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The Journal of Biological Chemistry May 2023Metastasis-suppressor 1 (MTSS1) is a membrane-interacting scaffolding protein that regulates the integrity of epithelial cell-cell junctions and functions as a tumor...
Metastasis-suppressor 1 (MTSS1) is a membrane-interacting scaffolding protein that regulates the integrity of epithelial cell-cell junctions and functions as a tumor suppressor in a wide range of carcinomas. MTSS1 binds phosphoinositide-rich membranes through its I-BAR domain and is capable of sensing and generating negative membrane curvature in vitro. However, the mechanisms by which MTSS1 localizes to intercellular junctions in epithelial cells and contributes to their integrity and maintenance have remained elusive. By carrying out EM and live-cell imaging on cultured Madin-Darby canine kidney cell monolayers, we provide evidence that adherens junctions of epithelial cells harbor lamellipodia-like, dynamic actin-driven membrane folds, which exhibit high negative membrane curvature at their distal edges. BioID proteomics and imaging experiments demonstrated that MTSS1 associates with an Arp2/3 complex activator, the WAVE-2 complex, in dynamic actin-rich protrusions at cell-cell junctions. Inhibition of Arp2/3 or WAVE-2 suppressed actin filament assembly at adherens junctions, decreased the dynamics of junctional membrane protrusions, and led to defects in epithelial integrity. Together, these results support a model in which membrane-associated MTSS1, together with the WAVE-2 and Arp2/3 complexes, promotes the formation of dynamic lamellipodia-like actin protrusions that contribute to the integrity of cell-cell junctions in epithelial monolayers.
Topics: Animals; Dogs; Actin Cytoskeleton; Actin-Related Protein 2-3 Complex; Actins; Adherens Junctions; Epithelial Cells; Intercellular Junctions; Madin Darby Canine Kidney Cells; Membrane Proteins; Pseudopodia; Microfilament Proteins
PubMed: 36871754
DOI: 10.1016/j.jbc.2023.104571 -
Inflammation Research : Official... May 2021As an integral part of the innate immune system, the epithelial membrane is exposed to an array of insults that may trigger an immune response. One of the immune... (Review)
Review
As an integral part of the innate immune system, the epithelial membrane is exposed to an array of insults that may trigger an immune response. One of the immune system's main functions is to regulate the level of communications between the mucosa and the lumen of various tissues. While it is clear that inhaled or ingested substances, or microorganisms may induce changes that affect the epithelial barrier in various ways, the proteins involved in the signaling cascades and physiological events leading to the regulation and maintenance of the barrier are not always well characterized. We review here some of the signaling components involved in regulating the barrier's paracellular permeability, and their potential effects on the activation of an immune response. While an effective immune response must be launched against pathogenic insults, tolerance must also be maintained for non-pathogenic antigens such as those in the commensal flora or for endogenous metabolites. Along with other members of the innate and adaptive immunity, the endocannabinoid system also plays an instrumental role in maintaining the balance between inflammation and tolerance. We discuss the potential effects of endo- and phytocannabinoids on epithelial permeability and how the dysregulation of this system could be involved in diseases and targeted for therapy.
Topics: Adherens Junctions; Animals; Cell Polarity; Epithelial Cells; Humans; Permeability; Tight Junctions
PubMed: 33721031
DOI: 10.1007/s00011-021-01454-1 -
The Journal of Medical Investigation :... 2017The adherens junction (AJ) is a cadherin-based and actin filament associated cell-to-cell junction. AJs can contribute to tissue morphogenesis and homeostasis and their... (Review)
Review
The adherens junction (AJ) is a cadherin-based and actin filament associated cell-to-cell junction. AJs can contribute to tissue morphogenesis and homeostasis and their association with actin filaments is crucial for the functions. There are three types of AJs in terms of the mode of actin filament/AJ association. Among many actin-binding proteins associated with AJs, α-catenin is one of the most important actin filament/AJ linkers that functions in all types of AJs. Although α-catenin in cadherin-catenin complex appears to bind to actin filaments within cells, it fails to bind to actin filaments in vitro mysteriously. Recent report revealed that α-catenin in the complex can bind to actin filaments in vitro when forces are applied to the filament. In addition to force-sensitive vinculin binding, α-catenin has another force-sensitive property of actin filament-binding. Elucidation of its significance and the molecular mechanism is indispensable for understanding AJ formation and maintenance during tissue morphogenesis, function and repair. J. Med. Invest. 64: 14-19, February, 2017.
