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)

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

Fer kinase is a 94-kDa cytoplasmic cell-cell actin-based adherens junction (AJ)-associated nonreceptor protein tyrosine kinase (PTK) found in multiple epithelia including the testis, whereas FerT kinase (51 kDa) is the truncated testis-specific form of Fer kinase, lacking the Fps/Fes/Fer/CIP4 (products of oncogenes identified in avian and feline sarcoma, encoding tyrosine protein kinases) and the three coiled-coil domains versus Fer kinase. Yet the role(s) of Fer kinase in AJ dynamics in the testis remains largely unexplored. We have used an in vitro model of AJ assembly with Sertoli-germ cell cocultures and an in vivo model of AJ disassembly in which adult rats were treated with 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) to study changes in the expression and/or localization of Fer kinase during AJ restructuring. Fer kinase/FerT was expressed by Sertoli and germ cells when cultured in vitro. Using an antibody prepared against a synthetic peptide, NH2-SAPQNCPEEIFTIMMKCWDYK-COOH, corresponding to residues 779-799 of Fer kinase in the rat, which failed to cross-react with FerT kinase, for immunohistochemistry, Fer kinase was detected in the seminiferous epithelium in virtually all stages of the epithelial cycle. At stages XIII-VI, Fer kinase was associated largely with round and elongating spermatids. At stages VII-VIII, Fer kinase associated almost exclusively with round spermatids with very weak staining associated with elongated spermatids. This stage-specific localization of Fer kinase in the epithelium was confirmed by using staged tubules for semiquantitative reverse transcription-polymerase chain reaction. Studies by immunoprecipitation revealed that Fer kinase associated with N-cadherin, gamma-catenin, p120ctn, c-Src (a putative PTK and the product of the transforming, sarcoma-inducing gene of Rous sarcoma virus), Rab 8 (a GTPase), actin, vimentin, but not E-cadherin, afadin, nectin-3, and integrin beta1, suggesting Fer kinase associates not only with the actin-based cell-cell AJ structures, such as the N-cadherin/catenin complex (but not the alpha6beta1 integrin/laminin and the afadin/nectin complex), but also with intermediate filament-based cell-cell desmosomes. An induction in Fer kinase expression was detected during Sertoli-germ cell AJ assembly in vitro but not during AF-2364-induced AJ disruption in vivo. Yet this AF-2364-induced Fer kinase plummeting associated with an induction in N-cadherin, beta-catenin, and p120ctn, particularly at the base of the seminiferous epithelium. In summary, Fer kinase structurally associates with the N-cadherin/catenin protein complex in the testis and can possibly be used to mediate signaling function via the cadherin/catenin protein complex.
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PMID:Fer kinase/FerT and adherens junction dynamics in the testis: an in vitro and in vivo study. 1270 Jan 84

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

Alpha-catenin, an integral part of cadherin-catenin adhesion complexes, is a major binding partner of beta-catenin, a key component of the Wnt pathway, which activates T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription and is often upregulated in cancers. Recently, we identified an alpha-catenin-related protein, alpha-catulin, whose function is poorly understood, as part of a Rho GTPase signaling complex. Here, based on evidence suggesting that alpha-catulin may associate with a beta-catenin fraction, we investigated the role of alpha-catenin family members in beta-catenin-mediated signals. Expression of the full length or a 103-residue region of alpha-catenin strongly inhibits the induction of the TCF/LEF-responsive TOPFLASH reporter in HEK293T cells expressing activated beta-catenin or in cancer cells with constitutively upregulated Wnt signaling, whereas alpha-catulin expression had no effect. Interestingly, alpha-catulin expression attenuates the activation of the cyclin D1 promoter, a target of Wnt pathway signals. Alpha-catulin appears to inhibit Ras-mediated signals to the cyclin D1 promoter, rather than beta-catenin signals, and the synergy between Ras and beta-catenin required to fully activate this promoter. Data suggesting the involvement of Rho in this response are presented and discussed. These results suggest a novel function for alpha-catulin and imply that alpha-catenin and alpha-catulin have distinct activities that downregulate, respectively, beta-catenin and Ras signals converging on the cyclin D1 promoter.
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PMID:Distinct activities of the alpha-catenin family, alpha-catulin and alpha-catenin, on beta-catenin-mediated signaling. 1499 80

