-
Open Biology Feb 2020Epithelial cells form highly organized polarized sheets with characteristic cell morphologies and tissue architecture. Cell-cell adhesion and intercellular communication... (Review)
Review
Epithelial cells form highly organized polarized sheets with characteristic cell morphologies and tissue architecture. Cell-cell adhesion and intercellular communication are prerequisites of such cohesive sheets of cells, and cell connectivity is mediated through several junctional assemblies, namely desmosomes, adherens, tight and gap junctions. These cell-cell junctions form signalling hubs that not only mediate cell-cell adhesion but impact on multiple aspects of cell behaviour, helping to coordinate epithelial cell shape, polarity and function. This review will focus on the tight and adherens junctions, constituents of the apical junctional complex, and aims to provide a comprehensive overview of the complex signalling that underlies junction assembly, integrity and plasticity.
Topics: Adherens Junctions; Animals; Cell Adhesion; Cell Communication; Cell Polarity; Desmosomes; Epithelial Cells; Gap Junctions; Gene Regulatory Networks; Humans; Intercellular Junctions
PubMed: 32070233
DOI: 10.1098/rsob.190278 -
Cellular and Molecular Life Sciences :... Sep 2016E-Cadherin-based Adherens Junctions (AJs) are a defining feature of all epithelial sheets. Through the homophilic association of E-Cadherin molecules expressed on... (Review)
Review
E-Cadherin-based Adherens Junctions (AJs) are a defining feature of all epithelial sheets. Through the homophilic association of E-Cadherin molecules expressed on neighboring cells, they ensure intercellular adhesion amongst epithelial cells, and regulate many key aspects of epithelial biology. While their adhesive role requires these structures to remain stable, AJs are also extremely plastic. This plasticity allows for the adaptation of the cell to its changing environment: changes in neighbors after cell division, cell death, or cell movement, and changes in cell shape during differentiation. In this review we focus on the recent advances highlighting the critical role of the apico-basal polarity machinery, and in particular of the Par3/Bazooka scaffold, in the regulation and remodeling of AJs. We propose that by regulating key phosphorylation events on the core E-Cadherin complex components, Par3 and epithelial polarity promote meta-stable protein complexes governing the correct formation, localization, and functioning of AJ.
Topics: Adherens Junctions; Animals; Cadherins; Catenins; Cell Polarity; Epithelial Cells; Membrane Proteins; Phosphoric Monoester Hydrolases; src-Family Kinases
PubMed: 27151512
DOI: 10.1007/s00018-016-2260-8 -
Science Signaling May 2023Linear and disturbed flow differentially regulate gene expression, with disturbed flow priming endothelial cells (ECs) for a proinflammatory, atheroprone expression...
Linear and disturbed flow differentially regulate gene expression, with disturbed flow priming endothelial cells (ECs) for a proinflammatory, atheroprone expression profile and phenotype. Here, we investigated the role of the transmembrane protein neuropilin-1 (NRP1) in ECs exposed to flow using cultured ECs, mice with an endothelium-specific knockout of NRP1, and a mouse model of atherosclerosis. We demonstrated that NRP1 was a constituent of adherens junctions that interacted with VE-cadherin and promoted its association with p120 catenin, stabilizing adherens junctions and inducing cytoskeletal remodeling in alignment with the direction of flow. We also showed that NRP1 interacted with transforming growth factor-β (TGF-β) receptor II (TGFBR2) and reduced the plasma membrane localization of TGFBR2 and TGF-β signaling. NRP1 knockdown increased the abundance of proinflammatory cytokines and adhesion molecules, resulting in increased leukocyte rolling and atherosclerotic plaque size. These findings describe a role for NRP1 in promoting endothelial function and reveal a mechanism by which NRP1 reduction in ECs may contribute to vascular disease by modulating adherens junction signaling and promoting TGF-β signaling and inflammation.
Topics: Animals; Mice; Adherens Junctions; Endothelial Cells; Endothelium; Neuropilin-1; Receptor, Transforming Growth Factor-beta Type II; Cadherins
PubMed: 37220183
DOI: 10.1126/scisignal.abo4863 -
Cold Spring Harbor Perspectives in... Dec 2022Button-like junctions are discontinuous contacts at the border of oak-leaf-shaped endothelial cells of initial lymphatic vessels. These junctions are distinctively... (Review)
Review
Button-like junctions are discontinuous contacts at the border of oak-leaf-shaped endothelial cells of initial lymphatic vessels. These junctions are distinctively different from continuous zipper-like junctions that create the endothelial barrier in collecting lymphatics and blood vessels. Button junctions are point contacts, spaced about 3 µm apart, that border valve-like openings where fluid and immune cells enter lymphatics. In intestinal villi, openings between button junctions in lacteals also serve as entry routes for chylomicrons. Like zipper junctions that join endothelial cells, buttons consist of adherens junction proteins (VE-cadherin) and tight junction proteins (claudin-5, occludin, and others). Buttons in lymphatics form from zipper junctions during embryonic development, can convert into zippers in disease or after experimental genetic or pharmacological manipulation, and can revert back to buttons with treatment. Multiple signaling pathways and local microenvironmental factors have been found to contribute to button junction plasticity and could serve as therapeutic targets in pathological conditions ranging from pulmonary edema to obesity.
