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)

IQGAP1 contains a domain related to the catalytic portion of the GTPase-activating proteins (GAPs) for the Ras small G proteins, yet it has no RasGAP activity and binds to the Rho family small G proteins Cdc42 and Rac1. It is thought that IQGAP1 is an effector of Rac1 and Cdc42, regulating cell-cell adhesion through the E-cadherin-catenin complex, which controls formation and maintenance of adherens junctions. This study investigates the binding interfaces of the Rac1-IQGAP1 and Cdc42-IQGAP1 complexes. We mutated Rac1 and Cdc42 and measured the effects of mutations on their affinity for IQGAP1. We have identified similarities and differences in the relative importance of residues used by Rac1 and Cdc42 to bind IQGAP1. Furthermore, the residues involved in the complexes formed with IQGAP1 differ from those formed with other effector proteins and GAPs. Relatively few mutations in switch I of Cdc42 or Rac1 affect IQGAP1 binding; only mutations in residues 32 and 36 significantly decrease affinity for IQGAP1. Switch II mutations also affect binding to IQGAP1 although the effects differ between Rac1 and Cdc42; mutation of either Asp-63, Arg-68, or Leu-70 abrogate Rac1 binding, whereas no switch II mutations affect Cdc42 binding to IQGAP1. The Rho family "insert loop" does not contribute to the binding affinity of Rac1/Cdc42 for IQGAP1. We also present thermodynamic data pertaining to the Rac1/Cdc42-RhoGAP complexes. Switch II contributes a large portion of the total binding energy to these complexes, whereas switch I mutations also affect binding. In addition we identify "cold spots" in the Rac1/Cdc42-RhoGAP/IQGAP1 interfaces. Competition data reveal that the binding sites for IQGAP1 and RhoGAP on the small G proteins overlap only partially. Overall, the data presented here suggest that, despite their 71% identity, Cdc42 and Rac1 appear to have only partially overlapping binding sites on IQGAP1, and each uses different determinants to achieve high affinity binding.
 ...
PMID:The IQGAP1-Rac1 and IQGAP1-Cdc42 interactions: interfaces differ between the complexes. 1798 89

The cadherin molecules at adherens junctions have multiple isoforms. Cadherin isoform switching (cadherin switching) occurs during normal developmental processes to allow cell types to segregate from one another. Tumor cells often recapitulate this activity and the result is an aggressive tumor cell that gains the ability to leave the site of the tumor and metastasize. At present, we understand some of the mechanisms that promote cadherin switching and some of the pathways downstream of this process that influence cell behavior. Specific cadherin family members influence growth-factor-receptor signaling and Rho GTPases to promote cell motility and invasion. In addition, p120-catenin probably plays multiple roles in cadherin switching, regulating Rho GTPases and stabilizing cadherins.
 ...
PMID:Cadherin switching. 1832 69

Ca(2+)-dependent cell-cell adhesion is regulated by the cadherin family of cell adhesion proteins. Cadherins form trans-interactions on opposing cell surfaces which result in weak cell-cell adhesion. Stronger cell-cell adhesion occurs by clustering of cadherins and through changes in the organization of the actin cytoskeleton. Although cadherins were thought to bind directly to the actin cytoskeleton through cytoplasmic proteins, termed alpha- and beta-catenin, recent studies with purified proteins indicate that the interaction is not direct, and instead an allosteric switch in alpha-catenin may mediate actin cytoskeleton reorganization. Organization and function of the cadherin-catenin complex are additionally regulated by phosphorylation and endocytosis. Direct studies of cell-cell adhesion has revealed that the cadherin-catenin complex and the underlying actin cytoskeleton undergo a series of reorganizations that are controlled by the Rho GTPases, Rac1 and RhoA, that result in the expansion and completion of cell-cell adhesion. In the present article, in vitro protein assembly studies and live-cell studies of de novo cell-cell adhesion are discussed in the context of how the cadherin-catenin complex and the actin cytoskeleton regulate cell-cell adhesion.
 ...
PMID:Regulation of cell-cell adhesion by the cadherin-catenin complex. 1836 55

p120-catenin is a cytoplasmic binding partner of cadherins and functions as a set point for cadherin expression by preventing cadherin endocytosis, and degradation. p120 is known to regulate cell motility and invasiveness by inhibiting RhoA activity. However, the relationship between these functions of p120 is not understood. Here, we provide evidence that p120 functions as part of a plasma membrane retention mechanism for VE-cadherin by preventing the recruitment of VE-cadherin into membrane domains enriched in components of the endocytic machinery, including clathrin and the adaptor complex AP-2. The mechanism by which p120 regulates VE-cadherin entry into endocytic compartments is dependent on p120's interaction with the cadherin juxtamembrane domain, but occurs independently of p120's prevention of Rho GTPase activity. These findings clarify the mechanism for p120's function in stabilizing VE-cadherin at the plasma membrane and demonstrate a novel role for p120 in modulating the availability of cadherins for entry into a clathrin-dependent endocytic pathway.
 ...
PMID:p120-catenin inhibits VE-cadherin internalization through a Rho-independent mechanism. 1921 43

