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Biochimica Et Biophysica Acta Mar 2008Anchoring junctions are cell adhesion apparatus present in all epithelia and endothelia. They are found at the cell-cell interface (adherens junction (AJ) and desmosome)... (Review)
Review
Anchoring junctions are cell adhesion apparatus present in all epithelia and endothelia. They are found at the cell-cell interface (adherens junction (AJ) and desmosome) and cell-matrix interface (focal contact and hemidesmosome). In this review, we focus our discussion on AJ in particular the dynamic changes and regulation of this junction type in normal epithelia using testis as a model. There are extensive restructuring of AJ (e.g., ectoplasmic specialization, ES, a testis-specific AJ) at the Sertoli-Sertoli cell interface (basal ES) and Sertoli-elongating spermatid interface (apical ES) during the seminiferous epithelial cycle of spermatogenesis to facilitate the migration of developing germ cells across the seminiferous epithelium. Furthermore, recent findings have shown that ES also confers cell orientation and polarity in the seminiferous epithelium, illustrating that some of the functions initially ascribed to tight junctions (TJ), such as conferring cell polarity, are also part of the inherent properties of the AJ (e.g., apical ES) in the testis. The biology and regulation based on recent studies in the testis are of interest to cell biologists in the field, in particular their regulation, which perhaps is applicable to tumorigenesis.
Topics: Adherens Junctions; Animals; Cell Polarity; Endocytosis; Homeostasis; Humans; Male; Membrane Proteins; Models, Biological; Multiprotein Complexes; Peptide Hydrolases; Phosphoprotein Phosphatases; Protease Inhibitors; Protein Kinases; Seminiferous Epithelium; Spermatogenesis; Testis
PubMed: 18068662
DOI: 10.1016/j.bbamem.2007.11.006 -
Microcirculation (New York, N.Y. : 1994) Apr 2019Sepsis is associated with dysfunction of MVEC resulting in organ edema and inflammation. VE-cadherin, a component of MVEC adherens junctions, may be disrupted in sepsis....
OBJECTIVE
Sepsis is associated with dysfunction of MVEC resulting in organ edema and inflammation. VE-cadherin, a component of MVEC adherens junctions, may be disrupted in sepsis. However, the direct connection between individual MVEC VE-cadherin disruption and increased paracellular permeability is uncertain.
METHODS
Human pulmonary MVEC were cultured on a biotin matrix and treated with cytomix, as a model of sepsis, vs PBS. MVEC permeability was assessed by trans-MVEC monolayer leak of Oregon green 488-conjugated avidin, which bound subcellular biotin to localize sites of paracellular leak. Leak was correlated with individual cell-specific MVEC surface VE-cadherin continuity by fluorescence microscopy.
RESULTS
Cytomix treatment reduced total MVEC VE-cadherin density, disrupted surface VE-cadherin continuity, was associated with intercellular gap formation, and enhanced paracellular avidin leak. Cytomix-induced MVEC paracellular avidin leak was strongly correlated temporally and was highly contiguous with focal MVEC surface VE-cadherin disruption. Total cellular VE-cadherin density was less strongly correlated with MVEC paracellular avidin leak and individual cell-specific focal surface VE-cadherin discontinuity.
CONCLUSIONS
These data support a mechanistic link between septic human lung MVEC VE-cadherin disruption and contiguous paracellular protein leak, and will permit more detailed assessment of individual cell-specific mechanisms of septic MVEC barrier dysfunction.
Topics: Adherens Junctions; Antigens, CD; Cadherins; Capillary Permeability; Cells, Cultured; Endothelial Cells; Humans; Lung; Sepsis
PubMed: 30636088
DOI: 10.1111/micc.12528 -
Archives of Biochemistry and Biophysics Aug 2012The molecular mechanisms leading to tumor progression and acquisition of a metastatic phenotype are highly complex and only partially understood. The spatiotemporal... (Review)
Review
The molecular mechanisms leading to tumor progression and acquisition of a metastatic phenotype are highly complex and only partially understood. The spatiotemporal regulation of E-cadherin-mediated adherens junctions is essential for normal epithelia function and tissue integrity. Perturbation of the E-cadherin complex assembly is a key event in epithelial-mesenchymal transition and is directed by a huge number of mechanisms that differ greatly with regard to cell types and tissues. The reduction in intercellular adhesion interferes with tissue integrity and allows cancer cells to disseminate from the primary tumor thereby initiating cancer metastasis. In the present review we will summarize the current findings about the influence of Rho GTPases on the formation and maintenance of adherens junction and will then proceed to discuss the involvement of p120-catenin on cell-cell adhesion and tumor cell migration.
