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Cardiovascular Research Mar 2017This review presents an extensively integrated model of the cardiac intercalated disc (ID), a highly orchestrated structure that connects adjacent cardiomyocytes.... (Review)
Review
This review presents an extensively integrated model of the cardiac intercalated disc (ID), a highly orchestrated structure that connects adjacent cardiomyocytes. Classically, three main structures are distinguished: gap junctions (GJs) metabolically and electrically connect cytoplasm of adjacent cardiomyocytes; adherens junctions (AJs) connect the actin cytoskeleton of adjacent cells; and desmosomes function as cell anchors and connect intermediate filaments. Furthermore, ion channels reside in the ID. Mutations in ID proteins have been associated with cardiac arrhythmias such as Brugada syndrome and arrhythmogenic cardiomyopathy. However, rather than being independent, all ID components work together intensively by multifunctional proteins such as ZO-1, Ankyrin G, and β-catenin, integrating mechanical and electrical functions. GJs form a plaque surrounded by the perinexus in which free connexons reside; the connexome integrates NaV channels, the desmosome and GJs; and the area composita hosts AJs and desmosomes, also integrated as adhering junctions. Furthermore, the transitional junction connects sarcomeres to the plasma membrane. Lastly, this review integrates all these findings in comprehensible figures, illustrating the interdependencies of ID proteins.
Topics: Adherens Junctions; Animals; Arrhythmias, Cardiac; Cell Communication; Desmosomes; Gap Junctions; Genetic Predisposition to Disease; Humans; Intercellular Junctions; Ion Channels; Mechanotransduction, Cellular; Membrane Proteins; Mutation; Myocytes, Cardiac; Signal Transduction
PubMed: 28069669
DOI: 10.1093/cvr/cvw259 -
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 -
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 -
International Journal of Molecular... Jul 2018Cell contacts exhibit a considerable influence on tissue physiology and homeostasis by controlling paracellular and intercellular transport processes, as well as by... (Review)
Review
Cell contacts exhibit a considerable influence on tissue physiology and homeostasis by controlling paracellular and intercellular transport processes, as well as by affecting signaling pathways. Since they maintain cell polarity, they play an important role in cell plasticity. The knowledge about the junctional protein families and their interactions has increased considerably during recent years. In contrast to most other tissues, the endometrium undergoes extensive physiological changes and reveals an extraordinary plasticity due to its crucial role in the establishment and maintenance of pregnancy. These complex changes are accompanied by changes in direct cell⁻cell contacts to meet the various requirements in the respective developmental stage. Impairment of this sophisticated differentiation process may lead to failure of implantation and embryo development and may be involved in the pathogenesis of endometrial diseases. In this article, we focus on the knowledge about the distribution and regulation of the different junctional proteins in the endometrium during cycling and pregnancy, as well as in pathologic conditions such as endometriosis and cancer. Decoding these sophisticated interactions should improve our understanding of endometrial physiology as well as of the mechanisms involved in pathological conditions.
Topics: Adherens Junctions; Animals; Cell Communication; Embryo Implantation; Endometrial Neoplasms; Endometriosis; Endometrium; Female; Hormones; Humans; Tight Junctions
PubMed: 30061539
DOI: 10.3390/ijms19082227 -
Seminars in Cell & Developmental Biology Dec 2014Epithelial cells form regulated and selective barriers between distinct tissue compartments. The Apical Junctional Complex (AJC) consisting of the tight junction (TJ)... (Review)
Review
Epithelial cells form regulated and selective barriers between distinct tissue compartments. The Apical Junctional Complex (AJC) consisting of the tight junction (TJ) and adherens junction (AJ) control epithelial homeostasis, paracellular permeability and barrier properties. The AJC is composed of mutliprotein complexes consisting of transmembrane proteins that affiliate with an underlying perijunctional F-actin myosin ring through cytoplasmic scaffold proteins. AJC protein associations with the apical actin-myosin cytoskeleton are tightly controlled by a number of signaling proteins including the Rho family of GTPases that orchestrate junctional biology, epithelial homeostasis and barrier function. This review highlights the vital relationship of Rho GTPases and AJCs in controlling the epithelial barrier. The pathophysiologic relationship of Rho GTPases, AJC, apical actomyosin cytoskeleton and epithelial barrier function is discussed.
