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Cell Reports Jul 2022Cadherins and integrins are intrinsically linked through the actin cytoskeleton and are largely responsible for the mechanical integrity and organization of tissues. We...
Cadherins and integrins are intrinsically linked through the actin cytoskeleton and are largely responsible for the mechanical integrity and organization of tissues. We show that cadherin clustering stimulates and spatially guides integrin activation. Adherens junction (AJ)-associated integrin activation depends on locally generated tension and does not require extracellular matrix ligands. It leads to the creation of primed integrin clusters, which spatially determine where focal adhesions will form if ligands are present and where ligands will be deposited. AJs that display integrin activation are targeted by microtubules facilitating their disassembly via caveolin-based endocytosis, showing that integrin activation impacts the stability of the core cadherin complex. Thus, the interplay between cadherins and integrins is more intimate than what was once believed and is rooted in the capacity of active integrins to be stabilized via AJ-generated tension. Altogether, our data establish a mechanism of cross-regulation between cadherins and integrins.
Topics: Adherens Junctions; Cadherins; Cell Adhesion; Extracellular Matrix; Focal Adhesions; Integrins; Ligands
PubMed: 35858563
DOI: 10.1016/j.celrep.2022.111091 -
Nature Communications Oct 2023Vascular endothelial cadherin (VE-cadherin) expressed at endothelial adherens junctions (AJs) is vital for vascular integrity and endothelial homeostasis. Here we...
Vascular endothelial cadherin (VE-cadherin) expressed at endothelial adherens junctions (AJs) is vital for vascular integrity and endothelial homeostasis. Here we identify the requirement of the ubiquitin E3-ligase CHFR as a key mechanism of ubiquitylation-dependent degradation of VE-cadherin. CHFR was essential for disrupting the endothelium through control of the VE-cadherin protein expression at AJs. We observe augmented expression of VE-cadherin in endothelial cell (EC)-restricted Chfr knockout (Chfr) mice. We also observe abrogation of LPS-induced degradation of VE-cadherin in Chfr mice, suggesting the pathophysiological relevance of CHFR in regulating the endothelial junctional barrier in inflammation. Lung endothelial barrier breakdown, inflammatory neutrophil extravasation, and mortality induced by LPS were all suppressed in Chfr mice. We find that the transcription factor FoxO1 is a key upstream regulator of CHFR expression. These findings demonstrate the requisite role of the endothelial cell-expressed E3-ligase CHFR in regulating the expression of VE-cadherin, and thereby endothelial junctional barrier integrity.
Topics: Animals; Mice; Adherens Junctions; Ubiquitin; Ligases; Lipopolysaccharides; Cadherins; Endothelium; Ubiquitination; Endothelium, Vascular; Cells, Cultured
PubMed: 37852964
DOI: 10.1038/s41467-023-42225-2 -
Experimental Cell Research Jun 2021The Hippo signaling pathway is a tumor suppressor pathway that plays an important role in tissue homeostasis and organ size control. KIBRA is one of the many upstream... (Review)
Review
The Hippo signaling pathway is a tumor suppressor pathway that plays an important role in tissue homeostasis and organ size control. KIBRA is one of the many upstream regulators of the Hippo pathway. It functions as a tumor suppressor by positively regulating the core Hippo kinase cascade. However, there are accumulating shreds of evidence showing that KIBRA has an oncogenic function, which we speculate may arise from its functions away from the Hippo pathway. In this review, we have attempted to provide an overview of the Hippo signaling with a special emphasis on evidence showing the paradoxical role of KIBRA in cancer.
Topics: Adherens Junctions; Animals; Cell Cycle Proteins; Cell Line, Tumor; Extracellular Signal-Regulated MAP Kinases; Focal Adhesions; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor; Hippo Signaling Pathway; Humans; Intracellular Signaling Peptides and Proteins; Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Serine-Threonine Kinase 3; Signal Transduction; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Tumor Suppressor Proteins
PubMed: 33901448
DOI: 10.1016/j.yexcr.2021.112613 -
Frontiers in Immunology 2023The mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin...
INTRODUCTION
The mechanism underlying radiation-induced gut microbiota dysbiosis is undefined. This study examined the effect of radiation on the intestinal Paneth cell α-defensin expression and its impact on microbiota composition and mucosal tissue injury and evaluated the radio-mitigative effect of human α-defensin 5 (HD5).
METHODS
Adult mice were subjected to total body irradiation, and Paneth cell α-defensin expression was evaluated by measuring α-defensin mRNA by RT-PCR and α-defensin peptide levels by mass spectrometry. Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. HD5 was administered in a liquid diet 24 hours before or after irradiation. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by cytokine expression. Systemic inflammation was evaluated by measuring plasma cytokine levels.