Oxidative stress is regarded as a causative factor in aging and various degenerative diseases. Here, we show the mechanism by which oxidative stress induces disruption of cell-cell junctions using retinal pigment epithelial cells. We demonstrated that reactive oxygen species (ROS)-mediated activation of Src kinase increases the tyrosine phosphorylation state of p120-catenin and rapidly triggers translocation of p120-catenin and internalization of N-cadherin from the cell-cell adhesion sites to an early endosomal compartment. Endosomal accumulation of p120-catenin resulted in stress fiber formation and cell-cell dissociation through the activation of Rho/Rho kinase pathway. However, these cytoskeletal remodeling and cell-cell dissociation induced by oxidative stress were transient, due to the activation of nuclear factor-kappaB (NF-kappaB) and the expression of manganese superoxide dismutase (Mn-SOD). Using the NF-kappaB specific inhibitor DHMEQ, we found that NF-kappaB is part of a negative feedback loop to control intracellular ROS levels. Finally, we demonstrated that H(2)O(2) treatment alone does not induce the epithelial mesenchymal transition (EMT) in retinal pigment epithelial cells, which can be induced by TNF-alpha treatment. These findings suggest that oxidative stress is a crucial factor to induce the cell-cell dissociation, an initial step of EMT, but does not provide sufficient signals to establish and to maintain the EMT.
 ...
PMID:Molecular mechanisms regulating dissociation of cell-cell junction of epithelial cells by oxidative stress. 1942 20

p120 catenin is a major regulator of cadherin stability at cell-cell contacts and a modulator of Rho GTPase activities. In C2C12 myoblasts, N-cadherin is stabilized at cell contacts through its association with cholesterol-rich membrane domains or lipid rafts (LR) and acts as an adhesion-activated receptor that activates RhoA, an event required for myogenesis induction. Here, we report that association of p120 catenin with N-cadherin at cell contacts occurs specifically in LR. We demonstrate that interaction of p120 catenin with N-cadherin is required for N-cadherin association with LR and for its stabilization at cell contacts. LR disruption inhibits myogenesis induction and N-cadherin-dependent RhoA activation as does the perturbation of the N-cadherin-p120 catenin complex after p120 catenin knockdown. Finally, we observe an N-cadherin-dependent accumulation of RhoA at phosphatidylinositol 4,5-bisphosphate-enriched cell contacts which is lost after LR disruption. Thus, a functional N-cadherin-catenin complex occurs in cholesterol-rich membrane microdomains which allows the recruitment of RhoA and the regulation of its activity during myogenesis induction.
 ...
PMID:N-cadherin/p120 catenin association at cell-cell contacts occurs in cholesterol-rich membrane domains and is required for RhoA activation and myogenesis. 1954 17

Recent evidence suggests a close association between extracellular E-cadherin mutation in diffuse-type gastric carcinoma and the acquisition of a migratory phenotype of tumour cells. To characterize the cellular machinery that mediates the gain of motility of tumour cells with mutant E-cadherin, we turned to the small Rho GTPases Rac1 and Rho because they have been implicated in pathological processes including tumour cell migration and invasion. In the present study, we analyse the activity of Rac1 and Rho in relation to E-cadherin harbouring an in-frame deletion of exon 8 and prove for the first time that the mutation reduces the ability of E-cadherin to activate Rac1 and to inhibit Rho. We provide evidence that the lack of Rac1 activation observed in response to mutant E-cadherin influences the downstream signalling of Rac1, as is shown by the decrease in the binding of the Rac1 effector protein IQGAP1 to Rac1-GTP. Moreover, reduced membranous localization of p120-catenin in mutant E-cadherin expressing cells provides an explanation for the lack of negative regulation of Rho by mutant E-cadherin. Further, we show by time-lapse laser scanning microscopy and invasion assay that the enhanced motility and invasion associated with mutant E-cadherin is sensitive to the inhibition of Rac1 and Rho. Together, these findings present evidence that the mutation of E-cadherin influences Rac1 and Rho activation in opposite directions and that Rac1 and Rho are involved in the establishment of the migratory and invasive phenotype of tumour cells that have an E-cadherin mutation.
 ...
PMID:Rac1 and Rho contribute to the migratory and invasive phenotype associated with somatic E-cadherin mutation. 1958 84

