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The Journal of Cell Biology Mar 2018In epithelia, cells adhere to each other in a dynamic fashion, allowing the cells to change their shape and move along each other during morphogenesis. The regulation of...
In epithelia, cells adhere to each other in a dynamic fashion, allowing the cells to change their shape and move along each other during morphogenesis. The regulation of adhesion occurs at the belt-shaped adherens junction, the zonula adherens (ZA). Formation of the ZA depends on components of the Par-atypical PKC (Par-aPKC) complex of polarity regulators. We have identified the Lin11, Isl-1, Mec-3 (LIM) protein Smallish (Smash), the orthologue of vertebrate LMO7, as a binding partner of Bazooka/Par-3 (Baz), a core component of the Par-aPKC complex. Smash also binds to Canoe/Afadin and the tyrosine kinase Src42A and localizes to the ZA in a planar polarized fashion. Animals lacking Smash show loss of planar cell polarity (PCP) in the embryonic epidermis and reduced cell bond tension, leading to severe defects during embryonic morphogenesis of epithelial tissues and organs. Overexpression of Smash causes apical constriction of epithelial cells. We propose that Smash is a key regulator of morphogenesis coordinating PCP and actomyosin contractility at the ZA.
Topics: Adherens Junctions; Animals; Drosophila Proteins; Drosophila melanogaster; Epidermis; Epithelial Cells; Morphogenesis
PubMed: 29358210
DOI: 10.1083/jcb.201610098 -
Journal of Cell Science Jun 2013Adherens junctions have an important role in the control of vascular permeability. These structures are located at cell-to-cell contacts, mediate cell adhesion and... (Review)
Review
Adherens junctions have an important role in the control of vascular permeability. These structures are located at cell-to-cell contacts, mediate cell adhesion and transfer intracellular signals. Adhesion is mediated by cadherins, which interact homophilically in trans and form lateral interactions in cis. VE-cadherin (also known as CDH5 and CD144) is the major component of endothelial adherens junctions and is specific to endothelial cells. Endothelial cells from different types of vessels, such as lymphatic vessels, arteries and veins, show differences in junction composition and organization. Vascular permeability is increased by modifications in the expression and function of adherens junction components. In some cases these defects might be cause of pathology. In this Cell Science at a Glance article, we present the example of the so-called cerebral cavernous malformation (CCM), where adherens junctions are dismantled in the vessels contributing to brain microcirculation. This causes the loss of endothelial cell apical-basal polarity and the formation of cavernomas, which are fragile and hemorrhagic. Other diseases are accompanied by persistent alterations of vascular morphology and permeability, such as seen in tumors. It will be important to achieve a better understanding of the relationship between vascular fragility, malformations and junctional integrity in order to develop more effective therapies.
Topics: Adherens Junctions; Animals; Brain; Capillary Permeability; Cell Adhesion; Endothelial Cells; Endothelium, Vascular; Humans; Microcirculation
PubMed: 23781019
DOI: 10.1242/jcs.124529 -
Biomolecules Oct 2019Adherens junctions, consisting of cadherins and catenins, are a group of cell-to-cell junctions that mediate mechanistic linkage between neighboring cells. By doing so,...
Adherens junctions, consisting of cadherins and catenins, are a group of cell-to-cell junctions that mediate mechanistic linkage between neighboring cells. By doing so, adherens junctions ensure direct intercellular contact and play an indispensable role in maintaining tissue architecture. Considering these critical functions, it is not surprising that adherens junctions are frequently involved in disease. In the present study, the effects of bile duct ligation-a surgical procedure to experimentally induce cholestatic and fibrotic liver pathology-on hepatic adherens junctions were investigated in mice. In essence, it was found that liver mRNA and protein levels of E-cadherin, β-catenin and γ-catenin drastically increase following bile duct ligation. These results could suggest a cytoprotective role for hepatic adherens junctions following bile duct ligation.
