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Current Opinion in Cell Biology Feb 2018Mechanical signals from the extracellular space are paramount to coordinate tissue morphogenesis and homeostasis. Although there is a wide variety of cellular mechanisms... (Review)
Review
Mechanical signals from the extracellular space are paramount to coordinate tissue morphogenesis and homeostasis. Although there is a wide variety of cellular mechanisms involved in transducing extracellular forces, recent literature emphasizes the central role of two main adhesion complexes in epithelial mechanosensitive processes: focal adhesions and adherens junctions. These biomechanical sensors can decode physical signals such as matrix stiffness or intercellular tension into a wide range of coordinated cellular responses, which can impact cell differentiation, migration, and proliferation. Communication between cells and their microenvironment plays a pivotal role both in physiological and pathological conditions. Here we summarize the most recent findings on the biology of these mechanotransduction pathways in epithelial cells, highlighting the extensive amount of biological processes coordinated by cell-matrix and cell-cell adhesion complexes.
Topics: Adherens Junctions; Animals; Cell Adhesion; Epithelial Cells; Focal Adhesions; Humans; Mechanotransduction, Cellular; Neoplasms
PubMed: 29454273
DOI: 10.1016/j.ceb.2018.01.013 -
Traffic (Copenhagen, Denmark) Dec 2016Cadherin-based adherens junctions are critical for connecting cells in tissues. Regulated cadherin trafficking also makes these complexes amazingly dynamic, with... (Review)
Review
Cadherin-based adherens junctions are critical for connecting cells in tissues. Regulated cadherin trafficking also makes these complexes amazingly dynamic, with permissive and instructive consequences on multicellular development. Here, we review how cadherin trafficking affects various forms of tissue morphogenesis from Drosophila and Caenorhabditis elegans to zebrafish, Xenopus and mouse. We describe how core trafficking machinery (such as clathrin, dynamin, Rab small G proteins and the exocyst complex) integrates with other molecular systems (transcriptional factors, signaling pathways, microtubules, actin networks, apico-basal polarity proteins and planar cell polarity proteins) to control cadherin endocytosis, exocytosis and recycling. This control can occur at all cell-cell contacts or specific junctions for distinct effects on tissue morphogenesis during animal development.
Topics: Adherens Junctions; Animals; Cadherins; Cell Polarity; Embryonic Development; Endocytosis; Exocytosis; Humans; Morphogenesis; Organogenesis; Protein Transport
PubMed: 27105637
DOI: 10.1111/tra.12407 -
The Journal of Biological Chemistry Nov 2019To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression... (Review)
Review
To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, and differentiation as well as the processes of tissue regeneration and wound repair. Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states, such as fibrosis, muscle diseases, and cancer. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical signals, like activation of specific genes and signaling cascades that enable cells to adapt to their physical environment. The signaling pathways involved in mechanical signaling are highly complex, but numerous studies have highlighted a central role for the Hippo pathway and other signaling networks in regulating the YAP and TAZ (YAP/TAZ) proteins to mediate the effects of mechanical stimuli on cellular behavior. How mechanical cues control YAP/TAZ has been poorly understood. However, rapid progress in the last few years is beginning to reveal a surprisingly diverse set of pathways for controlling YAP/TAZ. In this review, we will focus on how mechanical perturbations are sensed through changes in the actin cytoskeleton and mechanosensors at focal adhesions, adherens junctions, and the nuclear envelope to regulate YAP/TAZ.
Topics: Actin Cytoskeleton; Adaptor Proteins, Signal Transducing; Adherens Junctions; Animals; Focal Adhesions; Humans; Mechanotransduction, Cellular; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins
PubMed: 31594864
DOI: 10.1074/jbc.REV119.007963 -
Trends in Cell Biology Apr 2018Within tissues, key cellular adaptations occur via mechanotransduction responses at cell-cell junctions. Adherens junctions (AJs) typically form between cells as a... (Review)
Review
Within tissues, key cellular adaptations occur via mechanotransduction responses at cell-cell junctions. Adherens junctions (AJs) typically form between cells as a result of the binding of cadherin receptors of the same type (homotypic), and are linked to the force-propagating and -generating actomyosin cytoskeleton. Recent studies have found that AJs maintain monolayer integrity in dynamic tissues and drive collective cell behavior by converting into asymmetric remodeling entities. Here, we overview the molecular processes that may explain how asymmetric cell-cell junctions sense differences in cytoskeletal geometry between cells. We discuss the link between cadherin-complex dynamics and the actomyosin cytoskeleton at asymmetric cell-cell junctions. We then outline the role of Bin/Amphiphysin/Rvs (BAR) proteins, cytoplasmic regulators of endocytosis and cytoskeletal dynamics that sense force-induced membrane curvature, at AJs undergoing asymmetric remodeling. Lastly, we highlight the physiological importance of junctional asymmetry for epithelial and vascular tissue and discuss its potential role in disease.