Topics: Adherens Junctions; Animals; Catenins; Cell Adhesion; Humans; Neoplasm Metastasis; Neoplasms; rho GTP-Binding Proteins; Delta Catenin
PubMed: 22583808
DOI: 10.1016/j.abb.2012.04.019 -
Sub-cellular Biochemistry 2012The immunogroblin (Ig) superfamily proteins characterized by the presence of Ig-like domains are involved in various cellular functions. The properties of the Ig-like... (Review)
Review
The immunogroblin (Ig) superfamily proteins characterized by the presence of Ig-like domains are involved in various cellular functions. The properties of the Ig-like domains to form rod-like structures and to bind specifically to other proteins make them ideal for cell surface receptors and cell adhesion molecules (CAMs). Ig-CAMs, nectins in mammals and Echinoid in Drosophila, are crucial components of cadherin-based adherens junctions in the epithelium. Nectins form cell-cell adhesion by their trans-interactions and recruit cadherins to the nectin-initiated cell-cell adhesion site to establish adherens junctions. Thereafter junction adhesion molecules, occludin, and claudins, are recruited to the apical side of adherens junctions to establish tight junctions. The recruitment of these molecules by nectins is mediated both by the direct and indirect interactions of afadin with many proteins, such as catenins, and zonula occludens proteins, and by the nectin-induced reorganization of the actin cytoskeleton. Nectins contribute to the formation of both homotypic and heterotypic types of cell-cell junctions, such as synapses in the brain, contacts between pigment and non-pigment cell layers of the ciliary epithelium in the eye, Sertoli cell-spermatid junctions in the testis, and sensory cells and supporting cells in the sensory organs. In addition, cis- and trans-interactions of nectins with various cell surface proteins, such as integrins, growth factor receptors, and nectin-like molecules (Necls) play important roles in the regulation of many cellular functions, such as cell polarization, movement, proliferation, differentiation, survival, and cell sorting. Furthermore, the Ig-CAMs are implicated in many human diseases including viral infections, ectodermal dysplasia, cancers, and Alzheimer's disease.
Topics: Adherens Junctions; Animals; Cell Adhesion; Cell Adhesion Molecules; Humans; Immunoglobulins; Receptors, Immunologic; Signal Transduction
PubMed: 22674071
DOI: 10.1007/978-94-007-4186-7_7 -
Experimental Cell Research Oct 2005We previously reported that expression of tight-junction molecules occludin, claudin-6 and claudin-7, as well as establishment of epithelial polarity, was triggered in...
We previously reported that expression of tight-junction molecules occludin, claudin-6 and claudin-7, as well as establishment of epithelial polarity, was triggered in mouse F9 cells expressing hepatocyte nuclear factor (HNF)-4alpha [H. Chiba, T. Gotoh, T. Kojima, S. Satohisa, K. Kikuchi, M. Osanai, N. Sawada. Hepatocyte nuclear factor (HNF)-4alpha triggers formation of functional tight junctions and establishment of polarized epithelial morphology in F9 embryonal carcinoma cells, Exp. Cell Res. 286 (2003) 288-297]. Using these cells, we examined in the present study behavior of tight-junction, adherens-junction and cell polarity proteins and elucidated the molecular mechanism behind HNF-4alpha-initiated junction formation and epithelial polarization. We herein show that not only ZO-1 and ZO-2, but also ZO-3, junctional adhesion molecule (JAM)-B, JAM-C and cell polarity proteins PAR-3, PAR-6 and atypical protein kinase C (aPKC) accumulate at primordial adherens junctions in undifferentiated F9 cells. In contrast, CRB3, Pals1 and PATJ appeared to exhibit distinct subcellular localization in immature cells. Induced expression of HNF-4alpha led to translocation of these tight-junction and cell polarity proteins to beltlike tight junctions, where occludin, claudin-6 and claudin-7 were assembled, in differentiated cells. Interestingly, PAR-6, aPKC, CRB3 and Pals1, but not PAR-3 or PATJ, were also concentrated on the apical membranes in differentiated cells. These findings indicate that HNF-4alpha provokes not only expression of tight-junction adhesion molecules, but also modulation of subcellular distribution of junction and cell polarity proteins, resulting in junction formation and epithelial polarization.
