-
Biochimica Et Biophysica Acta.... Sep 2020Epithelial and endothelial monolayers are multicellular sheets that form barriers between the 'outside' and 'inside' of tissues. Cell-cell junctions, made by adherens... (Review)
Review
Epithelial and endothelial monolayers are multicellular sheets that form barriers between the 'outside' and 'inside' of tissues. Cell-cell junctions, made by adherens junctions, tight junctions and desmosomes, hold together these monolayers. They form intercellular contacts by binding their receptor counterparts on neighboring cells and anchoring these structures intracellularly to the cytoskeleton. During tissue development, maintenance and pathogenesis, monolayers encounter a range of mechanical forces from the cells themselves and from external systemic forces, such as blood pressure or tissue stiffness. The molecular landscape of cell-cell junctions is diverse, containing transmembrane proteins that form intercellular bonds and a variety of cytoplasmic proteins that remodel the junctional connection to the cytoskeleton. Many junction-associated proteins participate in mechanotransduction cascades to confer mechanical cues into cellular responses that allow monolayers to maintain their structural integrity. We will discuss force-dependent junctional molecular events and their role in cell-cell contact organization and remodeling.
Topics: Adherens Junctions; Blood Pressure; Cytoskeleton; Desmosomes; Endothelial Cells; Epithelial Cells; Humans; Intercellular Junctions; Mechanical Phenomena; Membrane Proteins; Tight Junctions
PubMed: 32360073
DOI: 10.1016/j.bbamem.2020.183316 -
Stem Cell Reports Mar 2023Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the...
Arrhythmogenic cardiomyopathy (ACM) is an inherited progressive disease characterized by electrophysiological and structural remodeling of the ventricles. However, the disease-causing molecular pathways, as a consequence of desmosomal mutations, are poorly understood. Here, we identified a novel missense mutation within desmoplakin in a patient clinically diagnosed with ACM. Using CRISPR-Cas9, we corrected this mutation in patient-derived human induced pluripotent stem cells (hiPSCs) and generated an independent knockin hiPSC line carrying the same mutation. Mutant cardiomyocytes displayed a decline in connexin 43, NaV1.5, and desmosomal proteins, which was accompanied by a prolonged action potential duration. Interestingly, paired-like homeodomain 2 (PITX2), a transcription factor that acts a repressor of connexin 43, NaV1.5, and desmoplakin, was induced in mutant cardiomyocytes. We validated these results in control cardiomyocytes in which PITX2 was either depleted or overexpressed. Importantly, knockdown of PITX2 in patient-derived cardiomyocytes is sufficient to restore the levels of desmoplakin, connexin 43, and NaV1.5.
Topics: Humans; Myocytes, Cardiac; Connexin 43; Desmoplakins; Induced Pluripotent Stem Cells; Mutation; Cardiomyopathies
PubMed: 36868229
DOI: 10.1016/j.stemcr.2023.01.015 -
Cell and Tissue Research Jun 2015
Topics: Connexins; Desmosomes; Gap Junctions; Genetic Diseases, Inborn; Health; Humans; Intercellular Junctions; Tight Junctions
PubMed: 25861756
DOI: 10.1007/s00441-015-2171-2 -
Tissue Engineering. Part C, Methods Nov 2019Cell-cell adhesion complexes are macromolecular adhesive organelles that integrate cells into tissues. This mechanochemical coupling in cell-cell adhesion is required... (Review)
Review
Cell-cell adhesion complexes are macromolecular adhesive organelles that integrate cells into tissues. This mechanochemical coupling in cell-cell adhesion is required for a large number of cell behaviors, and perturbations of the cell-cell adhesion structure or related mechanotransduction pathways can lead to critical pathological conditions such as skin and heart diseases, arthritis, and cancer. Mechanical stretching has been a widely used method to stimulate the mechanotransduction process originating from the cell-cell adhesion and cell-extracellular matrix (ECM) complexes. These studies aimed to reveal the biophysical processes governing cell proliferation, wound healing, gene expression regulation, and cell differentiation in various tissues, including cardiac, muscle, vascular, and bone. This review explores techniques in mechanical stretching in two-dimensional settings with different stretching regimens on different cell types. The mechanotransduction responses from these different cell types will be discussed with an emphasis on their biophysical transformations during mechanical stretching and the cross talk between the cell-cell and cell-ECM adhesion complexes. Therapeutic aspects of mechanical stretching are reviewed considering these cellular responses after the application of mechanical forces, with a focus on wound healing and tissue regeneration. Impact Statement Mechanical stretching has been proposed as a therapeutic option for tissue regeneration and wound healing. It has been accepted that mechanotransduction processes elicited by mechanical stretching govern cellular response and behavior, and these studies have predominantly focused on the cell-extracellular matrix (ECM) sites. This review serves the mechanobiology community by shifting the focus of mechanical stretching effects from cell-ECM adhesions to the less examined cell-cell adhesions, which we believe play an equally important role in orchestrating the response pathways.
