-
Journal of Cell Science Mar 2021Hippo signaling mediates influences of cytoskeletal tension on organ growth. TRIP6 and LIMD1 have each been identified as being required for tension-dependent inhibition...
Hippo signaling mediates influences of cytoskeletal tension on organ growth. TRIP6 and LIMD1 have each been identified as being required for tension-dependent inhibition of the Hippo pathway LATS kinases and their recruitment to adherens junctions, but the relationship between TRIP6 and LIMD1 was unknown. Using siRNA-mediated gene knockdown, we show that TRIP6 is required for LIMD1 localization to adherens junctions, whereas LIMD1 is not required for TRIP6 localization. TRIP6, but not LIMD1, is also required for the recruitment of vinculin and VASP to adherens junctions. Knockdown of TRIP6 or vinculin, but not of LIMD1, also influences the localization of myosin and F-actin. In TRIP6 knockdown cells, actin stress fibers are lost apically but increased basally, and there is a corresponding increase in the recruitment of vinculin and VASP to basal focal adhesions. Our observations identify a role for TRIP6 in organizing F-actin and maintaining tension at adherens junctions that could account for its influence on LIMD1 and LATS. They also suggest that focal adhesions and adherens junctions compete for key proteins needed to maintain attachments to contractile F-actin.
Topics: Actin Cytoskeleton; Actins; Adherens Junctions; Cytoskeleton; Focal Adhesions; Vinculin
PubMed: 33558314
DOI: 10.1242/jcs.247866 -
Journal of Cell Science Dec 2014Epithelia are compact tissues comprising juxtaposed cells that function as mechanical and chemical barriers between the body and the environment. This barrier relies, in... (Review)
Review
Epithelia are compact tissues comprising juxtaposed cells that function as mechanical and chemical barriers between the body and the environment. This barrier relies, in part, on adhesive contacts within adherens junctions, which are formed and stabilized by E-cadherin and catenin proteins linked to the actomyosin cytoskeleton. During development and throughout adult life, epithelia are continuously growing or regenerating, largely as a result of cell division. Although persistence of adherens junctions is needed for epithelial integrity, these junctions are continually remodelled during cell division. In this Commentary, we will focus on cytokinesis, the final step of mitosis, a multiparty phenomenon in which the adherens junction belt plays an essential role and during which a new cell-cell interface is generated between daughter cells. This new interface is the site of intense remodelling, where new adhesive contacts are assembled and cell polarity is transmitted from mother to daughter cells, ultimately becoming the site of cell signalling.
Topics: Adherens Junctions; Animals; Cell Division; Cell Polarity; Cytokinesis; Epithelial Cells; Mitosis
PubMed: 25344250
DOI: 10.1242/jcs.151472 -
Biochimica Et Biophysica Acta.... Sep 2020The apical junctional complex (AJC) is a cell-cell adhesion system present at the upper portion of the lateral membrane of epithelial cells integrated by the tight...
The apical junctional complex (AJC) is a cell-cell adhesion system present at the upper portion of the lateral membrane of epithelial cells integrated by the tight junction (TJ) and the adherens junction (AJ). This complex is crucial to initiate and stabilize cell-cell adhesion, to regulate the paracellular transit of ions and molecules and to maintain cell polarity. Moreover, we now consider the AJC as a hub of signal transduction that regulates cell-cell adhesion, gene transcription and cell proliferation and differentiation. The molecular components of the AJC are multiple and diverse and depending on the cellular context some of the proteins in this complex act as tumor suppressors or as promoters of cell transformation, migration and metastasis outgrowth. Here, we describe these new roles played by TJ and AJ proteins and their potential use in cancer diagnostics and as targets for therapeutic intervention.
Topics: Adherens Junctions; Cell Adhesion; Cell Differentiation; Cell Movement; Cell Polarity; Cell Proliferation; Cell Transformation, Neoplastic; Gene Expression Regulation; Humans; Intercellular Junctions; Neoplasms; Signal Transduction; Tight Junctions; Transcription, Genetic; Zonula Occludens-1 Protein
PubMed: 32240623
DOI: 10.1016/j.bbamem.2020.183278 -
Development (Cambridge, England) Dec 2020Planar cell polarity (PCP) is essential for tissue morphogenesis and homeostasis; however, the mechanisms that orchestrate the cell shape and packing dynamics required...