Topics: Adherens Junctions; Animals; Cell Line; Cell Polarity; Claudins; DNA-Binding Proteins; Epithelial Cells; Gene Expression; Hepatocyte Nuclear Factor 4; Immunoblotting; Membrane Proteins; Mice; Models, Biological; Phosphoproteins; Reverse Transcriptase Polymerase Chain Reaction; Tight Junctions; Transcription Factors
PubMed: 16098509
DOI: 10.1016/j.yexcr.2005.06.025 -
The Journal of Cell Biology Mar 2011The epithelial cadherin (E-cadherin)-catenin complex binds to cytoskeletal components and regulatory and signaling molecules to form a mature adherens junction (AJ).... (Review)
Review
The epithelial cadherin (E-cadherin)-catenin complex binds to cytoskeletal components and regulatory and signaling molecules to form a mature adherens junction (AJ). This dynamic structure physically connects neighboring epithelial cells, couples intercellular adhesive contacts to the cytoskeleton, and helps define each cell's apical-basal axis. Together these activities coordinate the form, polarity, and function of all cells in an epithelium. Several molecules regulate AJ formation and integrity, including Rho family GTPases and Par polarity proteins. However, only recently, with the development of live-cell imaging, has the extent to which E-cadherin is actively turned over at junctions begun to be appreciated. This turnover contributes to junction formation and to the maintenance of epithelial integrity during tissue homeostasis and remodeling.
Topics: Adherens Junctions; Animals; Cadherins; Cell Polarity; Cytoskeleton; Epithelial Cells; Epithelium; Morphogenesis; beta Catenin; rho GTP-Binding Proteins
PubMed: 21422226
DOI: 10.1083/jcb.201009141 -
European Journal of Cardio-thoracic... Mar 2016Previous animal studies have demonstrated that endothelial adherens-junction molecules are significantly altered in animal myocardium and microvasculature after...
OBJECTIVES
Previous animal studies have demonstrated that endothelial adherens-junction molecules are significantly altered in animal myocardium and microvasculature after cardioplegia and cardiopulmonary bypass (CP/CPB). We investigated the effects of diabetes on expression/phosphorylation/localization of vascular endothelial (VE)-cadherin, β- and γ-catenin in human atrial myocardium and coronary vasculature in the setting of CP/CPB.
METHODS
Right atrial tissue was harvested pre- and post-CP/CPB from non-diabetic (ND) [haemoglobin A1c (HbA1c): 5.4 ± 0.15], controlled (CDM) (HbA1c: 6.3 ± 0.14) and uncontrolled diabetic (UDM) (HbA1c: 9.9 ± 0.72) patients (n = 10/group). Expression/phosphorylation/localization of VE-cadherin, β- and γ-catenin were assessed by immunoblotting, immunoprecipitation and immunohistochemistry. In vitro atrial microvascular reactivity was assessed by videomicroscopy in response to the endothelium-dependent vasodilator adenosine 5'-diphosphate (ADP).
RESULTS
There were no significant differences in VE-cadherin protein expression between pre- and post-CP/CPB among groups. There were significant decreases in VE-cadherin densities in vessels of the UDM group versus the ND group at baseline or post-CP/CPB, respectively (P < 0.05). The level of basal phosphorylated VE-cadherin tends to be higher in the UDM compared with the ND group (P < 0.05). CP/CPB induced more phosphorylation of VE-cadherin in all groups (versus pre-CP/CPB; P < 0.05, respectively) and this effect was more pronounced in the UDM group (P < 0.05 versus ND or CDM). The protein levels of both catenins (β and γ) were lower in post-CP/CPB in UDM than ND patients (P < 0.05). There were significant decreases in vasodilatory response to endothelial-dependent vasodilator ADP after CP/CPB (P < 0.05). This alteration was more pronounced in UDM patients (P < 0.05).
CONCLUSIONS
These data suggest that poorly controlled diabetes down-regulates endothelial adherens-junction protein activation/expression/localization in the setting of CP/CPB. The increased tyrosine phosphorylation and deterioration of VE-cadherin indicate the damage of the cell-cell endothelial junctions in the diabetic vessels undergoing CP/CPB and cardiac surgery. These alterations may lead to increase in vascular permeability and endothelial dysfunction and affect outcomes in diabetic patients after cardiac surgery.