Catenins of the p120 subclass display an array of intracellular localizations and functions. Although the genetic knockout of mouse delta-catenin results in mild cognitive dysfunction, we found severe effects of its depletion in Xenopus. delta-catenin in Xenopus is transcribed as a full-length mRNA, or as three (or more) alternatively spliced isoforms designated A, B and C. Further structural and functional complexity is suggested by three predicted and alternative translation initiation sites. Transcript analysis suggests that each splice isoform is expressed during embryogenesis, with the B and C transcript levels varying according to developmental stage. Unlike the primarily neural expression of delta-catenin reported in mammals, delta-catenin is detectable in most adult Xenopus tissues, although it is enriched in neural structures. delta-catenin associates with classical cadherins, with crude embryo fractionations further revealing non-plasma-membrane pools that might be involved in cytoplasmic and/or nuclear functions. Depletion of delta-catenin caused gastrulation defects, phenotypes that were further enhanced by co-depletion of the related p120-catenin. Depletion was significantly rescued by titrated p120-catenin expression, suggesting that these catenins have shared roles. Biochemical assays indicated that delta-catenin depletion results in reduced cadherin levels and cell adhesion, as well as perturbation of RhoA and Rac1. Titrated doses of C-cadherin, dominant-negative RhoA or constitutively active Rac1 significantly rescued delta-catenin depletion. Collectively, our experiments indicate that delta-catenin has an essential role in amphibian development, and has functional links to cadherins and Rho-family GTPases.
 ...
PMID:Xenopus delta-catenin is essential in early embryogenesis and is functionally linked to cadherins and small GTPases. 1984 87

Vascular and neuronal networks share a similar branching morphology, and emerging evidence implicates common mechanisms in the formation of both systems. delta-Catenin is considered a neuronal catenin regulating neuron cell-cell adhesion and cell motility. Here, we report expression of delta-catenin in vascular endothelium, and show that deletion of only one allele of delta-catenin is sufficient to impair endothelial cell motility and vascular assembly in vitro and pathological angiogenesis in vivo, thereby inhibiting tumor growth and wound healing. In contrast, deletion of one or both allele of delta-catenin had no effects on hormone-induced physiological angiogenesis in the uterus. Molecular analysis confirmed a gene dosage effect of delta-catenin on Rho GTPase activity. Moreover, we show that inflammatory cytokines, but not angiogenic factors, regulate delta-catenin expression, and the levels of delta-catenin positively correlate to human lung cancers. Collectively, our data suggest that inflammation, commonly associated with disease conditions, induces delta-catenin expression that specifically regulates pathological, and not physiological, angiogenesis. Because only pathological angiogenesis is sensitive to decreased levels of delta-catenin, this may provide a good target for antiangiogenic therapy.
 ...
PMID:Heterozygous deficiency of delta-catenin impairs pathological angiogenesis. 2004 86

The phosphatases of regenerating liver (PRLs) are a unique family of plasma membrane-associated protein tyrosine phosphatases that have been hypothesized to be involved in metastatic cancer. How PRLs control cancer cell migration, invasion, and proliferation remains largely unknown. In the current study, we demonstrate a role for PRL-1 in the regulation of filamentous actin dynamics, which could promote cell metastatic processes. Human A549 non-small-cell lung cancer cells stably expressing wild-type PRL-1 exhibited a 60% increase in migration and a 3-fold increase in invasion. Cells expressing catalytic mutants of PRL-1 (C104S and D72A) lacked increased cell migration and invasion, indicating that these phenotypic changes required PRL-1 phosphatase activity. In contrast, PRL-1 small interfering RNA decreased in vitro lung cancer cell migration and invasion. The cadherin-catenin complex and dynamic filamentous actin are believed to control cellular invasiveness. Expression of wild-type PRL-1, but not phosphatase-inactive PRL-1 (C104S or D72A), decreased E-cadherin, vinculin, and paxillin expression. Ectopic expression of wild-type PRL-1 increased RhoA levels, which have an important role in actin filament assembly and stabilization of focal adhesion, and decreased activated Cdc42 and Rac. The Rho-associated protein kinase inhibitor, (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride (Y-27632), decreased RhoA activity, actin filament levels, and cellular migration and invasion in PRL-1-expressing cells. These results suggest that PRL-1 could be a productive cancer therapeutic target and support further efforts to identify its substrates.
 ...
PMID:Phosphatase of regenerating liver-1 promotes cell migration and invasion and regulates filamentous actin dynamics. 2048 58


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>