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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 -
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 -
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 -
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 -
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 -
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 -
Current Biology : CB Apr 2018Cell-cell junctions are specializations of the plasma membrane responsible for physically integrating cells into tissues. We are now beginning to appreciate the diverse... (Review)
Review
Cell-cell junctions are specializations of the plasma membrane responsible for physically integrating cells into tissues. We are now beginning to appreciate the diverse impacts that mechanical forces exert upon the integrity and function of these junctions. Currently, this is best understood for cadherin-based adherens junctions in epithelia and endothelia, where cell-cell adhesion couples the contractile cytoskeletons of cells together to generate tissue-scale tension. Junctional tension participates in morphogenesis and tissue homeostasis. Changes in tension can also be detected by mechanotransduction pathways that allow cells to communicate with each other. In this review, we discuss progress in characterising the forces present at junctions in physiological conditions; the cellular mechanisms that generate intrinsic tension and detect changes in tension; and, finally, we consider how tissue integrity is maintained in the face of junctional stresses.
Topics: Adherens Junctions; Animals; Cadherins; Cell Adhesion; Cell Membrane; Cytoskeleton; Epithelium; Humans; Intercellular Junctions; Mechanotransduction, Cellular; Tensile Strength
PubMed: 29689229
DOI: 10.1016/j.cub.2018.02.003 -
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