Topics: Adherens Junctions; Animals; Cell Adhesion; Desmosomes; Disease; Humans; Regeneration; Stress, Mechanical
PubMed: 31407627
DOI: 10.1089/ten.TEC.2019.0098 -
Cold Spring Harbor Perspectives in... Jun 2017Adherens junctions (AJs) and desmosomes connect the actin and keratin filament networks of adjacent cells into a mechanical unit. Whereas AJs function in mechanosensing... (Review)
Review
Adherens junctions (AJs) and desmosomes connect the actin and keratin filament networks of adjacent cells into a mechanical unit. Whereas AJs function in mechanosensing and in transducing mechanical forces between the plasma membrane and the actomyosin cytoskeleton, desmosomes and intermediate filaments (IFs) provide mechanical stability required to maintain tissue architecture and integrity when the tissues are exposed to mechanical stress. Desmosomes are essential for stable intercellular cohesion, whereas keratins determine cell mechanics but are not involved in generating tension. Here, we summarize the current knowledge of the role of IFs and desmosomes in tissue mechanics and discuss whether the desmosome-keratin scaffold might be actively involved in mechanosensing and in the conversion of chemical signals into mechanical strength.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Adhesion; Cell Membrane; Cytoskeletal Proteins; Cytoskeleton; Desmosomes; Epithelium; Humans; Intermediate Filaments; Keratinocytes; Keratins; Microtubules; Protein Domains; Signal Transduction; Stress, Mechanical; Tissue Engineering
PubMed: 28096266
DOI: 10.1101/cshperspect.a029157 -
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 -
Oncology Research 2021The Yes-associated protein (YAP) is a downstream effector of the Hippo pathway and acts as a key transcription co-factor to regulate cell migration, proliferation, and... (Review)
Review
The Yes-associated protein (YAP) is a downstream effector of the Hippo pathway and acts as a key transcription co-factor to regulate cell migration, proliferation, and survival. The Hippo pathway is evolutionarily conserved and controls tissue growth and organ size. Dysregulation and heterogeneity of this pathway are found in cancers, including oral squamous cell carcinoma (OSCC), leading to overexpression of YAP and its regulated proliferation machinery. The activity of YAP is associated with its nuclear expression and is negatively regulated by the Hippo kinase-mediated phosphorylation resulting in an induction of its cytoplasmic translocation. This review focuses on the role of YAP in OSCC in the context of cancer metastatic potential and highlights the latest findings about the heterogeneity of YAP expression and its nuclear transcription activity in oral cancer cell lines. The review also discusses the potential target of YAP in oral cancer therapy and the recent finding of the unprecedented role of the desmosomal cadherin desmoglein-3 (DSG3) in regulating Hippo-YAP signaling.
