Mislocalization of Adherens Junction- Associated Proteins in a Patient with Darier Disease

2018 ◽  
Vol 2 (3) ◽  
pp. 184-201
Author(s):  
George D Glinos ◽  
Irena Pastar ◽  
Marjana Tomic-Canic ◽  
Rivka C Stone
Keyword(s):  
Adherens Junction ◽  
Cellular Adhesion ◽  
Calcium Flux ◽  
Keratinocyte Differentiation ◽  
Calcium Dependent ◽  
Endoplasmic Reticulum Calcium ◽  
Darier Disease ◽  
Associated Proteins ◽  
Attachment Proteins ◽  
E Cadherin

Darier disease (DD) is an autosomal dominant keratinizing genodermatosis that manifests clinically with red-brown pruritic papules in a seborrheic distribution often in association with palmoplantar pits and dystrophic nail changes. It is caused by mutation in ATP2A2 which encodes a sarco/endoplasmic reticulum calcium ATPase isoform 2 (SERCA2) pump that regulates calcium flux. Consequent alteration of intracellular calcium homeostasis is thought to impair trafficking of cellular adhesion proteins and to lead to aberrant keratinocyte differentiation, contributing to the characteristic histopathologic features of acantholysis and dyskeratosis in DD, though the precise mechanisms are incompletely understood. Previous studies have identified defective localization of desmosomal attachment proteins in skin biopsies and cultured keratinocytes from DD patients, but reports of effects on adherens junction proteins (including calcium-dependent E-cadherin) are conflicting. Here we describe a case of DD presenting with characteristic clinical and histologic features in which we performed immunofluorescence staining of four adherens junction-associated proteins (E-cadherin, α-catenin, β-catenin, and vinculin). In lesional (acantholytic) DD skin, we identified loss of distinctive bright membranous staining that was present at the periphery of keratinocytes throughout the epidermis in the healthy skin of a matched donor. Perilesional (non-acantholytic) portions of DD skin partially recapitulated the normal phenotype. Our findings support a role for SERCA2 dysfunction in impaired assembly of adherens junctions, which together with defective desmosomes contribute to acantholysis in DD.

scholarly journals Structure-Based Virtual Screening Allows the Identification of Efficient Modulators of E-Cadherin-Mediated Cell–Cell Adhesion

2019 ◽  
Vol 20 (14) ◽  
pp. 3404 ◽  
Author(s):  
Andrea Dalle Vedove ◽  
Federico Falchi ◽  
Stefano Donini ◽  
Aurelie Dobric ◽  
Sebastien Germain ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Virtual Screening ◽  
Adherens Junction ◽  
Large Family ◽  
Calcium Dependent ◽  
Molecule Inhibitor ◽  
Dependent Cell ◽  
Cell Adhesion Proteins ◽  
E Cadherin ◽  
Cell Cell

Cadherins are a large family of transmembrane calcium-dependent cell adhesion proteins that orchestrate adherens junction formation and are crucially involved in tissue morphogenesis. Due to their important role in cancer development and metastasis, cadherins can be considered attractive targets for drug discovery. A recent crystal structure of the complex of a cadherin extracellular portion and a small molecule inhibitor allowed the identification of a druggable interface, thus providing a viable strategy for the design of cadherin dimerization modulators. Here, we report on a structure-based virtual screening approach that led to the identification of efficient and selective modulators of E-cadherin-mediated cell–cell adhesion. Of all the putative inhibitors that were identified and experimentally tested by cell adhesion assays using human pancreatic tumor BxPC-3 cells expressing both E-cadherin and P-cadherin, two compounds turned out to be effective in inhibiting stable cell–cell adhesion at micromolar concentrations. Moreover, at the same concentrations, one of them also showed anti-invasive properties in cell invasion assays. These results will allow further development of novel and selective cadherin-mediated cell–cell adhesion modulators for the treatment of a variety of cadherin-expressing solid tumors and for improving the efficiency of drug delivery across biological barriers.