Topics: Adherens Junctions; Animals; Bile Ducts; Cholestasis; Ligation; Liver; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL
PubMed: 31652629
DOI: 10.3390/biom9100636 -
Microcirculation (New York, N.Y. : 1994) Jun 2001Shear stresses induce marked morphologic responses from endothelium which include alterations to cell shape and orientation and changes to cytoskeletal organization.... (Review)
Review
Shear stresses induce marked morphologic responses from endothelium which include alterations to cell shape and orientation and changes to cytoskeletal organization. These morphologic changes necessitate remodeling of cell-cell adhesion complexes that are important to control of endothelial cell physiology. Reorganization of endothelial adherens junctions has been characterized, and there are some data that pertain to the signaling pathways that regulate this reorganization. Shear-induced activation of Src, mitogen-activated protein (MAP) kinase (ERK1/2 and p38), and PI 3'-kinase pathways are important candidate pathways, and there is evidence for a role for the Rho GTPases. Very little is known concerning shear-dependence of other junctional complexes, but available data indicates a high degree of shear sensitivity. Given the continuous changes in hemodynamics which occur physiologically in vivo, sensitivity of endothelial cell-cell adhesion complexes to shear will likely prove important to vascular pathophysiology.
Topics: Actins; Adherens Junctions; Animals; Cell Size; Endothelium, Vascular; Focal Adhesions; Heterotrimeric GTP-Binding Proteins; Humans; Stress, Mechanical; Tensile Strength; rho GTP-Binding Proteins
PubMed: 11498782
DOI: 10.1038/sj/mn/7800085 -
FEBS Letters Jan 2022The apical junctional complex (AJC) is a membrane protein ultrastructure that regulates cell adhesion and homeostasis. The tight junction (TJ) and the adherens junction...
The apical junctional complex (AJC) is a membrane protein ultrastructure that regulates cell adhesion and homeostasis. The tight junction (TJ) and the adherens junction (AJ) are substructures of the AJC. The interplay between TJ and AJ membrane proteins to assemble the AJC remains unclear. We employed synthetic biology strategies to express the basic membrane elements of a simple AJC-the adhesive extracellular domains of junctional adhesion molecule A (JAM-A), epithelial cadherin, claudin 1, and occludin-to study their interactions. Our results suggest that calcium concentration fluctuations and JAM-A, acting as an interface molecule between the TJ and AJ, orchestrate their interplay. Calcium affects the secondary structure, oligomerization, and binding affinity of homotypic and heterotypic interactions of TJ and AJ components, thus acting as a molecular switch influencing AJC dynamics.
Topics: Adherens Junctions
PubMed: 34882783
DOI: 10.1002/1873-3468.14252 -
Microvascular Research Jan 2012Lipid peroxidation of polyunsaturated fatty acids generates bioactive aldehydes, which exhibit pro- and anti-inflammatory effects in cells and tissues. Accumulating... (Review)
Review
Hydroxyalkenals and oxidized phospholipids modulation of endothelial cytoskeleton, focal adhesion and adherens junction proteins in regulating endothelial barrier function.
Lipid peroxidation of polyunsaturated fatty acids generates bioactive aldehydes, which exhibit pro- and anti-inflammatory effects in cells and tissues. Accumulating evidence indicates that 4-hydroxynonenal (4-HNE), a major aldehyde derived from lipid peroxidation of n-6 polyunsaturated fatty acids trigger signals that modulates focal adhesion and adherens junction proteins thereby inducing endothelial barrier dysfunction. Similarly, oxidized phospholipids (Ox-PLs) generated by lipid peroxidation of phospholipids with polyunsaturated fatty acids have been implicated in atherogenesis, inflammation and gene expression. Interestingly, physiological concentration of Ox-PLs is anti-inflammatory and protect against endotoxin- and ventilator-associated acute lung injury. Thus, excess generation of bioactive hydroxyalkenals and Ox-PLs during oxidative stress contributes to pathophysiology of various diseases by modulating signaling pathways that regulate pro- and anti-inflammatory responses and barrier regulation. This review summarizes the role of 4-HNE and Ox-PLs affecting cell signaling pathways and endothelial barrier dysfunction through modulation of the activities of proteins/enzymes by Michael adducts formation, enhancing the level of protein tyrosine phosphorylation of the target proteins, and by reorganization of cytoskeletal, focal adhesion, and adherens junction proteins. A better understanding of molecular mechanisms of hydroxyalkenals- and Ox-PLs-mediated pro-and anti-inflammatory responses and barrier function may lead to development of novel therapies to ameliorate oxidative stress related cardio-pulmonary disorders.
Topics: Adherens Junctions; Aldehydes; Animals; Capillary Permeability; Cytoskeleton; Endothelial Cells; Fatty Acids, Unsaturated; Focal Adhesions; Humans; Inflammation Mediators; Lipid Peroxidation; Oxidation-Reduction; Oxidative Stress; Phospholipids; Signal Transduction
PubMed: 21570987
DOI: 10.1016/j.mvr.2011.04.012 -
Developmental Cell Nov 2018During epithelial contraction, cells generate forces to constrict their surface and, concurrently, fine-tune the length of their adherens junctions to ensure force...