RESULTS
Ionizing radiation reduced the Paneth cell α-defensin expression and depleted α-defensin peptides in the intestinal lumen. α-Defensin down-regulation was associated with the time-dependent alteration of gut microbiota composition, increased gut permeability, and endotoxemia. Administration of human α-defensin 5 (HD5) in the diet 24 hours before irradiation (prophylactic) significantly blocked radiation-induced gut microbiota dysbiosis, disruption of intestinal epithelial tight junction and adherens junction, mucosal barrier dysfunction, and mucosal inflammatory response. HD5, administered 24 hours after irradiation (treatment), reversed radiation-induced microbiota dysbiosis, tight junction and adherens junction disruption, and barrier dysfunction. Furthermore, HD5 treatment also prevents and reverses radiation-induced endotoxemia and systemic inflammation.
CONCLUSION
These data demonstrate that radiation induces Paneth cell dysfunction in the intestine, and HD5 feeding prevents and mitigates radiation-induced intestinal mucosal injury, endotoxemia, and systemic inflammation.
Topics: Humans; Adult; Animals; Mice; Paneth Cells; alpha-Defensins; Dysbiosis; Endotoxemia; RNA, Ribosomal, 16S; Radiation Injuries; Cytokines; Inflammation
PubMed: 37638013
DOI: 10.3389/fimmu.2023.1174140 -
Journal of Personalized Medicine Apr 2023Cerebral cavernous malformations (CCMs) arise when capillaries within the brain enlarge abnormally, causing the blood-brain barrier (BBB) to break down. The BBB serves... (Review)
Review
Cerebral cavernous malformations (CCMs) arise when capillaries within the brain enlarge abnormally, causing the blood-brain barrier (BBB) to break down. The BBB serves as a sophisticated interface that controls molecular interactions between the bloodstream and the central nervous system. The neurovascular unit (NVU) is a complex structure made up of neurons, astrocytes, endothelial cells (ECs), pericytes, microglia, and basement membranes, which work together to maintain blood-brain barrier (BBB) permeability. Within the NVU, tight junctions (TJs) and adherens junctions (AJs) between endothelial cells play a critical role in regulating the permeability of the BBB. Disruptions to these junctions can compromise the BBB, potentially leading to a hemorrhagic stroke. Understanding the molecular signaling cascades that regulate BBB permeability through EC junctions is, therefore, essential. New research has demonstrated that steroids, including estrogens (ESTs), glucocorticoids (GCs), and metabolites/derivatives of progesterone (PRGs), have multifaceted effects on blood-brain barrier (BBB) permeability by regulating the expression of tight junctions (TJs) and adherens junctions (AJs). They also have anti-inflammatory effects on blood vessels. PRGs, in particular, have been found to play a significant role in maintaining BBB integrity. PRGs act through a combination of its classic and non-classic PRG receptors (nPR/mPR), which are part of a signaling network known as the CCM signaling complex (CSC). This network couples both nPR and mPR in the CmPn/CmP pathway in endothelial cells (ECs).
PubMed: 37240921
DOI: 10.3390/jpm13050751 -
Cell Death & Disease Jul 2019The functions of Sertoli cells in spermatogenesis have attracted much more attention recently. Normal spermatogenesis depends on Sertoli cells, mainly due to their... (Review)
Review
The functions of Sertoli cells in spermatogenesis have attracted much more attention recently. Normal spermatogenesis depends on Sertoli cells, mainly due to their influence on nutrient supply, maintenance of cell junctions, and support for germ cells' mitosis and meiosis. Accumulating evidence in the past decade has highlighted the dominant functions of the MAPK, AMPK, and TGF-β/Smad signaling pathways during spermatogenesis. Among these pathways, the MAPK signaling pathway regulates dynamics of tight junctions and adherens junctions, proliferation and meiosis of germ cells, proliferation and lactate production of Sertoli cells; the AMPK and the TGF-β/Smad signaling pathways both affect dynamics of tight junctions and adherens junctions, as well as the proliferation of Sertoli cells. The AMPK signaling pathway also regulates lactate supply. These signaling pathways combine to form a complex regulatory network for spermatogenesis. In testicular tumors or infertile patients, the activities of these signaling pathways in Sertoli cells are abnormal. Clarifying the mechanisms of signaling pathways in Sertoli cells on spermatogenesis provides new insights into the physiological functions of Sertoli cells in male reproduction, and also serves as a pre-requisite to identify potential therapeutic targets in abnormal spermatogenesis including testicular tumor and male infertility.
Topics: Adherens Junctions; Animals; Carcinogenesis; Humans; Infertility, Male; Lactic Acid; Male; Sertoli Cells; Signal Transduction; Spermatogenesis; Testicular Neoplasms; Tight Junctions
PubMed: 31316051
DOI: 10.1038/s41419-019-1782-z -
Frontiers in Cellular and Infection... 2023disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected...
disseminates hematogenously to reach the target organs by disrupting epithelial adherens junctions (AJs), thus causing leptospirosis, which is a globally neglected zoonotic disease. induces E-cadherin (E-cad) endocytosis and cytoskeletal rearrangement during AJ disassembly, but the detailed mechanism remains unknown. Elucidation of AJ disassembly mechanisms will guide new approaches to developing vaccines and diagnostic methods. In this study, we combine proteomic and imaging analysis with chemical inhibition studies to demonstrate that disrupting the AJs of renal proximal tubule epithelial cells involves the degradation of two armadillo repeat-containing proteins, p0071 and p120-catenin, that stabilize E-cad at the plasma membrane. Combining proteasomal and lysosomal inhibitors substantially prevented p120-catenin degradation, and monolayer integrity destruction without preventing p0071 proteolysis. In contrast, the pan-caspase inhibitor Z-VAD-FMK inhibited p0071 proteolysis and displacement of both armadillo repeat-containing proteins from the cell-cell junctions. Our results show that induces p120-catenin and p0071 degradation, which mutually regulates E-cad stability by co-opting multiple cellular degradation pathways. This strategy may allow to disassemble AJs and disseminate through the body efficiently.