scholarly journals A Novel Role for Integrin-linked Kinase in Epithelial Sheet Morphogenesis

2005 ◽  
Vol 16 (9) ◽  
pp. 4084-4095 ◽  
Author(s):  
Alisa Vespa ◽  
Sudhir J.A. D'Souza ◽  
Lina Dagnino
Keyword(s):  
Cell Membrane ◽  
Adherens Junction ◽  
Focal Adhesions ◽  
Cell Junctions ◽  
Keratinocyte Differentiation ◽  
Epidermal Keratinocytes ◽  
Cell Periphery ◽  
Integrin Linked Kinase ◽  
E Cadherin ◽  
Cell Cell

Integrin-linked kinase (ILK) is a multidomain protein involved in cell motility and cell-extracellular matrix interactions. ILK is found in integrin-containing focal adhesions in undifferentiated primary epidermal keratinocytes. Induction of keratinocyte differentiation by treatment with Ca2+ triggers formation of cell–cell junctions, loss of focal adhesions, and ILK distribution to cell borders. We now show that Ca2+ treatment of keratinocytes induces rapid (≤1 h) translocation to the cell membrane of the adherens junction (AJ) proteins E-cadherin and β-catenin. This is followed by slower (>6 h) localization of tight junction (TJ) proteins. The kinetics of ILK movement toward the cell periphery mimics that of AJ components, suggesting that ILK plays a role in the early formation of cell–cell contacts. Whereas the N terminus in ILK mediates localization to cell borders, expression of an ILK deletion mutant incapable of localizing to the cell membrane (ILK 191-452) interferes with translocation of E-cadherin/β-catenin to cell borders, precluding Ca2+-induced AJ formation. Cells expressing ILK 191-452 also fail to form TJ and sealed cell–cell borders and do not form epithelial sheets. Thus, we have uncovered a novel role for ILK in epithelial cell–cell adhesion, independent of its well-established role in integrin-mediated adhesion and migration.

scholarly journals Expression of Wnt-1 in PC12 cells results in modulation of plakoglobin and E-cadherin and increased cellular adhesion.

1993 ◽  
Vol 123 (6) ◽  
pp. 1857-1865 ◽  
Author(s):  
R S Bradley ◽  
P Cowin ◽  
A M Brown
Keyword(s):  
Cell Adhesion ◽  
Pc12 Cells ◽  
Morphological Changes ◽  
Fetal Brain ◽  
Cell Types ◽  
Cellular Adhesion ◽  
Signaling Mechanism ◽  
Calcium Dependent ◽  
Junction Protein ◽  
E Cadherin

The Wnt-1 gene plays an essential role in fetal brain development and encodes a secreted protein whose signaling mechanism is presently unknown. In this report we have investigated intracellular mechanisms by which the Wnt-1 gene induces morphological changes in PC12 pheochromocytoma cells. PC12 cells expressing Wnt-1 show increased steady-state levels of the adhesive junction protein plakoglobin, and an altered distribution of this protein within the cell. This effect appears similar to a modulation of the plakoglobin homolog, Armadillo, that occurs in Drosophila embryos in response to the Wnt-1 homolog, wingless (Riggleman, B., P. Schedl, and E. Wieschaus. 1990. Cell. 63:549-560). In addition, PC12/Wnt-1 cells show elevated expression of E-cadherin and increased calcium-dependent cell-cell adhesion. These results imply evolutionary conservation of cellular responses to Wnt-1/wingless and indicate that in certain cell types Wnt-1 may act to modulate cell adhesion mechanisms.