Topics: Actin Cytoskeleton; Actins; Adherens Junctions; Animals; Humans; Protein Binding; Protein Interaction Domains and Motifs; alpha Catenin
PubMed: 28373611
DOI: 10.2152/jmi.64.14 -
Annals of the New York Academy of... Jun 2017Epithelial tissues form a selective barrier via direct cell-cell interactions to separate and establish concentration gradients between the different compartments of the... (Review)
Review
Epithelial tissues form a selective barrier via direct cell-cell interactions to separate and establish concentration gradients between the different compartments of the body. Proper function and formation of this barrier rely on the establishment of distinct intercellular junction complexes. These complexes include tight junctions, adherens junctions, desmosomes, and gap junctions. The tight junction is by far the most diverse junctional complex in the epithelial barrier. Its composition varies greatly across different epithelial tissues to confer various barrier properties. Thus, epithelial cells rely on tightly regulated transcriptional mechanisms to ensure proper formation of the epithelial barrier and to achieve tight junction diversity. Here, we review different transcriptional mechanisms utilized during embryogenesis and disease development to promote tight junction assembly and maintenance of intercellular barrier integrity. We focus particularly on the Grainyhead-like transcription factors and ligand-activated nuclear hormone receptors, two central families of proteins in epithelialization.
Topics: Adherens Junctions; Animals; Cadherins; Cell Differentiation; Claudin-4; DNA-Binding Proteins; Epithelial Cells; Epithelium; Humans; Models, Genetic; Tight Junctions; Transcription Factors; Transcription, Genetic
PubMed: 28636799
DOI: 10.1111/nyas.13367 -
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 -
Tissue Barriers Oct 2022E-cadherin is the main component of epithelial adherens junctions (AJs), which play a crucial role in the maintenance of stable cell-cell adhesion and overall tissue... (Review)
Review
E-cadherin is the main component of epithelial adherens junctions (AJs), which play a crucial role in the maintenance of stable cell-cell adhesion and overall tissue integrity. Down-regulation of E-cadherin expression has been found in many carcinomas, and loss of E-cadherin is generally associated with poor prognosis in patients. During the last decade, however, numerous studies have shown that E-cadherin is essential for several aspects of cancer cell biology that contribute to cancer progression, most importantly, active cell migration. In this review, we summarize the available data about the input of E-cadherin in cancer progression, focusing on the latest advances in the research of the various roles E-cadherin-based AJs play in cancer cell dissemination. The review also touches upon the "cadherin switching" in cancer cells where N- or P-cadherin replace or are co-expressed with E-cadherin and its influence on the migratory properties of cancer cells.
Topics: Humans; Epithelial-Mesenchymal Transition; Cadherins; Adherens Junctions; Cell Adhesion; Cell Movement; Neoplasms
PubMed: 34821540
DOI: 10.1080/21688370.2021.2005420 -
Advances in Experimental Medicine and... 2018The formation of solid tissues is not a simple aggregation of individual cells but rather an ordered assembly of cells connected by junctions. These junctions provide a... (Review)
Review
The formation of solid tissues is not a simple aggregation of individual cells but rather an ordered assembly of cells connected by junctions. These junctions provide a diffusion barrier as well as mechanical support and a conduit for signalling changes in the environment to the cells. Cell junctions are functionally categorized as occluding (e.g. tight junctions, TJs), anchoring (e.g. adherens junctions, AJs) and communicating junctions (e.g. gap junctions). Each type of the cell junction is formed by protein complexes with extracellular domains and/or intracellular domains, which bind partners that provide scaffolding and signalling components. Cell junctions are ubiquitously expressed in multiple tissues and organs, including the retina. In the retina, their biological impact is not limited to regulating tissue growth and development. Disruption of the complexes mediates both congenital and postnatal pathogenesis. In this review, we will focus on cell junctions, specifically AJs and TJs in the external limiting membrane, in order to articulate their influence on pathophysiology of the retina.