To investigate the effects of Rho GTPase inactivation on lens fiber cell cytoskeletal and morphological integrity, a transgenic mouse model expressing C3-exoenzyme (a bacterial toxin) in a lens-specific manner was utilized. Cryosections of whole eyes from C3 transgenic mice and littermate controls were stained for F-actin with rhodamine-phalloidin or immunostained for beta-catenin, aquaporin-0 or connexin-50, and confocal images were recorded. Lens fiber cell morphology was examined at both light and electron microscopic levels. To investigate the influence of Rho GTPase inactivation on the profiles of gene expression, cDNA libraries generated from transgenic and littermate control mouse lenses were screened by cDNA microarray analysis. In contrast to the wild-type lens, fiber cells of the transgenic lens were grossly swollen and disorganized, with abnormal membrane architecture. Staining of F-actin, beta-catenin, aquaporin-0 and connexin-50 was reduced dramatically in the C3 transgenic lens as compared to controls. Western blot analysis and cDNA microarray analysis did not reveal any noticeable decreases in actin, beta-catenin and aquaporin-0 protein levels or expression in C3 transgenic lenses, indicating that altered cytoskeletal organization in response to Rho GTPase inactivation might underlie the noted changes in staining for these proteins. Additionally, cDNA microarray analysis of C3 lens revealed altered expression (at least two-fold, compared to littermate controls) of 44 genes. These include genes encoding extracellular matrix and basement membrane proteins, cell survival and apoptotic pathways, and ion and protein transport. These data indicate that disruption of Rho GTPase function in the developing mouse lens results in abnormal cytoskeletal organization, fiber cell interactions, impaired lens fiber cell morphology and altered gene expression of cellular proteins involved in diverse functions. This work reveals that the morphological and cytoskeletal abnormalities triggered upon Rho GTPase inactivation in lens could be one of the important insults associated with cataract formation in C3 transgenic mouse lens.
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PMID:Impaired cytoskeletal organization and membrane integrity in lens fibers of a Rho GTPase functional knockout transgenic mouse. 1509 15

E-cadherin is a major cell-cell adhesion protein of epithelia that is trafficked to the basolateral cell surface in a polarized fashion. The exact post-Golgi route and regulation of E-cadherin transport have not been fully described. The Rho GTPases Cdc42 and Rac1 have been implicated in many cell functions, including the exocytic trafficking of other proteins in polarized epithelial cells. These Rho family proteins are also associated with the cadherin-catenin complexes at the cell surface. We have used functional mutants of Rac1 and Cdc42 and inactivating toxins to demonstrate specific roles for both Cdc42 and Rac1 in the post-Golgi transport of E-cadherin. Dominant-negative mutants of Cdc42 and Rac1 accumulate E-cadherin at a distinct post-Golgi step. This accumulation occurs before p120(ctn) interacts with E-cadherin, because p120(ctn) localization was not affected by the Cdc42 or Rac1 mutants. Moreover, the GTPase mutants had no effect on the trafficking of a targeting mutant of E-cadherin, consistent with the selective involvement of Cdc42 and Rac1 in basolateral trafficking. These results provide a new example of Rho GTPase regulation of basolateral trafficking and demonstrate novel roles for Cdc42 and Rac1 in the post-Golgi transport of E-cadherin.
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PMID:Polarized trafficking of E-cadherin is regulated by Rac1 and Cdc42 in Madin-Darby canine kidney cells. 1568 11

Endothelial barrier function depends on the integrity of intercellular adherens junctions controlled by the association of VE-cadherin/catenin complex with cortical actin filaments. Both tyrosine phosphorylation/dephosphorylation of junctional proteins and actin reorganization mediated by rho-GTPases regulate barrier function but the relationship between these regulatory mechanisms is unclear. Here we studied the effects of factors increasing protein tyrosine phosphorylation, pervanadate (PV) and VEGF, on distribution of VE-cadherin, F-actin polymerization and transendothelial electrical resistance (TER) in human umbilical vein endothelial cells (HUVECs). Changes in protein tyrosine phosphorylation of cytoplasmic and junctional proteins, as well as the activity of rho-GTPase racl, were also measured. We report for the first time that PV and VEGF induced a rapid transient increase in endothelial barrier function accompanied by rac1 activation, a differentiated tyrosine phosphorylation of the VE-cadherin/catenin complex, recruitment of actin filament to cell junctions and ruffle formation. A sustained decrease in endothelial barrier function was observed at later times of PV and VEGF treatment. Expression of dominant negative rac1, N17rac1 abolished the barrier-enhancing effects of PV and VEGF, while the sustained decrease in barrier function was unaffected. These observations bring into focus early short-term effects of protein tyrosine phosphorylation in cells, often overshadowed by more pronounced and long-lasting later effects and may play an important role in the regulation of endothelial barrier function.
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PMID:Tyrosine phosphorylation and the small GTPase rac cross-talk in regulation of endothelial barrier function. 1626 81