Topics: Adherens Junctions; Antigens, CD; Cadherins; Capillary Permeability; Diabetes Mellitus; Endothelium, Vascular; Female; Heart Arrest, Induced; Humans; Male; Phosphorylation; gamma Catenin
PubMed: 26069241
DOI: 10.1093/ejcts/ezv202 -
Cell Reports Jul 2022Cadherins and integrins are intrinsically linked through the actin cytoskeleton and are largely responsible for the mechanical integrity and organization of tissues. We...
Cadherins and integrins are intrinsically linked through the actin cytoskeleton and are largely responsible for the mechanical integrity and organization of tissues. We show that cadherin clustering stimulates and spatially guides integrin activation. Adherens junction (AJ)-associated integrin activation depends on locally generated tension and does not require extracellular matrix ligands. It leads to the creation of primed integrin clusters, which spatially determine where focal adhesions will form if ligands are present and where ligands will be deposited. AJs that display integrin activation are targeted by microtubules facilitating their disassembly via caveolin-based endocytosis, showing that integrin activation impacts the stability of the core cadherin complex. Thus, the interplay between cadherins and integrins is more intimate than what was once believed and is rooted in the capacity of active integrins to be stabilized via AJ-generated tension. Altogether, our data establish a mechanism of cross-regulation between cadherins and integrins.
Topics: Adherens Junctions; Cadherins; Cell Adhesion; Extracellular Matrix; Focal Adhesions; Integrins; Ligands
PubMed: 35858563
DOI: 10.1016/j.celrep.2022.111091 -
Molecular Biology of the Cell Feb 2022Distant organ metastasis is linked to poor prognosis during cancer progression. The expression level of the focal adhesion adapter protein paxillin varies among...
Distant organ metastasis is linked to poor prognosis during cancer progression. The expression level of the focal adhesion adapter protein paxillin varies among different human cancers, but its role in tumor progression is unclear. Herein we utilize a newly generated PyMT mammary tumor mouse model with conditional paxillin ablation in breast tumor epithelial cells, combined with in vitro three-dimensional (3D) tumor organoids invasion analysis and 2D calcium switch assays, to assess the roles for paxillin in breast tumor cell invasion. Paxillin had little effect on primary tumor initiation and growth but is critical for the formation of distant lung metastasis. In paxillin-depleted 3D tumor organoids, collective cell invasion was substantially perturbed. The 2D cell culture revealed paxillin-dependent stabilization of adherens junctions (AJ). Mechanistically, paxillin is required for AJ assembly through facilitating E-cadherin endocytosis and recycling and HDAC6-mediated microtubule acetylation. Furthermore, Rho GTPase activity analysis and rescue experiments with a RhoA activator or Rac1 inhibitor suggest paxillin is potentially regulating the E-cadherin-dependent junction integrity and contractility through control of the balance of RhoA and Rac1 activities. Together, these data highlight new roles for paxillin in the regulation of cell-cell adhesion and collective tumor cell migration to promote the formation of distance organ metastases.
Topics: Adherens Junctions; Animals; Breast; Breast Neoplasms; Cadherins; Cell Adhesion; Cell Line, Tumor; Cell Movement; Epithelial Cells; Female; Focal Adhesions; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasm Invasiveness; Paxillin; rho GTP-Binding Proteins
PubMed: 34851720
DOI: 10.1091/mbc.E21-09-0432 -
Tissue Barriers Apr 2023The oral cavity is directly exposed to a variety of environmental stimuli and contains a diverse microbiome that continuously interacts with the oral epithelium....
The oral cavity is directly exposed to a variety of environmental stimuli and contains a diverse microbiome that continuously interacts with the oral epithelium. Therefore, establishment and maintenance of the barrier function of the oral mucosa is of paramount importance for its function and for the body's overall health. The adherens junction is a cell-cell adhesion complex that is essential for epithelial barrier function. Although a considerable body of work has associated barrier disruption with oral diseases, the molecular underpinnings of these associations have not been equally investigated. This is critical, since adherens junction components also possess significant signaling roles in the cell, in addition to their architectural ones. Here, we summarize current knowledge involving adherens junction components in oral pathologies, such as cancer and oral pathogen-related diseases, while we also discuss gaps in the knowledge and opportunities for future investigation of the relationship between adherens junctions and oral diseases.
Topics: Adherens Junctions; Mouth Mucosa; Signal Transduction
PubMed: 35659464
DOI: 10.1080/21688370.2022.2084320