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Integrative Biology : Quantitative... Oct 2015The shaping of a multicellular body, and the maintenance and repair of adult tissues require fine-tuning of cell adhesion responses and the transmission of mechanical... (Review)
Review
The shaping of a multicellular body, and the maintenance and repair of adult tissues require fine-tuning of cell adhesion responses and the transmission of mechanical load between the cell, its neighbors and the underlying extracellular matrix. A growing field of research is focused on how single cells sense mechanical properties of their micro-environment (extracellular matrix, other cells), and on how mechanotransduction pathways affect cell shape, migration, survival as well as differentiation. Within multicellular assemblies, the mechanical load imposed by the physical properties of the environment is transmitted to neighboring cells. Force imbalance at cell-cell contacts induces essential morphogenetic processes such as cell-cell junction remodeling, cell polarization and migration, cell extrusion and cell intercalation. However, how cells respond and adapt to the mechanical properties of neighboring cells, transmit forces, and transform mechanical signals into chemical signals remain open questions. A defining feature of compact tissues is adhesion between cells at the specialized adherens junction (AJ) involving the cadherin super-family of Ca(2+)-dependent cell-cell adhesion proteins (e.g., E-cadherin in epithelia). Cadherins bind to the cytoplasmic protein β-catenin, which in turn binds to the filamentous (F)-actin binding adaptor protein α-catenin, which can also recruit vinculin, making the mechanical connection between cell-cell adhesion proteins and the contractile actomyosin cytoskeleton. The cadherin-catenin adhesion complex is a key component of the AJ, and contributes to cell assembly stability and dynamic cell movements. It has also emerged as the main route of propagation of forces within epithelial and non-epithelial tissues. Here, we discuss recent molecular studies that point toward force-dependent conformational changes in α-catenin that regulate protein interactions in the cadherin-catenin adhesion complex, and show that α-catenin is the core mechanosensor that allows cells to locally sense, transduce and adapt to environmental mechanical constrains.
Topics: Actins; Adherens Junctions; Animals; Biomechanical Phenomena; Cadherins; Catenins; Cell Adhesion; Cellular Microenvironment; Humans; Mechanotransduction, Cellular; Models, Biological; Protein Conformation; Protein Unfolding
PubMed: 25968913
DOI: 10.1039/c5ib00070j -
The Journal of Cell Biology Apr 2007Identifying genes involved in the control of adherens junction (AJ) remodeling is essential to understanding epithelial morphogenesis. During follicular epithelium...
Identifying genes involved in the control of adherens junction (AJ) remodeling is essential to understanding epithelial morphogenesis. During follicular epithelium development in Drosophila melanogaster, the main body follicular cells (MBFCs) are displaced toward the oocyte and become columnar. Concomitantly, the stretched cells (StCs) become squamous and flatten around the nurse cells. By monitoring the expression of epithelial cadherin and Armadillo, I have discovered that the rate of AJ disassembly between the StCs is affected in follicles with somatic clones mutant for fringe or Delta and Serrate. This results in abnormal StC flattening and delayed MBFC displacement. Additionally, accumulation of the myosin II heavy chain Zipper is delayed at the AJs that require disassembly. Together, my results demonstrate that the Notch pathway controls AJ remodeling between the StCs and that this role is crucial for the timing of MBFC displacement and StC flattening. This provides new evidence that Notch, besides playing a key role in cell differentiation, also controls cell morphogenesis.
Topics: Adherens Junctions; Animals; Cadherins; Cell Differentiation; Drosophila Proteins; Drosophila melanogaster; Female; Models, Biological; Morphogenesis; Mutation; Myosin Type II; N-Acetylglucosaminyltransferases; Oogenesis; Ovarian Follicle; RNA, Messenger; Receptors, Notch
PubMed: 17420294
DOI: 10.1083/jcb.200609079 -
Communications Biology Mar 2024Through its involvement in gene transcription and heterochromatin formation, DNA methylation regulates how cells interact with their environment. Nevertheless, the...
Through its involvement in gene transcription and heterochromatin formation, DNA methylation regulates how cells interact with their environment. Nevertheless, the extracellular signaling cues that modulate the distribution of this central chromatin modification are largely unclear. DNA methylation is highly abundant at repetitive elements, but its investigation in live cells has been complicated by methodological challenges. Utilizing a CRISPR/dCas9 biosensor that reads DNA methylation of human α-satellite repeats in live cells, we here uncover a signaling pathway linking the chromatin and transcriptional state of repetitive elements to epithelial adherens junction integrity. Specifically, we find that in confluent breast epithelial cell monolayers, α-satellite repeat methylation is reduced by comparison to low density cultures. This is coupled with increased transcriptional activity at repeats. Through comprehensive perturbation experiments, we identify the junctional protein E-cadherin, which links to the actin cytoskeleton, as a central molecular player for signal relay into the nucleus. Furthermore, we find that this pathway is impaired in cancer cells that lack E-cadherin and are not contact-inhibited. This suggests that the molecular connection between cell density and repetitive element methylation could play a role in the maintenance of epithelial tissue homeostasis.