Topics: Actin Cytoskeleton; Actins; Actomyosin; Adherens Junctions; Epithelial Cells; Humans; Myosins; Permeability; Signal Transduction; Tight Junctions; rho GTP-Binding Proteins
PubMed: 25223584
DOI: 10.1016/j.semcdb.2014.09.003 -
Biophysical Journal Mar 2022Cadherin-based adherens junctions and desmosomes help stabilize cell-cell contacts with additional function in mechano-signaling, while clustered protocadherin junctions...
Cadherin-based adherens junctions and desmosomes help stabilize cell-cell contacts with additional function in mechano-signaling, while clustered protocadherin junctions are responsible for directing neuronal circuits assembly. Structural models for adherens junctions formed by epithelial cadherin (CDH1) proteins indicate that their long, curved ectodomains arrange to form a periodic, two-dimensional lattice stabilized by tip-to-tip trans interactions (across junction) and lateral cis contacts. Less is known about the exact architecture of desmosomes, but desmoglein (DSG) and desmocollin (DSC) cadherin proteins are also thought to form ordered junctions. In contrast, clustered protocadherin (PCDH)-based cell-cell contacts in neuronal tissues are thought to be responsible for self-recognition and avoidance, and structural models for clustered PCDH junctions show a linear arrangement in which their long and straight ectodomains form antiparallel overlapped trans complexes. Here, we report all-atom molecular dynamics simulations testing the mechanics of minimalistic adhesive junctions formed by CDH1, DSG2 coupled to DSC1, and PCDHγB4, with systems encompassing up to 3.7 million atoms. Simulations generally predict a favored shearing pathway for the adherens junction model and a two-phased elastic response to tensile forces for the adhesive adherens junction and the desmosome models. Complexes within these junctions first unbend at low tensile force and then become stiff to unbind without unfolding. However, cis interactions in both the CDH1 and DSG2-DSC1 systems dictate varied mechanical responses of individual dimers within the junctions. Conversely, the clustered protocadherin PCDHγB4 junction lacks a distinct two-phased elastic response. Instead, applied tensile force strains trans interactions directly, as there is little unbending of monomers within the junction. Transient intermediates, influenced by new cis interactions, are observed after the main rupture event. We suggest that these collective, complex mechanical responses mediated by cis contacts facilitate distinct functions in robust cell-cell adhesion for classical cadherins and in self-avoidance signaling for clustered PCDHs.
Topics: Adherens Junctions; Cadherins; Cell Adhesion; Cell Communication
PubMed: 35150618
DOI: 10.1016/j.bpj.2022.02.008 -
Cold Spring Harbor Perspectives in... Nov 2018Cadherin-based adherens junctions (AJs) and desmosomes are crucial to couple intercellular adhesion to the actin or intermediate filament cytoskeletons, respectively. As... (Review)
Review
Cadherin-based adherens junctions (AJs) and desmosomes are crucial to couple intercellular adhesion to the actin or intermediate filament cytoskeletons, respectively. As such, these intercellular junctions are essential to provide not only integrity to epithelia and other tissues but also the mechanical machinery necessary to execute complex morphogenetic and homeostatic intercellular rearrangements. Moreover, these spatially defined junctions serve as signaling hubs that integrate mechanical and chemical pathways to coordinate tissue architecture with behavior. This review takes an evolutionary perspective on how the emergence of these two essential intercellular junctions at key points during the evolution of multicellular animals afforded metazoans with new opportunities to integrate adhesion, cytoskeletal dynamics, and signaling. We discuss known literature on cross-talk between the two junctions and, using the skin epidermis as an example, provide a model for how these two junctions function in concert to orchestrate tissue organization and function.
