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Nature Reviews. Molecular Cell Biology Feb 2016Collective cell migration has a key role during morphogenesis and during wound healing and tissue renewal in the adult, and it is involved in cancer spreading. In... (Review)
Review
Collective cell migration has a key role during morphogenesis and during wound healing and tissue renewal in the adult, and it is involved in cancer spreading. In addition to displaying a coordinated migratory behaviour, collectively migrating cells move more efficiently than if they migrated separately, which indicates that a cellular interplay occurs during collective cell migration. In recent years, evidence has accumulated confirming the importance of such intercellular communication and exploring the molecular mechanisms involved. These mechanisms are based both on direct physical interactions, which coordinate the cellular responses, and on the collective cell behaviour that generates an optimal environment for efficient directed migration. The recent studies have described how leader cells at the front of cell groups drive migration and have highlighted the importance of follower cells and cell-cell communication, both between followers and between follower and leader cells, to improve the efficiency of collective movement.
Topics: Actin Cytoskeleton; Adherens Junctions; Animals; Cell Communication; Cell Movement; Cell Polarity; Extracellular Matrix Proteins; Gene Expression Regulation; Humans; Morphogenesis; Neoplasm Invasiveness; Signal Transduction; Wound Healing; rac1 GTP-Binding Protein
PubMed: 26726037
DOI: 10.1038/nrm.2015.14 -
Physiological Reviews Jul 2004Intercellular junctions mediate adhesion and communication between adjoining endothelial and epithelial cells. In the endothelium, junctional complexes comprise tight... (Review)
Review
Intercellular junctions mediate adhesion and communication between adjoining endothelial and epithelial cells. In the endothelium, junctional complexes comprise tight junctions, adherens junctions, and gap junctions. The expression and organization of these complexes depend on the type of vessels and the permeability requirements of perfused organs. Gap junctions are communication structures, which allow the passage of small molecular weight solutes between neighboring cells. Tight junctions serve the major functional purpose of providing a "barrier" and a "fence" within the membrane, by regulating paracellular permeability and maintaining cell polarity. Adherens junctions play an important role in contact inhibition of endothelial cell growth, paracellular permeability to circulating leukocytes and solutes. In addition, they are required for a correct organization of new vessels in angiogenesis. Extensive research in the past decade has identified several molecular components of the tight and adherens junctions, including integral membrane and intracellular proteins. These proteins interact both among themselves and with other molecules. Here, we review the individual molecules of junctions and their complex network of interactions. We also emphasize how the molecular architectures and interactions may represent a mechanistic basis for the function and regulation of junctions, focusing on junction assembly and permeability regulation. Finally, we analyze in vivo studies and highlight information that specifically relates to the role of junctions in vascular endothelial cells.
Topics: Adherens Junctions; Animals; Blood Vessels; Endothelium, Vascular; Homeostasis; Humans; Intercellular Junctions; Tight Junctions
PubMed: 15269339
DOI: 10.1152/physrev.00035.2003 -
The Journal of Clinical Investigation Nov 2019Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact... (Clinical Trial)
Clinical Trial
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder with rising incidence. Diseased tissues are heavily vascularized. Surprisingly, the pathogenic impact of the vasculature in IBD and the underlying regulatory mechanisms remain largely unknown. IFN-γ is a major cytokine in IBD pathogenesis, but in the context of the disease, it is almost exclusively its immune-modulatory and epithelial cell-directed functions that have been considered. Recent studies by our group demonstrated that IFN-γ also exerts potent effects on blood vessels. Based on these considerations, we analyzed the vessel-directed pathogenic functions of IFN-γ and found that it drives IBD pathogenesis through vascular barrier disruption. Specifically, we show that inhibition of the IFN-γ response in vessels by endothelial-specific knockout of IFN-γ receptor 2 ameliorates experimentally induced colitis in mice. IFN-γ acts pathogenic by causing a breakdown of the vascular barrier through disruption of the adherens junction protein VE-cadherin. Notably, intestinal vascular barrier dysfunction was also confirmed in human IBD patients, supporting the clinical relevance of our findings. Treatment with imatinib restored VE-cadherin/adherens junctions, inhibited vascular permeability, and significantly reduced colonic inflammation in experimental colitis. Our findings inaugurate the pathogenic impact of IFN-γ-mediated intestinal vessel activation in IBD and open new avenues for vascular-directed treatment of this disease.