Topics: Humans; DNA Methylation; Adherens Junctions; Cadherins; Signal Transduction; Chromatin
PubMed: 38454140
DOI: 10.1038/s42003-024-05990-4 -
Molecular Biology of the Cell Jul 2023During embryonic development, dramatic cell shape changes and movements reshape the embryonic body plan. These require robust but dynamic linkage between the cell-cell...
During embryonic development, dramatic cell shape changes and movements reshape the embryonic body plan. These require robust but dynamic linkage between the cell-cell adherens junctions and the force-generating actomyosin cytoskeleton. Our view of this linkage has evolved, and we now realize linkage is mediated by mechanosensitive multiprotein complexes assembled via multivalent connections. Here we combine genetic, cell biological, and modeling approaches to define the mechanism of action and functions of an important player, , homologue of mammalian ZO-1. Our data reveal that Pyd reinforces cell junctions under elevated tension, and facilitates cell rearrangements. Pyd is important to maintain junctional contractility and in its absence cell rearrangements stall. We next use structured illumination microscopy to define the molecular architecture of cell-cell junctions during these events. The cadherin-catenin complex and Cno both localize to puncta along the junctional membrane, but are differentially enriched in different puncta. Pyd, in contrast, exhibits a distinct localization to strands that extend out from the region occupied by core junction proteins. We then discuss the implications for the protein network at the junction-cytoskeletal interface, suggesting different proteins localize and function in distinct ways, perhaps in distinct subcomplexes, but combine to produce robust connections.
Topics: Animals; Actin Cytoskeleton; Adherens Junctions; Cadherins; Cytoskeleton; Drosophila; Drosophila melanogaster; Drosophila Proteins; Mammals; Tight Junctions
PubMed: 37163320
DOI: 10.1091/mbc.E23-03-0077 -
Cell Biology International Mar 2016Cell-matrix adhesion and cell-cell contacts are essential for the metabolism, protein synthesis, survival, and cancer metastasis of cells. Major transmembrane receptors... (Review)
Review
Cell-matrix adhesion and cell-cell contacts are essential for the metabolism, protein synthesis, survival, and cancer metastasis of cells. Major transmembrane receptors are the integrins, which are responsible for cell-matrix adhesions, and the cadherins, which are important for cell-cell adhesions. Adherent cells anchor via focal adhesion proteins to the extracellular matrix, whereas cell-cell contacts connect via focal adherens junction proteins. The temporal formation of these connections is greatly strengthened either through externally applied stresses on the cell or by myosin-driven cell contractility. The mechanism by which protein(s) within these connections sense, transmit, and respond to mechanochemical signaling is currently strongly debated and various candidates have been named. Vinculin has been described as one of the key players in cell-matrix and cell-cell adhesions that build a strong physical connection for transmitting forces between the cytoskeleton, the extracellular matrix, and cell-cell connections.
Topics: Actins; Adherens Junctions; Cell Adhesion; Crk-Associated Substrate Protein; Extracellular Matrix; Humans; Integrins; Mechanotransduction, Cellular; Protein Binding; Vinculin
PubMed: 26909547
DOI: 10.1002/cbin.10563 -
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 -
American Journal of Physiology.... Sep 2016The Hippo pathway effector Yes-associated protein (YAP) regulates liver size by promoting cell proliferation and inhibiting apoptosis. However, recent in vivo studies...
The Hippo pathway effector Yes-associated protein (YAP) regulates liver size by promoting cell proliferation and inhibiting apoptosis. However, recent in vivo studies suggest that YAP has important cellular functions other than controlling proliferation and apoptosis. Transgenic YAP expression in mouse hepatocytes results in severe jaundice. A possible explanation for the jaundice could be defects in adherens junctions that prevent bile from leaking into the blood stream. Indeed, immunostaining of E-cadherin and electron microscopic examination of bile canaliculi of Yap transgenic livers revealed abnormal adherens junction structures. Using primary hepatocytes from Yap transgenic livers and Yap knockout livers, we found that YAP antagonizes E-cadherin-mediated cell-cell junction assembly by regulating the cellular actin architecture, including its mechanical properties (elasticity and cortical tension). Mechanistically, we found that YAP promoted contractile actin structure formation by upregulating nonmuscle myosin light chain expression and cellular ATP generation. Thus, by modulating actomyosin organization, YAP may influence many actomyosin-dependent cellular characteristics, including adhesion, membrane protrusion, spreading, morphology, and cortical tension and elasticity, which in turn determine cell differentiation and tissue morphogenesis.
Topics: Actin Cytoskeleton; Adaptor Proteins, Signal Transducing; Adherens Junctions; Animals; Cadherins; Cell Cycle Proteins; Cells, Cultured; DNA-Binding Proteins; Gene Expression Regulation; Hepatocytes; Male; Mice; Mice, Knockout; Mice, Transgenic; Phosphoproteins; TEA Domain Transcription Factors; Transcription Factors; YAP-Signaling Proteins
PubMed: 27229120
DOI: 10.1152/ajpgi.00027.2016 -
Human Pathology May 2013It has been proposed that an epithelial injury may be one of the multiple primary events in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this...