Topics: Humans; Mouth Neoplasms; Carcinoma, Squamous Cell; Transcription Factors; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms
PubMed: 37304649
DOI: 10.32604/or.2022.026085 -
The Journal of Dermatology Apr 2018Desmosomes provide the main intercellular adhesive properties between epidermal keratinocytes. Their distribution becomes uneven in severe dermatitis, multiple allergies... (Review)
Review
Desmosomes provide the main intercellular adhesive properties between epidermal keratinocytes. Their distribution becomes uneven in severe dermatitis, multiple allergies and metabolic wasting syndrome due to desmoglein 1 deficiency and the loss of intercellular adhesion or acantholysis. When keratinocytes differentiate from granular cells into cornified cells, desmosomes are transformed into corneodesmosomes and can provide stronger intercellular adhesion. Degradation of corneodesmosomes is a tightly regulated process involving a number of proteases and their inhibitors. Peripheral corneodesmosomes are protected from proteolytic degradation by the tight junction-related structures around them, and this construction provides the basis for the normal basket weave-like structure of the stratum corneum. In Netherton syndrome, which is caused by an absence of the protease inhibitor lymphoepithelial Kazal-type-related inhibitor, premature degradation of corneodesmosomes occurs due to the overactivation of proteases involved in corneodesmosome degradation. Inflammatory peeling skin disease is caused by the absence of corneodesmosin, a unique component of corneodesmosomes. In this disease, corneodesmosomes are structurally abnormal, and their adhesiveness is compromised, which leads to intercellular splitting between the stratum corneum and stratum granulosum. The better we understand desmosome and corneodesmosome ultrastructure in normal and diseased skin, the clearer the physiological and pathological mechanisms of epidermal integrity become.
Topics: Desmosomal Cadherins; Desmosomes; Epidermal Cells; Epidermis; Glycoproteins; Humans; Intercellular Signaling Peptides and Proteins; Keratinocytes; Mutation; Serine Peptidase Inhibitor Kazal-Type 5; Skin Diseases, Genetic; Tight Junctions
PubMed: 29349851
DOI: 10.1111/1346-8138.14202 -
Methods in Molecular Biology (Clifton,... 2021Desmosomes are cell-cell junctions responsible for mechanically integrating adjacent cells. Due to the small size of the junctions, their protein architecture cannot be...
Desmosomes are cell-cell junctions responsible for mechanically integrating adjacent cells. Due to the small size of the junctions, their protein architecture cannot be elucidated using conventional fluorescence microscopy. Super-resolution microscopy techniques, including dSTORM, deliver higher-resolution images which can reveal the localization or arrangement of proteins within individual desmosomes. Herein we describe an imaging and analysis method to determine the nanoscale architecture of desmosomes using super-resolution dSTORM.
Topics: Desmosomes; Microscopy, Fluorescence; Proteins
PubMed: 33225407
DOI: 10.1007/7651_2020_325 -
Life (Basel, Switzerland) Nov 2022The Hippo pathway is an evolutionarily conserved pathway that serves to promote cell death and differentiation while inhibiting cellular proliferation across species.... (Review)
Review
The Hippo pathway is an evolutionarily conserved pathway that serves to promote cell death and differentiation while inhibiting cellular proliferation across species. The downstream effectors of this pathway, yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), are considered vital in promoting the output of the Hippo pathway, with activation of upstream kinases negatively regulating YAP/TAZ activity. The upstream regulation of the Hippo pathway is not entirely understood on a molecular level. However, several studies have shown that numerous cellular and non-cellular mechanisms such as cell polarity, contact inhibition, soluble factors, mechanical forces, and metabolism can convey external stimuli to the intracellular kinase cascade, promoting the activation of key components of the Hippo pathway and therefore regulating the subcellular localisation and protein activity of YAP/TAZ. This review will summarise what we have learnt about the role of intercellular junction-associated proteins in the activation of this pathway, including adherens junctions and tight junctions, and in particular our latest findings about the desmosomal components, including desmoglein-3 (DSG3), in the regulation of YAP signalling, phosphorylation, and subcellular translocation.
PubMed: 36362947
DOI: 10.3390/life12111792