Topics: Adherens Junctions; Adult; Aged; Animals; Antigens, CD; Cadherins; Endothelial Cells; Female; Humans; Imatinib Mesylate; Inflammatory Bowel Diseases; Interferon-gamma; Male; Mice; Mice, Knockout; Middle Aged
PubMed: 31566580
DOI: 10.1172/JCI124884 -
Journal of Gastroenterology Feb 2019Acute and chronic pancreatitises are gastrointestinal inflammatory diseases, the incidence of which is increasing worldwide. Most (~ 80%) acute pancreatitis (AP)... (Review)
Review
Acute and chronic pancreatitises are gastrointestinal inflammatory diseases, the incidence of which is increasing worldwide. Most (~ 80%) acute pancreatitis (AP) patients have mild disease, and about 20% have severe disease, which causes multiple organ failure and has a high mortality rate. Chronic pancreatitis (CP) is characterized by chronic inflammation and destruction of normal pancreatic parenchyma, which leads to loss of exocrine and endocrine tissues. Patients with CP also have a higher incidence of pancreatic ductal adenocarcinoma. Although a number of factors are associated with the development and progression of AP and CP, the underlying mechanism is unclear. Adhesion molecules play important roles in cell migration, proliferation, and signal transduction, as well as in development and tissue repair. Loosening of cell-cell adhesion between pancreatic acinar cells and/or endothelial cells increases solute permeability, resulting in interstitial edema, which promotes inflammatory cell migration and disrupts tissue structure. Oxidative stress, which is one of the important pathogenesis of pancreatitis, leads to upregulation of adhesion molecules. Soluble adhesion molecules are reportedly involved in AP. In this review, we focus on the roles of tight junctions (occludin, tricellulin, claudin, junctional adhesion molecule, and zonula occludin), adherens junctions (E-cadherin and p120-, α-, and β-catenin), and other adhesion molecules (selectin and intercellular adhesion molecules) in the progression of AP and CP. Maintaining the normal function of adhesion molecules and preventing their abnormal activation maintain the structure of the pancreas and prevent the development of pancreatitis.
Topics: Adherens Junctions; Animals; Cadherins; Catenins; Cell Adhesion Molecules; Humans; Intercellular Adhesion Molecule-1; Pancreatitis; Tight Junction Proteins; Tight Junctions
PubMed: 30140950
DOI: 10.1007/s00535-018-1500-0 -
Developmental Dynamics : An Official... Mar 2016In epithelial tissues, cells constantly generate and transmit forces between each other. Forces generated by the actomyosin cytoskeleton regulate tissue shape and... (Review)
Review
In epithelial tissues, cells constantly generate and transmit forces between each other. Forces generated by the actomyosin cytoskeleton regulate tissue shape and structure and also provide signals that influence cells' decisions to divide, die, or differentiate. Forces are transmitted across epithelia because cells are mechanically linked through junctional complexes, and forces can propagate through the cell cytoplasm. Here, we review some of the molecular mechanisms responsible for force generation, with a specific focus on the actomyosin cortex and adherens junctions. We then discuss evidence for how these mechanisms promote cell shape changes and force transmission in tissues.
Topics: Actomyosin; Adherens Junctions; Animals; Cell Division; Epithelial Cells; Epithelium; Humans
PubMed: 26756938
DOI: 10.1002/dvdy.24384 -
Experimental Cell Research Sep 2017Cell-cell adhesions are critical for the development and maintenance of tissues. Present at sites of cell-cell contact are the adherens junctions and tight junctions.... (Review)
Review
Cell-cell adhesions are critical for the development and maintenance of tissues. Present at sites of cell-cell contact are the adherens junctions and tight junctions. The adherens junctions mediate cell-cell adhesion via the actions of nectins and cadherins. The tight junctions regulate passage of ions and small molecules between cells and establish cell polarity. Historically, the adherens and tight junctions have been thought of as discrete complexes. However, it is now clear that a high level of interdependency exists between the two junctional complexes. The adherens junctions and tight junctions are physically linked, by the zonula occludens proteins, and linked via signaling molecules including several polarity complexes and actin cytoskeletal modifiers. This review will first describe the individual components of both the adherens and tight junctions and then discuss the coupling of the two complexes with an emphasis on the signaling links and physical interactions between the two junctional complexes.