It has been proposed that an epithelial injury may be one of the multiple primary events in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to characterize the tight junction and adherens junction proteins in normal human lung, IPF, cryptogenic organizing pneumonia, and asbestosis. We determined the immunohistochemical cell-specific expression of tight junction proteins claudin-1, claudin-2, claudin-3, claudin-4, claudin-5, and claudin-7, as well as 3 adherens junction proteins, E-cadherin, N-cadherin, and β-catenin. We further analyzed the expression of claudin-1, claudin-3, and claudin-4 and E-cadherin, N-cadherin, and β-catenin at the transcriptional level by quantitative real-time reverse transcriptase polymerase chain reaction. The expression levels of both tight junction and adherens junction proteins were elevated in regenerative alveolar epithelium in pulmonary fibrosis as compared with the expression of these proteins in normal alveolar epithelium. In particular, the expression levels of claudins-1 and claudin-3 were clearly elevated in all diseases. Furthermore, the amounts of adherens junction proteins messenger RNAs (mRNAs) were also all increased in pulmonary fibroses in comparison with healthy controls, with N-cadherin showing the greatest increase in mRNA levels in all diseases. However, the amounts of claudin-1, claudin-3, and claudin-4 mRNAs in fibrotic lung were similar to or even lower than those measured in the healthy controls. It is possible that the diminished capacity to produce claudin mRNAs may be one explanation for poor repair capacity of alveolar epithelial cells in IPF.
Topics: Adherens Junctions; Asbestosis; Cadherins; Claudins; Epithelium; Humans; Immunohistochemistry; Lung; Pulmonary Alveoli; Pulmonary Fibrosis; RNA, Messenger; Reverse Transcriptase Polymerase Chain Reaction; Tight Junctions
PubMed: 23253490
DOI: 10.1016/j.humpath.2012.08.016 -
Molecular Cancer Research : MCR Mar 2014The PI3K-AKT signaling pathway regulates all phenotypes that contribute to progression of human cancers, including breast cancer. AKT mediates signal relay by...
UNLABELLED
The PI3K-AKT signaling pathway regulates all phenotypes that contribute to progression of human cancers, including breast cancer. AKT mediates signal relay by phosphorylating numerous substrates, which are causally implicated in biologic responses such as cell growth, survival, metabolic reprogramming, migration, and invasion. Here a new AKT substrate is identified, the adherens junction protein Afadin, which is phosphorylated by AKT at Ser1718. Importantly, under conditions of physiologic IGF-1 signaling and oncogenic PI3K and AKT, Afadin is phosphorylated by all AKT isoforms, and this phosphorylation elicits a relocalization of Afadin from adherens junctions to the nucleus. Also, phosphorylation of Afadin increased breast cancer cell migration that was dependent on Ser1718 phosphorylation. Finally, nuclear localization of Afadin was observed in clinical breast cancer specimens, indicating that regulation of Afadin by the PI3K-AKT pathway has pathophysiologic significance.
IMPLICATIONS
Phosphorylation of the adhesion protein Afadin by AKT downstream of the PI3K pathway, leads to redistribution of Afadin and controls cancer cell migration.
Topics: Adherens Junctions; Breast Neoplasms; Cell Culture Techniques; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Female; Humans; Microfilament Proteins; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 24269953
DOI: 10.1158/1541-7786.MCR-13-0398 -
International Review of Cell and... 2013Adherens junctions (AJs) are evolutionarily conserved plasma-membrane structures that mediate cell-cell adhesions in multicellular organisms. They are organized by... (Review)
Review
Adherens junctions (AJs) are evolutionarily conserved plasma-membrane structures that mediate cell-cell adhesions in multicellular organisms. They are organized by several types of adhesive integral membrane proteins, most notably cadherins and nectins that are clustered and stabilized by a number of cytoplasmic scaffolds. AJs are key regulators of tissue architecture and dynamics via control of cell proliferation, polarity, shape, motility, and survival. They are absolutely critical for normal tissue morphogenesis and their disruption results in pathological abnormalities in different tissues. Although the field of adherens-junction research dramatically progressed in recent years, a number of important questions remain controversial and poorly understood. This review outlines basic principles that regulate organization of AJs in mammalian epithelia and discusses recent advances and standing controversies in the field. A special attention is paid to the regulation of AJs by vesicle trafficking and the intracellular cytoskeleton as well as roles and mechanisms of adherens-junction disruption during tumor progression and tissue inflammation.
Topics: Adherens Junctions; Animals; Cytoskeleton; Disease; Epithelial Cells; Humans; Protein Transport; Transport Vesicles
PubMed: 23445808
DOI: 10.1016/B978-0-12-407697-6.00002-7