Planar cell polarity (PCP) is essential for tissue morphogenesis and homeostasis; however, the mechanisms that orchestrate the cell shape and packing dynamics required to establish PCP are poorly understood. Here, we identified a major role for the globular (G)-actin-binding protein thymosin-β4 (TMSB4X) in PCP establishment and cell adhesion in the developing epidermis. Depletion of in mouse embryos hindered eyelid closure and hair-follicle angling owing to PCP defects. depletion did not preclude epidermal cell adhesion or ; however, it resulted in abnormal structural organization and stability of adherens junction (AJ) due to defects in filamentous (F)-actin and G-actin distribution. In cultured keratinocytes, TMSB4X depletion increased the perijunctional G/F-actin ratio and decreased G-actin incorporation into junctional actin networks, but it did not change the overall actin expression level or cellular F-actin content. A pharmacological treatment that increased the G/F-actin ratio and decreased actin polymerization mimicked the effects of depletion on both AJs and PCP. Our results provide insights into the regulation of the actin pool and its involvement in AJ function and PCP establishment.
Topics: Actin Cytoskeleton; Actins; Adherens Junctions; Animals; Cell Adhesion; Cell Polarity; Cell Shape; Embryonic Development; Epidermal Cells; Epidermis; Homeostasis; Keratinocytes; Mice; Microfilament Proteins; Morphogenesis; Thymosin
PubMed: 33310787
DOI: 10.1242/dev.193425 -
Clinical Reviews in Allergy & Immunology Apr 2021Crohn's disease (CD) is a type of inflammatory bowel disease (IBD) and affects diverse segments of the entire gastrointestinal tract. Although the underlying causes of... (Review)
Review
Crohn's disease (CD) is a type of inflammatory bowel disease (IBD) and affects diverse segments of the entire gastrointestinal tract. Although the underlying causes of CD are not completely known, it is believed that disruption of the intestinal barrier and cell polarity may contribute to pathogenesis. The formation of the intestinal epithelial barrier, which is mainly regulated by cytoskeletal modulations, and apico-basal cell polarity are two major and mutually dependent features of the intestinal epithelial layer. As this layer serves as an important barrier between the external environment and the internal milieu, the defect can start an inflammatory cascade by failing to block the entrance of luminal pathogens and lead to CD. In this review, we highlight the factors and impact of intestinal barrier function and cell polarity in the natural history of CD. The discussion in the present review further strengthens the new challenge in facilitating the development of viable pharmacological targets.
Topics: Adherens Junctions; Animals; Cell Polarity; Crohn Disease; Cytoskeleton; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Tight Junctions
PubMed: 32474815
DOI: 10.1007/s12016-020-08795-5 -
ELife Feb 2018Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers...
Formation of blood vessel networks by sprouting angiogenesis is critical for tissue growth, homeostasis and regeneration. How endothelial cells arise in adequate numbers and arrange suitably to shape functional vascular networks is poorly understood. Here we show that YAP/TAZ promote stretch-induced proliferation and rearrangements of endothelial cells whilst preventing bleeding in developing vessels. Mechanistically, YAP/TAZ increase the turnover of VE-Cadherin and the formation of junction associated intermediate lamellipodia, promoting both cell migration and barrier function maintenance. This is achieved in part by lowering BMP signalling. Consequently, the loss of YAP/TAZ in the mouse leads to stunted sprouting with local aggregation as well as scarcity of endothelial cells, branching irregularities and junction defects. Forced nuclear activity of TAZ instead drives hypersprouting and vascular hyperplasia. We propose a new model in which YAP/TAZ integrate mechanical signals with BMP signaling to maintain junctional compliance and integrity whilst balancing endothelial cell rearrangements in angiogenic vessels.