Topics: Actomyosin; Adherens Junctions; Animals; Cadherins; Cell Membrane; Cytoskeleton; Endocytosis; Humans; Mechanotransduction, Cellular; Models, Biological
PubMed: 29195724
DOI: 10.1016/j.tcb.2017.11.002 -
Biochemistry. Biokhimiia Dec 2018Epithelial-mesenchymal transition (EMT) is a fundamental process of morphogenesis whereby epithelial cells acquire the mesenchymal phenotype. Multiple data suggest a... (Review)
Review
Epithelial-mesenchymal transition (EMT) is a fundamental process of morphogenesis whereby epithelial cells acquire the mesenchymal phenotype. Multiple data suggest a critical role of EMT in tumor progression. In carcinomas, EMT can be initiated and promoted by many oncogenic signaling pathways, hypoxia, and signals of tumor microenvironment resulting in epithelial cells losing their cell polarity and cell-cell adhesion and gaining the migratory and invasive properties. Downregulation of expression of the cell adhesion protein E-cadherin is considered a poor prognostic factor in cancer. Many tumors are characterized by incomplete EMT, where tumor cells acquire mesenchymal characteristics but retain their epithelial markers, in particular, E-cadherin. In cells with the hybrid epithelial-mesenchymal phenotype, E-cadherin is accumulated in adherens junctions which are less stable than adherens junctions in normal epithelial cells. E-cadherin-based adherens junctions are essential for efficient collective migration and invasion of carcinoma cells, and their survival in metastasis. The plasticity of the hybrid epithelial-mesenchymal phenotype improves adaptive capabilities of cancer cells. By undergoing EMT, carcinoma cells become resistant to chemotherapy and acquire the ability to suppress immune response. Emergence of cancer stem cells after EMT activation has been observed in many types of carcinoma.
Topics: Adherens Junctions; Animals; Cadherins; Disease Progression; Epithelial-Mesenchymal Transition; Humans; Neoplasms; Phenotype
PubMed: 30878022
DOI: 10.1134/S0006297918120052 -
Journal of Cell Science Feb 2015The epithelium is a highly organized type of animal tissue. Except for blood and lymph vessels, epithelial cells cover the body, line its cavities in single or... (Review)
Review
The epithelium is a highly organized type of animal tissue. Except for blood and lymph vessels, epithelial cells cover the body, line its cavities in single or stratified layers and support exchange between compartments. In addition, epithelia offer to the body a barrier to pathogen invasion. To transit through or to replicate in epithelia, viruses have to face several obstacles, starting from cilia and glycocalyx where they can be neutralized by secreted immunoglobulins. Tight junctions and adherens junctions also prevent viruses to cross the epithelial barrier. However, viruses have developed multiple strategies to blaze their path through the epithelium by utilizing components of cell–cell adhesion structures as receptors. In this Commentary, we discuss how viruses take advantage of the apical junction complex to spread. Whereas some viruses quickly disrupt epithelium integrity, others carefully preserve it and use cell adhesion proteins and their cytoskeletal connections to rapidly spread laterally. This is exemplified by the hidden transmission of enveloped viruses that use nectins as receptors. Finally, several viruses that replicate preferentially in cancer cells are currently used as experimental cancer therapeutics. Remarkably, these viruses use cell adhesion molecules as receptors, probably because--to reach tumors and metastases--ncolytic viruses must efficiently traverse or break epithelia.
Topics: Adherens Junctions; Cell Adhesion; Cell Adhesion Molecules; Epithelial Cells; Epithelium; Humans; Receptors, Virus; Tight Junctions; Virus Internalization; Viruses
PubMed: 26046138
DOI: 10.1242/jcs.159400 -
Developmental Cell Jan 2021Cell-cell junctions, in particular adherens junctions, are major determinants of tissue mechanics during morphogenesis and homeostasis. In attempts to link junctional... (Review)
Review
Cell-cell junctions, in particular adherens junctions, are major determinants of tissue mechanics during morphogenesis and homeostasis. In attempts to link junctional mechanics to tissue mechanics, many have utilized explicitly or implicitly equilibrium approaches based on adhesion energy, surface energy, and contractility to determine the mechanical equilibrium at junctions. However, it is increasingly clear that they have significant limitations, such as that it remains challenging to link the dynamics of the molecular components to the resulting physical properties of the junction, to its remodeling ability, and to its adhesion strength. In this perspective, we discuss recent attempts to consider the aspect of energy dissipation at junctions to draw contact points with soft matter physics where energy loss plays a critical role in adhesion theories. We set the grounds for a theoretical framework of the junction mechanics that bridges the dynamics at the molecular scale to the mechanics at the tissue scale.
Topics: Adherens Junctions; Animals; Biophysics; Cell Adhesion; Homeostasis; Humans; Mechanotransduction, Cellular; Morphogenesis
PubMed: 33453154
DOI: 10.1016/j.devcel.2020.12.018 -
Cardiovascular Research Jul 2020Microvesicles (MVs) conduct intercellular communication and impact diverse biological processes by transferring bioactive cargos to other cells. We investigated whether...