Topics: Adherens Junctions; Cell Communication; Eye Proteins; Gap Junctions; Humans; Membrane Proteins; Nerve Tissue Proteins; Retina; Retinal Diseases; Tight Junctions; Tomography, Optical Coherence
PubMed: 29721986
DOI: 10.1007/978-3-319-75402-4_66 -
F1000Research 2019Mechanical forces drive the remodeling of tissues during morphogenesis. This relies on the transmission of forces between cells by cadherin-based adherens junctions,... (Review)
Review
Mechanical forces drive the remodeling of tissues during morphogenesis. This relies on the transmission of forces between cells by cadherin-based adherens junctions, which couple the force-generating actomyosin cytoskeletons of neighboring cells. Moreover, components of cadherin adhesions adopt force-dependent conformations that induce changes in the composition of adherens junctions, enabling transduction of mechanical forces into an intracellular response. Cadherin mechanotransduction can mediate reinforcement of cell-cell adhesions to withstand forces but also induce biochemical signaling to regulate cell behavior or direct remodeling of cell-cell adhesions to enable cell rearrangements. By transmission and transduction of mechanical forces, cadherin adhesions coordinate cellular behaviors underlying morphogenetic processes of collective cell migration, cell division, and cell intercalation. Here, we review recent advances in our understanding of this central role of cadherin adhesions in force-dependent regulation of morphogenesis.
Topics: Adherens Junctions; Cadherins; Cell Adhesion; Mechanotransduction, Cellular; Morphogenesis
PubMed: 31327995
DOI: 10.12688/f1000research.18779.1 -
The Journal of Cell Biology Dec 2023Notch receptors control tissue morphogenic processes that involve coordinated changes in cell architecture and gene expression, but how a single receptor can produce...
Notch receptors control tissue morphogenic processes that involve coordinated changes in cell architecture and gene expression, but how a single receptor can produce these diverse biological outputs is unclear. Here, we employ a 3D model of a human ductal epithelium to reveal tissue morphogenic defects result from loss of Notch1, but not Notch1 transcriptional signaling. Instead, defects in duct morphogenesis are driven by dysregulated epithelial cell architecture and mitogenic signaling which result from the loss of a transcription-independent, Notch1 cortical signaling mechanism that ultimately functions to stabilize adherens junctions and cortical actin. We identify that Notch1 localization and cortical signaling are tied to apical-basal cell restructuring and discover that a Notch1-FAM83H interaction underlies control of epithelial adherens junctions and cortical actin. Together, these results offer new insights into Notch1 signaling and regulation and advance a paradigm in which transcriptional and cell adhesive programs might be coordinated by a single receptor.
Topics: Humans; Actins; Adherens Junctions; Cell Adhesion; Cell Proliferation; Epithelial Cells; Proteins; Receptor, Notch1; Signal Transduction
PubMed: 37796194
DOI: 10.1083/jcb.202303013 -
Annals of the American Thoracic Society Sep 2017Mucosal tissues represent surfaces that are exposed to the outside world and provide a conduit for internal and external communication. Tissues such as the intestine and... (Review)
Review
Mucosal tissues represent surfaces that are exposed to the outside world and provide a conduit for internal and external communication. Tissues such as the intestine and the lung are lined by layer(s) of epithelial cells that, when organized in three dimensions, provide a critical barrier to the flux of luminal contents. This selective barrier is provided through the regulated expression of junctional proteins and mucins. Tissue oxygen metabolism is central to the maintenance of homeostasis in the mucosa. In some organs (e.g., the colon), low baseline Po determines tissue metabolism and results in basal expression of the transcription factor, hypoxia-inducible factor (HIF), which is enhanced after ischemia/inflammation. Recent studies have indicated that HIF contributes fundamentally to the expression of barrier-related genes and in the regulation of barrier-adaptive responses within the mucosa. Here, we briefly review recent literature on the topic of hypoxia and HIF regulation of barrier in mucosal health and during disease.
Topics: Adherens Junctions; Animals; Epithelial Cells; Homeostasis; Humans; Hypoxia-Inducible Factor 1; Mucous Membrane; Oxygen; Tight Junctions
PubMed: 28945477
DOI: 10.1513/AnnalsATS.201608-610MG