During epithelial contraction, cells generate forces to constrict their surface and, concurrently, fine-tune the length of their adherens junctions to ensure force transmission. While many studies have focused on understanding force generation, little is known on how junctional length is controlled. Here, we show that, during amnioserosa contraction in Drosophila dorsal closure, adherens junctions reduce their length in coordination with the shrinkage of apical cell area, maintaining a nearly constant junctional straightness. We reveal that junctional straightness and integrity depend on the endocytic machinery and on the mechanosensitive activity of the actomyosin cytoskeleton. On one hand, upon junctional stretch and decrease in E-cadherin density, actomyosin relocalizes from the medial area to the junctions, thus maintaining junctional integrity. On the other hand, when junctions have excess material and ruffles, junction removal is enhanced, and high junctional straightness and tension are restored. These two mechanisms control junctional length and integrity during morphogenesis.
Topics: Actin Cytoskeleton; Actomyosin; Adherens Junctions; Animals; Cadherins; Drosophila Proteins; Drosophila melanogaster; Endocytosis; Morphogenesis
PubMed: 30458138
DOI: 10.1016/j.devcel.2018.10.025 -
International Journal of Molecular... Jan 2021Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers...
Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.
Topics: Adherens Junctions; Animals; Antibiotics, Antineoplastic; Antigens, CD; Caco-2 Cells; Cadherins; Carrier Proteins; Catenins; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Female; Gene Expression Regulation, Neoplastic; Humans; Inflammatory Breast Neoplasms; Lymphatic Metastasis; Mice; Mice, SCID; Polyethylene Glycols; Signal Transduction; Spheroids, Cellular; Tumor Burden; Xenograft Model Antitumor Assays; Delta Catenin
PubMed: 33525380
DOI: 10.3390/ijms22031275 -
Frontiers in Cellular and Infection... 2023disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected...
disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected zoonotic disease. induces E-cadherin (E-cad) endocytosis and cytoskeletal rearrangement during AJ disassembly, but the detailed mechanism remains unknown. Elucidation of AJ disassembly mechanisms will guide new approaches to developing vaccines and diagnostic methods. In this study, we combine proteomic and imaging analysis with chemical inhibition studies to demonstrate that disrupting the AJs of renal proximal tubule epithelial cells involves the degradation of two armadillo repeat-containing proteins, p0071 and p120-catenin, that stabilize E-cad at the plasma membrane. Combining proteasomal and lysosomal inhibitors substantially prevented p120-catenin degradation, and monolayer integrity destruction without preventing p0071 proteolysis. In contrast, the pan-caspase inhibitor Z-VAD-FMK inhibited p0071 proteolysis and displacement of both armadillo repeat-containing proteins from the cell-cell junctions. Our results show that induces p120-catenin and p0071 degradation, which mutually regulates E-cad stability by co-opting multiple cellular degradation pathways. This strategy may allow to disassemble AJs and disseminate through the body efficiently.
Topics: Delta Catenin; Adherens Junctions; Leptospira interrogans; Proteomics; Catenins
PubMed: 37795382
DOI: 10.3389/fcimb.2023.1228051 -
Current Opinion in Cell Biology Oct 2011The adherens junction (AJ) is a major cell-cell junction that mediates cell recognition, adhesion, morphogenesis, and tissue integrity. Although AJs transmit forces... (Review)
Review
The adherens junction (AJ) is a major cell-cell junction that mediates cell recognition, adhesion, morphogenesis, and tissue integrity. Although AJs transmit forces generated by actomyosin from one cell to another, AJs have long been considered as an area where signal transduction from cadherin ligation takes place through cell adhesion. Through the efforts to understand embryonic or cellular morphogenesis, dynamic interactions between the AJ and actin filaments have become crucial issues to be addressed since actin association is essential for AJ development, remodeling and function. Here, I provide an overview of cadherin-actin interaction from morphological aspects and of possible molecular mechanisms revealed by recent studies.
Topics: Actins; Actomyosin; Adherens Junctions; Animals; Cadherins; Cell Adhesion; Cell Adhesion Molecules; Cell Communication; Cytoskeleton; Humans; Intercellular Junctions; Morphogenesis
PubMed: 21807490
DOI: 10.1016/j.ceb.2011.07.001