The endothelial adherens junctions (AJs) consist of trans-oligomers of membrane spanning vascular endothelial (VE)-cadherin proteins, which bind beta-catenin through their cytoplasmic domain. beta-Catenin in turn binds alpha-catenin and connects the AJ complex with the actin cytoskeleton. We addressed the in vivo effects of loss of VE-cadherin interactions on lung vascular endothelial permeability and the role of specific Rho GTPase effectors in regulating the increase in permeability induced by AJ destabilization. We used cationic liposomes encapsulating the mutant of VE-cadherin lacking the extracellular domain (DeltaEXD) to interfere with AJ assembly in mouse lung endothelial cells. We observed that lung vascular permeability (quantified as microvessel filtration coefficient [K(f,c)]) was increased 5-fold in lungs expressing DeltaEXD. This did not occur to the same degree on expression of the VE-cadherin mutant, DeltaEXDDeltabeta, lacking the beta-catenin-binding site. The increased vascular permeability was the result of destabilization of VE-cadherin homotypic interaction induced by a shift in the binding of beta-catenin from wild-type VE-cadherin to the expressed DeltaEXD mutant. Because DeltaEXD expression in endothelial cells activated the Rho GTPase Cdc42, we addressed its role in the mechanism of increased endothelial permeability induced by AJ destabilization. Coexpression of dominant-negative Cdc42 (N17Cdc42) prevented the increase in K(f,c) induced by DeltaEXD. This was attributed to inhibition of the association of alpha-catenin with the DeltaEXD-beta-catenin complex. The results demonstrate that Cdc42 regulates AJ permeability by controlling the binding of alpha-catenin with beta-catenin and the consequent interaction of the VE-cadherin/catenin complex with the actin cytoskeleton.
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PMID:Cdc42 regulates adherens junction stability and endothelial permeability by inducing alpha-catenin interaction with the vascular endothelial cadherin complex. 1632 81

Both the cadherin-catenin complex and Rho-family GTPases have been shown to regulate dendrite development. We show here a role for p120 catenin (p120ctn) in regulating spine and synapse formation in the developing mouse brain. p120catenin gene deletion in hippocampal pyramidal neurons in vivo resulted in reduced spine and synapse densities along dendrites. In addition, p120 catenin loss resulted in reduced cadherin levels and misregulation of Rho-family GTPases, with decreased Rac1 and increased RhoA activity. Analyses in vitro indicate that the reduced spine density reflects aberrant Rho-family GTPase signaling, whereas the effects on spine maturation appear to result from reduced cadherin levels and possibly aberrant Rho-family GTPase signaling. Thus, p120ctn acts as a signal coordinator between cadherins and Rho-family GTPases to regulate cytoskeletal changes required during spine and synapse development.
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PMID:p120 catenin regulates dendritic spine and synapse development through Rho-family GTPases and cadherins. 1681 31

The catenin p120 (hereafter p120(ctn)) was first identified as a Src kinase substrate and subsequently characterized as an Armadillo catenin member of the cell-cell adhesion cadherin-catenin complex. In the past decade, many studies have revealed roles for p120(ctn) in regulating Rho family GTPase activity and E-cadherin stability and turnover, events that occur predominantly at the plasma membrane or in the cytoplasm. However, the recent discovery of the nuclear BTB/POZ-ZF transcription factor Kaiso as a p120(ctn) binding partner, coupled with the detection of p120(ctn) in the nucleus of some cell lines and tumor tissues, suggested that like the classical beta-catenin, p120(ctn) undergoes nucleocytoplasmic trafficking and regulates gene expression. Indeed, p120(ctn) has a classic nuclear localization signal and does traffic to the nucleus. Moreover, nuclear p120(ctn) regulates Kaiso DNA-binding and transcriptional activity, similar to beta-catenin's modulation of TCF/LEF transcription activity. However unlike beta-catenin, p120(ctn) does not appear to be a transcriptional activator. Hence it remains to be determined whether the sole role of nuclear p120(ctn) is regulation of Kaiso or whether p120(ctn) binds and regulates other transcription factors or nuclear proteins.
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PMID:Dancing in and out of the nucleus: p120(ctn) and the transcription factor Kaiso. 1705 9


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