madin-Darby canine kidney (MDCK) and LLC-PK epithelial cells. Calpeptin induced disassembly of stress fibers and inhibition of Rho GTPase activity in MDCK cells. Interestingly, calpeptin augmented stress fiber formation in LLC-PK epithelial cells. Calpeptin treatment of MDCK cells resulted in a displacement of zonula occludens-1 (ZO-1) and occludin from cell-cell junctions and a loss of phosphotyrosine on ZO-1 and ZO-2, without any detectable effect on tight junction permeability. Surprisingly, calpeptin increased paracellular permeability in LLC-PK cells even though it did not affect tight junction assembly. Calpeptin also modulated adherens junction assembly in MDCK cells but not in LLC-PK cells. Calpeptin treatment of MDCK cells induced redistribution of E-cadherin and beta-catenin from intercellular junctions and reduced the association of p120ctn with the E-cadherin/catenin complex. Together, our studies demonstrate that calpeptin differentially regulates stress fiber and junctional complex assembly in MDCK and LLC-PK epithelial cells, indicating that these pathways may be regulated in a cell line-specific manner.
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PMID:Differential regulation of junctional complex assembly in renal epithelial cell lines. 1277 55


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