Topics: Adaptor Proteins, Signal Transducing; Adherens Junctions; Animals; Bone Morphogenetic Protein Receptors; Cadherins; Cell Cycle Proteins; Cell Movement; Cell Proliferation; Endothelial Cells; Mice; Neovascularization, Physiologic; Phosphoproteins; Signal Transduction; Trans-Activators; Transcription Factors; YAP-Signaling Proteins
PubMed: 29400648
DOI: 10.7554/eLife.31037 -
Circulation Research Jan 2017The monolayer of endothelial cells lining the vessel wall forms a semipermeable barrier (in all tissue except the relatively impermeable blood-brain and inner retinal... (Review)
Review
The monolayer of endothelial cells lining the vessel wall forms a semipermeable barrier (in all tissue except the relatively impermeable blood-brain and inner retinal barriers) that regulates tissue-fluid homeostasis, transport of nutrients, and migration of blood cells across the barrier. Permeability of the endothelial barrier is primarily regulated by a protein complex called adherens junctions. Adherens junctions are not static structures; they are continuously remodeled in response to mechanical and chemical cues in both physiological and pathological settings. Here, we discuss recent insights into the post-translational modifications of junctional proteins and signaling pathways regulating plasticity of adherens junctions and endothelial permeability. We also discuss in the context of what is already known and newly defined signaling pathways that mediate endothelial barrier leakiness (hyperpermeability) that are important in the pathogenesis of cardiovascular and lung diseases and vascular inflammation.
Topics: Adherens Junctions; Animals; Capillary Permeability; Endothelial Cells; Endothelium, Vascular; Gap Junctions; Humans; Protein Binding; Signal Transduction
PubMed: 28057793
DOI: 10.1161/CIRCRESAHA.116.306534 -
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 May 2015Unique intercellular junctional complexes between the central nervous system (CNS) microvascular endothelial cells and the choroid plexus epithelial cells form the... (Review)
Review
Unique intercellular junctional complexes between the central nervous system (CNS) microvascular endothelial cells and the choroid plexus epithelial cells form the endothelial blood-brain barrier (BBB) and the epithelial blood-cerebrospinal fluid barrier (BCSFB), respectively. These barriers inhibit paracellular diffusion, thereby protecting the CNS from fluctuations in the blood. Studies of brain barrier integrity during development, normal physiology, and disease have focused on BBB and BCSFB tight junctions but not the corresponding endothelial and epithelial adherens junctions. The crosstalk between adherens junctions and tight junctions in maintaining barrier integrity is an understudied area that may represent a promising target for influencing brain barrier function.
Topics: Adherens Junctions; Animals; Biological Transport; Blood-Brain Barrier; Brain; Endothelial Cells; Endothelium, Vascular; Humans; Microvessels; Tight Junctions
PubMed: 26008742
DOI: 10.1083/jcb.201412147 -
FASEB Journal : Official Publication of... Mar 2021Histamine-induced vascular leakage is a core process of allergic pathologies, including anaphylaxis. Here, we show that glycolysis is integral to histamine-induced...
Histamine-induced vascular leakage is a core process of allergic pathologies, including anaphylaxis. Here, we show that glycolysis is integral to histamine-induced endothelial barrier disruption and hyperpermeability. Histamine rapidly enhanced glycolysis in endothelial cells via a pathway that involved histamine receptor 1 and phospholipase C beta signaling. Consistently, partial inhibition of glycolysis with 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) prevented histamine-induced hyperpermeability in human microvascular endothelial cells, by abolishing the histamine-induced actomyosin contraction, focal adherens junction formation, and endothelial barrier disruption. Pharmacologic blockade of glycolysis with 3PO in mice reduced histamine-induced vascular hyperpermeability, prevented vascular leakage in passive cutaneous anaphylaxis and protected from systemic anaphylaxis. In conclusion, we elucidated the role of glycolysis in histamine-induced disruption of endothelial barrier integrity. Our data thereby point to endothelial glycolysis as a novel therapeutic target for human pathologies related to excessive vascular leakage, such as systemic anaphylaxis.
Topics: Adherens Junctions; Anaphylaxis; Animals; Capillary Permeability; Endothelial Cells; Endothelium, Vascular; Glycolysis; Histamine; Mice; Phospholipase C beta; Signal Transduction
PubMed: 33566443
DOI: 10.1096/fj.202001634R