Cadherin function in junctional complex rearrangement and posttranslational control of cadherin expression

1999 ◽  
Vol 276 (2) ◽  
pp. C404-C418 ◽  
Author(s):  
Megan L. Troxell ◽  
Yih-Tai Chen ◽  
Nicole Cobb ◽  
W. James Nelson ◽  
James A. Marrs
Keyword(s):  
Tight Junction ◽  
Adherens Junction ◽  
Junctional Complex ◽  
Adhesion Protein ◽  
Cell Monolayers ◽  
Calcium Dependent ◽  
Protein Levels ◽  
Epithelial Junctions ◽  
Junctional Complexes ◽  
E Cadherin

The role of E-cadherin, a calcium-dependent adhesion protein, in organizing and maintaining epithelial junctions was examined in detail by expressing a fusion protein (GP2-Cad1) composed of the extracellular domain of a nonadherent glycoprotein (GP2) and the transmembrane and cytoplasmic domains of E-cadherin. All studies shown were also replicated using an analogous cell line that expresses a mutant cadherin construct (T151) under the control of tet repressor. Mutant cadherin was expressed at ∼10% of the endogenous E-cadherin level and had no apparent effect on tight junction function or on distributions of adherens junction, tight junction, or desmosomal marker proteins in established Madin-Darby canine kidney cell monolayers. However, GP2-Cad1 accelerated the disassembly of epithelial junctional complexes and delayed their reassembly in calcium switch experiments. Inducing expression of GP2-Cad1 to levels approximately threefold greater than endogenous E-cadherin expression levels in control cells resulted in a decrease in endogenous E-cadherin levels. This was due in part to increased protein turnover, indicating a cellular mechanism for sensing and controlling E-cadherin levels. Cadherin association with catenins is necessary for strong cadherin-mediated cell-cell adhesion. In cells expressing low levels of GP2-Cad1, protein levels and stoichiometry of the endogenous cadherin-catenin complex were unaffected. Thus effects of GP2-Cad1 on epithelial junctional complex assembly and stability were not due to competition with endogenous E-cadherin for catenin binding. Rather, we suggest that GP2-Cad1 interferes with the packing of endogenous cadherin-catenin complexes into higher-order structures in junctional complexes that results in junction destabilization.

E-cadherin mediates adhesion and suppresses cell motility via distinct mechanisms

1997 ◽  
Vol 110 (3) ◽  
pp. 345-356 ◽  
Author(s):  
H. Chen ◽  
N.E. Paradies ◽  
M. Fedor-Chaiken ◽  
R. Brackenbury
Keyword(s):  
Cell Motility ◽  
Cell Movement ◽  
Cytoplasmic Domain ◽  
Cellular Adhesion ◽  
Binding Domain ◽  
Calcium Dependent ◽  
L Cells ◽  
Rat Astrocyte ◽  
E Cadherin

Expression of the calcium-dependent adhesion molecule E-cadherin suppresses the invasion of cells in vitro, but the mechanism of this effect is unknown. To investigate this mechanism, we analyzed the effects of expressing E-cadherin in mouse L-cells and rat astrocyte-like WC5 cells. Increased cellular adhesion mediated by E-cadherin reduced invasion in WC5 cells and in some L-cells, but not in others. In all cases, suppression of invasion was correlated with decreased cell movement as assessed in an in vitro wound-filling assay and a transwell motility assay. To define the relationship between adhesion mediated by E-cadherin and suppression of motility, we analyzed the effects of deleting different regions of the E-cadherin cytoplasmic domain. E-cadherin lacking the entire cytoplasmic domain did not mediate calcium-dependent adhesion and did not reduce cell motility when expressed in WC5 cells. E-cadherin lacking a portion of the catenin-binding domain did not associate with the cytoskeleton and did not promote adhesion, yet still suppressed the motility of WC5 cells. In addition, E-cadherin that retains an intact catenin-binding domain, but lacks a juxtamembrane portion of the cytoplasmic domain, mediated effective adhesion, but did not suppress motility. These results indicate E-cadherin mediates adhesion and suppresses cell motility via distinct of E-cadherin plays a key role in suppressing motility.

scholarly journals Notch1 destabilizes the adherens junction complex through upregulation of the Snail family of E-cadherin repressors in non-small cell lung cancer