AIMS
Microvesicles (MVs) conduct intercellular communication and impact diverse biological processes by transferring bioactive cargos to other cells. We investigated whether and how endothelial production of MVs contribute to vascular dysfunction during inflammation.
METHODS AND RESULTS
We measured the levels and molecular properties of endothelial-derived MVs (EC-MVs) from mouse plasma following a septic injury elicited by cecal ligation and puncture, as well as those from supernatants of cultured endothelial cells stimulated by inflammatory agents including cytokines, thrombin, and complement 5a. The mouse studies showed that sepsis caused a significant increase in total plasma vesicles and VE-cadherin+ EC-MVs compared to sham control. In cultured ECs, different inflammatory agents caused diverse patterns of EC-MV production and cargo contents. When topically applied to endothelial cells, EC-MVs induced a cytoskeleton-junction response characterized by myosin light chain phosphorylation, contractile fibre reorganization, VE-cadherin phosphorylation, and adherens junction dissociation, functionally measured as increased albumin transendothelial flux and decreased barrier resistance. The endothelial response was coupled with protein tyrosine phosphorylation promoted by MV cargo containing c-Src kinase, whereas MVs produced from c-Src deficient cells did not exert barrier-disrupting effects. Additionally, EC-MVs contribute to endothelial inflammatory injury by promoting neutrophil-endothelium adhesion and release of neutrophil extracellular traps containing citrullinated histones and myeloperoxidase, a response unaltered by c-Src knockdown.
CONCLUSION
Endothelial-derived microparticles cause endothelial barrier dysfunction by impairing adherens junctions and activating neutrophils. The signalling mechanisms underlying the endothelial cytoskeleton-junction response to EC-MVs involve protein phosphorylation promoted by MV cargo carrying c-Src. However, EC-MV-induced neutrophil activation was not dependent on c-Src.
Topics: Adherens Junctions; Adolescent; Adult; Animals; Cell-Derived Microparticles; Cells, Cultured; Cytoskeleton; Disease Models, Animal; Endothelial Cells; Female; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Inflammation Mediators; Male; Mice, Inbred C57BL; Middle Aged; Permeability; Protein Transport; Sepsis; Young Adult; src-Family Kinases
PubMed: 31504252
DOI: 10.1093/cvr/cvz238 -
Heart Failure Reviews Jan 2019Intercalated discs (ICDs) are highly orchestrated structures that connect neighboring cardiomyocytes in the heart. Three major complexes are distinguished in ICD:... (Review)
Review
Intercalated discs (ICDs) are highly orchestrated structures that connect neighboring cardiomyocytes in the heart. Three major complexes are distinguished in ICD: desmosome, adherens junction (AJ), and gap junction (GJ). Desmosomes are major cell adhesion junctions that anchor cell membrane to the intermediate filament network; AJs connect the actin cytoskeleton of adjacent cells; and gap junctions metabolically and electrically connect the cytoplasm of adjacent cardiomyocytes. All these complexes work as a single unit, the so-called area composita, interdependently rather than individually. Mutation or altered expression of ICD proteins results in various cardiac diseases, such as ARVC (arrhythmogenic right ventricular cardiomyopathy), dilated cardiomyopathy, and hypotrophy cardiomyopathy, eventually leading to heart failure. In this article, we first review the recent findings on the structural organization of ICD and their functions and then focus on the recent advances in molecular pathogenesis of the ICD-related heart diseases, which include two major areas: i) the ICD gene mutations in cardiac diseases, and ii) the involvement of ICD proteins in signal transduction pathways leading to myocardium remodeling and eventual heart failure. These major ICD-related signaling pathways include Wnt/β-catenin pathway, p38 MAPK cascade, Rho-dependent serum response factor (SRF) signaling, calcineurin/NFAT signaling, Hippo kinase cascade, etc., which are differentially regulated in pathological conditions.
Topics: Adherens Junctions; Animals; Cell Adhesion; Desmosomes; Gap Junctions; Heart Diseases; Humans; Mutation, Missense; Myocardium; Myocytes, Cardiac; Signal Transduction
PubMed: 30288656
DOI: 10.1007/s10741-018-9743-7 -
Current Topics in Developmental Biology 2015Cell-cell adhesions are necessary for structural integrity and barrier formation of the epidermis. Here, we discuss insights from genetic and cell biological studies... (Review)
Review
Cell-cell adhesions are necessary for structural integrity and barrier formation of the epidermis. Here, we discuss insights from genetic and cell biological studies into the roles of individual cell-cell junctions and their composite proteins in regulating epidermal development and function. In addition to individual adhesive functions, we will discuss emerging ideas on mechanosensation/transduction of junctions in the epidermis, noncanonical roles for adhesion proteins, and crosstalk/interdependencies between the junctional systems. These studies have revealed that cell adhesion proteins are connected to many aspects of tissue physiology including growth control, differentiation, and inflammation.
Topics: Adherens Junctions; Animals; Cell Adhesion; Cell Adhesion Molecules; Cell Differentiation; Epidermal Cells; Epidermis; Humans; Signal Transduction
PubMed: 25733147
DOI: 10.1016/bs.ctdb.2014.11.027