Topics: Humans; Adherens Junctions; Cadherins; Endothelial Cells; Lymphatic Vessels; Occludin; Tight Junctions
PubMed: 35534209
DOI: 10.1101/cshperspect.a041178 -
International Journal of Molecular... Jan 2020The tight junction (TJ) and the adherens junction (AJ) bridge the paracellular cleft of epithelial and endothelial cells. In addition to their role as protective... (Review)
Review
The tight junction (TJ) and the adherens junction (AJ) bridge the paracellular cleft of epithelial and endothelial cells. In addition to their role as protective barriers against bacteria and their toxins they maintain ion homeostasis, cell polarity, and mechano-sensing. Their functional loss leads to pathological changes such as tissue inflammation, ion imbalance, and cancer. To better understand the consequences of such malfunctions, the junctional nanoarchitecture is of great importance since it remains so far largely unresolved, mainly because of major difficulties in dynamically imaging these structures at sufficient resolution and with molecular precision. The rapid development of super-resolution imaging techniques ranging from structured illumination microscopy (SIM), stimulated emission depletion (STED) microscopy, and single molecule localization microscopy (SMLM) has now enabled molecular imaging of biological specimens from cells to tissues with nanometer resolution. Here we summarize these techniques and their application to the dissection of the nanoscale molecular architecture of TJs and AJs. We propose that super-resolution imaging together with advances in genome engineering and functional analyses approaches will create a leap in our understanding of the composition, assembly, and function of TJs and AJs at the nanoscale and, thereby, enable a mechanistic understanding of their dysfunction in disease.
Topics: Adherens Junctions; Endothelial Cells; Humans; Microscopy, Fluorescence; Single Molecule Imaging; Tight Junctions
PubMed: 31979366
DOI: 10.3390/ijms21030744 -
Current Biology : CB Jul 2023Collective cell movements contribute to tissue development and repair and spread metastatic disease. In epithelia, cohesive cell movements require reorganization of...
Collective cell movements contribute to tissue development and repair and spread metastatic disease. In epithelia, cohesive cell movements require reorganization of adherens junctions and the actomyosin cytoskeleton. However, the mechanisms that coordinate cell-cell adhesion and cytoskeletal remodeling during collective cell migration in vivo are unclear. We investigated the mechanisms of collective cell migration during epidermal wound healing in Drosophila embryos. Upon wounding, the cells adjacent to the wound internalize cell-cell adhesion molecules and polarize actin and the motor protein non-muscle myosin II to form a supracellular cable around the wound that coordinates cell movements. The cable anchors at former tricellular junctions (TCJs) along the wound edge, and TCJs are reinforced during wound closure. We found that the small GTPase Rap1 was necessary and sufficient for rapid wound repair. Rap1 promoted myosin polarization to the wound edge and E-cadherin accumulation at TCJs. Using embryos expressing a mutant form of the Rap1 effector Canoe/Afadin that cannot bind Rap1, we found that Rap1 signals through Canoe for adherens junction remodeling, but not for actomyosin cable assembly. Instead, Rap1 was necessary and sufficient for RhoA/Rho1 activation at the wound edge. The RhoGEF Ephexin localized to the wound edge in a Rap1-dependent manner, and Ephexin was necessary for myosin polarization and rapid wound repair, but not for E-cadherin redistribution. Together, our data show that Rap1 coordinates the molecular rearrangements that drive embryonic wound healing, promoting actomyosin cable assembly through Ephexin-Rho1, and E-cadherin redistribution through Canoe, thus enabling rapid collective cell migration in vivo.
Topics: Animals; Actomyosin; Cell Adhesion; Drosophila melanogaster; Drosophila Proteins; Cell Movement; Myosins; Adherens Junctions; Cadherins
PubMed: 37244252
DOI: 10.1016/j.cub.2023.05.009 -
International Journal of Molecular... Jul 2023The intercalated disk is a cardiac specific structure composed of three main protein complexes-adherens junctions, desmosomes, and gap junctions-that work in concert to... (Review)
Review
The intercalated disk is a cardiac specific structure composed of three main protein complexes-adherens junctions, desmosomes, and gap junctions-that work in concert to provide mechanical stability and electrical synchronization to the heart. Each substructure is regulated through a variety of mechanisms including proteolysis. Calpain proteases, a class of cysteine proteases dependent on calcium for activation, have recently emerged as important regulators of individual intercalated disk components. In this review, we will examine how calcium homeostasis regulates normal calpain function. We will also explore how calpains modulate gap junctions, desmosomes, and adherens junctions activity by targeting specific proteins, and describe the molecular mechanisms of how calpain dysregulation leads to structural and signaling defects within the heart. We will then examine how changes in calpain activity affects cardiomyocytes, and how such changes underlie various heart diseases.