Topics: Adherens Junctions; Animals; Biological Evolution; Cell Polarity; Desmosomes; Epithelial Cells; Signal Transduction
PubMed: 28893859
DOI: 10.1101/cshperspect.a029207 -
Cold Spring Harbor Perspectives in... Mar 2017Cadherin-based adherens junctions are conserved structures that mediate epithelial cell-cell adhesion in invertebrates and vertebrates. Despite their pivotal function in... (Review)
Review
Cadherin-based adherens junctions are conserved structures that mediate epithelial cell-cell adhesion in invertebrates and vertebrates. Despite their pivotal function in epithelial integrity, adherens junctions show a remarkable plasticity that is a prerequisite for tissue architecture and morphogenesis. Epithelial cadherin (E-cadherin) is continuously turned over and undergoes cycles of endocytosis, sorting and recycling back to the plasma membrane. Mammalian cell culture and genetically tractable model systems such as have revealed conserved, but also distinct, mechanisms in the regulation of E-cadherin membrane trafficking. Here, we discuss our current knowledge about molecules and mechanisms controlling endocytosis, sorting and recycling of E-cadherin during junctional remodeling.
Topics: Adherens Junctions; Animals; Biological Transport; Cadherins; Catenins; Endocytosis; Endosomes; Protein Processing, Post-Translational
PubMed: 28096264
DOI: 10.1101/cshperspect.a029140 -
Cold Spring Harbor Perspectives in... Oct 2018Endothelial cell-cell adherens junctions (AJs) supervise fundamental vascular functions, such as the control of permeability and transmigration of circulating... (Review)
Review
Endothelial cell-cell adherens junctions (AJs) supervise fundamental vascular functions, such as the control of permeability and transmigration of circulating leukocytes, and the maintenance of existing vessels and formation of new ones. These processes are often dysregulated in pathologies. However, the evidence that links dysfunction of endothelial AJs to human pathologies is mostly correlative. In this review, we present an update of the molecular organization of AJ complexes in endothelial cells (ECs) that is mainly based on observations from experimental models. Furthermore, we report in detail on a human pathology, cerebral cavernous malformation (CCM), which is initiated by loss-of-function mutations in the genes that encode the three cytoplasmic components of AJs (CCM1, CCM2, and CCM3). At present, these represent a unique example of mutations in components of endothelial AJs that cause human disease. We describe also how studies into the defects of AJs in CCM are shedding light on the crucial regulatory mechanisms and signaling activities of these endothelial structures. Although these observations are specific for CCM, they support the concept that dysfunction of endothelial AJs can directly contribute to human pathologies.
Topics: Adherens Junctions; Antigens, CD; Cadherins; Gene Expression Regulation; Humans; Signal Transduction; Vascular Diseases
PubMed: 28851747
DOI: 10.1101/cshperspect.a029322 -
Nature Communications Jun 2021The LIM and SH3 domain protein 1 (Lasp1) was originally cloned from metastatic breast cancer and characterised as an adaptor molecule associated with tumourigenesis and...
The LIM and SH3 domain protein 1 (Lasp1) was originally cloned from metastatic breast cancer and characterised as an adaptor molecule associated with tumourigenesis and cancer cell invasion. However, the regulation of Lasp1 and its function in the aggressive transformation of cells is unclear. Here we use integrative epigenomic profiling of invasive fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and from mouse models of the disease, to identify Lasp1 as an epigenomically co-modified region in chronic inflammatory arthritis and a functionally important binding partner of the Cadherin-11/β-Catenin complex in zipper-like cell-to-cell contacts. In vitro, loss or blocking of Lasp1 alters pathological tissue formation, migratory behaviour and platelet-derived growth factor response of arthritic FLS. In arthritic human TNF transgenic mice, deletion of Lasp1 reduces arthritic joint destruction. Therefore, we show a function of Lasp1 in cellular junction formation and inflammatory tissue remodelling and identify Lasp1 as a potential target for treating inflammatory joint disorders associated with aggressive cellular transformation.
Topics: Adaptor Proteins, Signal Transducing; Adherens Junctions; Animals; Arthritis; Arthritis, Rheumatoid; Cadherins; Cell Transformation, Neoplastic; Cytoskeletal Proteins; Female; Fibroblasts; Homeodomain Proteins; LIM Domain Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoblasts; beta Catenin
PubMed: 34131132
DOI: 10.1038/s41467-021-23706-8