2013 ◽  
Vol 30 (3) ◽  
pp. 1423-1429 ◽  
Author(s):  
ARUM KIM ◽  
EUN YOUNG KIM ◽  
EUN NA CHO ◽  
HYUNG JUNG KIM ◽  
SE KYU KIM ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Adherens Junction ◽  
Small Cell ◽  
Small Cell Lung ◽  
Snail Family ◽  
E Cadherin

scholarly journals Deimination, Intermediate Filaments and Associated Proteins

2020 ◽  
Vol 21 (22) ◽  
pp. 8746
Author(s):  
Julie Briot ◽  
Michel Simon ◽  
Marie-Claire Méchin
Keyword(s):  
Rheumatoid Arthritis ◽  
Multiple Sclerosis ◽  
Cell Differentiation ◽  
Intermediate Filaments ◽  
Cross Linking ◽  
Post Translational Modification ◽  
Innate And Adaptive Immunity ◽  
Calcium Dependent ◽  
Physiological Processes ◽  
Associated Proteins

Deimination (or citrullination) is a post-translational modification catalyzed by a calcium-dependent enzyme family of five peptidylarginine deiminases (PADs). Deimination is involved in physiological processes (cell differentiation, embryogenesis, innate and adaptive immunity, etc.) and in autoimmune diseases (rheumatoid arthritis, multiple sclerosis and lupus), cancers and neurodegenerative diseases. Intermediate filaments (IF) and associated proteins (IFAP) are major substrates of PADs. Here, we focus on the effects of deimination on the polymerization and solubility properties of IF proteins and on the proteolysis and cross-linking of IFAP, to finally expose some features of interest and some limitations of citrullinomes.

scholarly journals Estrogens Determine Adherens Junction Organization and E-Cadherin Clustering in Breast Cancer Cells via Amphiregulin

iScience ◽  
2020 ◽  
Vol 23 (11) ◽  
pp. 101683
Author(s):  
Philip Bischoff ◽  
Marja Kornhuber ◽  
Sebastian Dunst ◽  
Jakob Zell ◽  
Beatrix Fauler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Adherens Junction ◽  
E Cadherin

scholarly journals Minus end–directed motor KIFC3 suppresses E-cadherin degradation by recruiting USP47 to adherens junctions

2014 ◽  
Vol 25 (24) ◽  
pp. 3851-3860 ◽  
Author(s):  
Kyoko Sako-Kubota ◽  
Nobutoshi Tanaka ◽  
Shigenori Nagae ◽  
Wenxiang Meng ◽  
Masatoshi Takeichi
Keyword(s):  
Cell Adhesion ◽  
Proteasome Inhibitors ◽  
Adherens Junction ◽  
Ubiquitin Protein Ligase ◽  
Juxtamembrane Region ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Epithelial Sheets ◽  
E Cadherin ◽  
Cell Cell

The adherens junction (AJ) plays a crucial role in maintaining cell–cell adhesion in epithelial tissues. Previous studies show that KIFC3, a minus end–directed kinesin motor, moves into AJs via microtubules that grow from clusters of CAMSAP3 (also known as Nezha), a protein that binds microtubule minus ends. The function of junction-associated KIFC3, however, remains to be elucidated. Here we find that KIFC3 binds the ubiquitin-specific protease USP47, a protease that removes ubiquitin chains from substrates and hence inhibits proteasome-mediated proteolysis, and recruits it to AJs. Depletion of KIFC3 or USP47 promotes cleavage of E-cadherin at a juxtamembrane region of the cytoplasmic domain, resulting in the production of a 90-kDa fragment and the internalization of E-cadherin. This cleavage depends on the E3 ubiquitin protein ligase Hakai and is inhibited by proteasome inhibitors. E-cadherin ubiquitination consistently increases after depletion of KIFC3 or USP47. These findings suggest that KIFC3 suppresses the ubiquitination and resultant degradation of E-cadherin by recruiting USP47 to AJs, a process that may be involved in maintaining stable cell–cell adhesion in epithelial sheets.

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