Topics: Calpain; Calcium; Myocardium; Myocytes, Cardiac; Adherens Junctions
PubMed: 37511485
DOI: 10.3390/ijms241411726 -
Current Opinion in Cell Biology Feb 2018Cell-cell junctions, acting as 'secret handshakes', mediate cell-cell interactions and make multicellularity possible. Work over the previous century illuminated key... (Review)
Review
Cell-cell junctions, acting as 'secret handshakes', mediate cell-cell interactions and make multicellularity possible. Work over the previous century illuminated key players comprising these junctions including the cadherin superfamily, nectins, CAMs, connexins, notch/delta, lectins, and eph/Ephrins. Recent work has focused on elucidating how interactions between these complex and often contradictory cues can ultimately give rise to large-scale organization in tissues. This effort, in turn, has enabled bioengineering advances such as cell-mimetic interfaces that allow us to better probe junction biology and to develop new biomaterials. This review details exciting, recent developments in these areas as well as providing both historical context and a discussion of some topical challenges and opportunities for the future.
Topics: Adherens Junctions; Animals; Biomimetics; Cell Adhesion Molecules; Cell Communication; Cell Engineering; Humans
PubMed: 29438902
DOI: 10.1016/j.ceb.2018.01.001 -
Acta Physiologica (Oxford, England) Jan 2018The endothelial barrier consists of intercellular contacts localized in the cleft between endothelial cells, which is covered by the glycocalyx in a sievelike manner.... (Review)
Review
The endothelial barrier consists of intercellular contacts localized in the cleft between endothelial cells, which is covered by the glycocalyx in a sievelike manner. Both types of barrier-forming junctions, i.e. the adherens junction (AJ) serving mechanical anchorage and mechanotransduction and the tight junction (TJ) sealing the intercellular space to limit paracellular permeability, are tethered to the actin cytoskeleton. Under resting conditions, the endothelium thereby builds a selective layer controlling the exchange of fluid and solutes with the surrounding tissue. However, in the situation of an inflammatory response such as in anaphylaxis or sepsis intercellular contacts disintegrate in post-capillary venules leading to intercellular gap formation. The resulting oedema can cause shock and multi-organ failure. Therefore, maintenance as well as coordinated opening and closure of interendothelial junctions is tightly regulated. The two principle underlying mechanisms comprise spatiotemporal activity control of the small GTPases Rac1 and RhoA and the balance of the phosphorylation state of AJ proteins. In the resting state, junctional Rac1 and RhoA activity is enhanced by junctional components, actin-binding proteins, cAMP signalling and extracellular cues such as sphingosine-1-phosphate (S1P) and angiopoietin-1 (Ang-1). In addition, phosphorylation of AJ components is prevented by junction-associated phosphatases including vascular endothelial protein tyrosine phosphatase (VE-PTP). In contrast, inflammatory mediators inhibiting cAMP/Rac1 signalling cause strong activation of RhoA and induce AJ phosphorylation finally leading to endocytosis and cleavage of VE-cadherin. This results in dissolution of TJs the outcome of which is endothelial barrier breakdown.
Topics: Adherens Junctions; Animals; Capillary Permeability; Endothelium, Vascular; Humans; Tight Junctions
PubMed: 28231640
DOI: 10.1111/apha.12860 -
Mediators of Inflammation 2015Endothelial cells form a semipermeable, regulated barrier that limits the passage of fluid, small molecules, and leukocytes between the bloodstream and the surrounding... (Review)
Review
Endothelial cells form a semipermeable, regulated barrier that limits the passage of fluid, small molecules, and leukocytes between the bloodstream and the surrounding tissues. The adherens junction, a major mechanism of intercellular adhesion, is comprised of transmembrane cadherins forming homotypic interactions between adjacent cells and associated cytoplasmic catenins linking the cadherins to the cytoskeleton. Inflammatory conditions promote the disassembly of the adherens junction and a loss of intercellular adhesion, creating openings or gaps in the endothelium through which small molecules diffuse and leukocytes transmigrate. Tyrosine kinase signaling has emerged as a central regulator of the inflammatory response, partly through direct phosphorylation and dephosphorylation of the adherens junction components. This review discusses the findings that support and those that argue against a direct effect of cadherin and catenin phosphorylation in the disassembly of the adherens junction. Recent findings indicate a complex interaction between kinases, phosphatases, and the adherens junction components that allow a fine regulation of the endothelial permeability to small molecules, leukocyte migration, and barrier resealing.
Topics: Adherens Junctions; Cadherins; Catenins; Cell Adhesion; Cell Movement; Endothelium, Vascular; Humans; Leukocytes; Phosphorylation; Protein Tyrosine Phosphatases; Protein-Tyrosine Kinases; Signal Transduction; Tyrosine
PubMed: 26556953
DOI: 10.1155/2015/272858