Topics: Delta Catenin; Adherens Junctions; Leptospira interrogans; Proteomics; Catenins
PubMed: 37795382
DOI: 10.3389/fcimb.2023.1228051 -
Journal of Vascular Research 2021Protein localization in endothelial cells is tightly regulated to create distinct signaling domains within their tight spatial restrictions including luminal membranes,... (Review)
Review
Protein localization in endothelial cells is tightly regulated to create distinct signaling domains within their tight spatial restrictions including luminal membranes, abluminal membranes, and interendothelial junctions, as well as caveolae and calcium signaling domains. Protein localization in endothelial cells is also determined in part by the vascular bed, with differences between arteries and veins and between large and small arteries. Specific protein polarity and localization is essential for endothelial cells in responding to various extracellular stimuli. In this review, we examine protein localization in the endothelium of resistance arteries, with occasional references to other vessels for contrast, and how that polarization contributes to endothelial function and ultimately whole organism physiology. We highlight the protein localization on the luminal surface, discussing important physiological receptors and the glycocalyx. The protein polarization to the abluminal membrane is especially unique in small resistance arteries with the presence of the myoendothelial junction, a signaling microdomain that regulates vasodilation, feedback to smooth muscle cells, and ultimately total peripheral resistance. We also discuss the interendothelial junction, where tight junctions, adherens junctions, and gap junctions all convene and regulate endothelial function. Finally, we address planar cell polarity, or axial polarity, and how this is regulated by mechanosensory signals like blood flow.
Topics: Animals; Arteries; Cell Polarity; Endothelial Cells; Glycocalyx; Humans; Intercellular Junctions; Mechanotransduction, Cellular; Protein Transport; Proteins; Regional Blood Flow; Vascular Resistance
PubMed: 33503620
DOI: 10.1159/000512618 -
The Journal of Biological Chemistry Nov 2019To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression... (Review)
Review
To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, and differentiation as well as the processes of tissue regeneration and wound repair. Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states, such as fibrosis, muscle diseases, and cancer. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical signals, like activation of specific genes and signaling cascades that enable cells to adapt to their physical environment. The signaling pathways involved in mechanical signaling are highly complex, but numerous studies have highlighted a central role for the Hippo pathway and other signaling networks in regulating the YAP and TAZ (YAP/TAZ) proteins to mediate the effects of mechanical stimuli on cellular behavior. How mechanical cues control YAP/TAZ has been poorly understood. However, rapid progress in the last few years is beginning to reveal a surprisingly diverse set of pathways for controlling YAP/TAZ. In this review, we will focus on how mechanical perturbations are sensed through changes in the actin cytoskeleton and mechanosensors at focal adhesions, adherens junctions, and the nuclear envelope to regulate YAP/TAZ.
Topics: Actin Cytoskeleton; Adaptor Proteins, Signal Transducing; Adherens Junctions; Animals; Focal Adhesions; Humans; Mechanotransduction, Cellular; Signal Transduction; Trans-Activators; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins
PubMed: 31594864
DOI: 10.1074/jbc.REV119.007963 -
BioEssays : News and Reviews in... Nov 2020Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin... (Review)
Review
Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin cytoskeleton are primarily transmitted through integrin-containing focal adhesions and cadherin-containing adherens junctions. Crosstalk between these complexes is well established and modulates the mechanical landscape of the cell. However, integrins and cadherins constitute large families of adhesion receptors and form multiple complexes by interacting with different ligands, adaptor proteins, and cytoskeletal filaments. Recent findings indicate that integrin-containing hemidesmosomes oppose force transduction and traction force generation by focal adhesions. The cytolinker plectin mediates this crosstalk by coupling intermediate filaments to the actin cytoskeleton. Similarly, cadherins in desmosomes might modulate force generation by adherens junctions. Moreover, mechanotransduction can be influenced by podosomes, clathrin lattices, and tetraspanin-enriched microdomains. This review discusses mechanotransduction by multiple integrin- and cadherin-based cell adhesion complexes, which together with the associated cytoskeleton form an integrated network that allows cells to sense, process, and respond to their physical environment.
Topics: Adherens Junctions; Cadherins; Cell Adhesion; Cytoskeleton; Humans; Integrins; Mechanotransduction, Cellular
PubMed: 32830356
DOI: 10.1002/bies.202000119