Topics: Adherens Junctions; Animals; Cadherins; Cell Membrane; Cell Polarity; Cytoskeleton; Humans; Tight Junctions
PubMed: 28372972
DOI: 10.1016/j.yexcr.2017.03.061 -
Tissue Barriers 2019The endothelium physically separates blood from surrounding tissue and yet allows for the regulated passage of nutrients, waste, and leukocytes into and out of the... (Review)
Review
The endothelium physically separates blood from surrounding tissue and yet allows for the regulated passage of nutrients, waste, and leukocytes into and out of the circulation. Trans-endothelium flux occurs across endothelial cells (transcellular) and between endothelial cells (paracellular). Paracellular endothelial barrier function depends on the regulation of cell-cell junctions. Interestingly, a functional relationship between cell-cell junctions and cell-matrix adhesions has long been appreciated but the molecular mechanisms underpinning this relationship are not fully understood. Here we review the evidence that supports the notion that cell-matrix interactions contribute to the regulation of cell-cell junctions, focusing primarily on the important adherens junction protein VE-cadherin. In particular, we will discuss recent insights gained into how integrin signaling impacts VE-cadherin stability in adherens junctions and endothelial barrier function.
Topics: Adherens Junctions; Endothelial Cells; Humans; Integrins
PubMed: 31690180
DOI: 10.1080/21688370.2019.1685844 -
Traffic (Copenhagen, Denmark) Jul 2022E-cadherin has a fundamental role in epithelial tissues by providing cell-cell adhesion. Polarised E-cadherin exocytosis to the lateral plasma membrane is central for...
E-cadherin has a fundamental role in epithelial tissues by providing cell-cell adhesion. Polarised E-cadherin exocytosis to the lateral plasma membrane is central for cell polarity and epithelial homeostasis. Loss of E-cadherin secretion compromises tissue integrity and is a prerequisite for metastasis. Despite this pivotal role of E-cadherin secretion, the transport mechanism is still unknown. Here we identify Myosin V as the motor for E-cadherin secretion. Our data reveal that Myosin V and F-actin are required for the formation of a continuous apicolateral E-cadherin belt, the zonula adherens. We show by live imaging how Myosin V transports E-cadherin vesicles to the plasma membrane, and distinguish two distinct transport tracks: an apical actin network leading to the zonula adherens and parallel actin bundles leading to the basal-most region of the lateral membrane. E-cadherin secretion starts in endosomes, where Rab11 and Sec15 recruit Myosin V for transport to the zonula adherens. We also shed light on the endosomal sorting of E-cadherin by showing how Rab7 and Snx16 cooperate in moving E-cadherin into the Rab11 compartment. Thus, our data help to understand how polarised E-cadherin secretion maintains epithelial architecture and prevents metastasis.
Topics: Actins; Adherens Junctions; Animals; Cadherins; Cell Adhesion; Endosomes; Exocytosis; Humans; Myosin Type V; Neoplasm Metastasis
PubMed: 35575181
DOI: 10.1111/tra.12846 -
Experimental Cell Research Sep 2017Endothelial cells line blood vessels and provide a dynamic interface between the blood and tissues. They remodel to allow leukocytes, fluid and small molecules to enter... (Review)
Review
Endothelial cells line blood vessels and provide a dynamic interface between the blood and tissues. They remodel to allow leukocytes, fluid and small molecules to enter tissues during inflammation and infections. Here we compare the signaling networks that contribute to endothelial permeability and leukocyte transendothelial migration, focusing particularly on signals mediated by small GTPases that regulate cell adhesion and the actin cytoskeleton. Rho and Rap GTPase signaling is important for both processes, but they differ in that signals are activated locally under leukocytes, whereas endothelial permeability is a wider event that affects the whole cell. Some molecules play a unique role in one of the two processes, and could therefore be targeted to selectively alter either endothelial permeability or leukocyte transendothelial migration.
Topics: Actins; Adherens Junctions; Animals; Cell Adhesion; Endothelial Cells; Humans; Leukocytes; Signal Transduction
PubMed: 28602626
DOI: 10.1016/j.yexcr.2017.06.003 -
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