The Experts below are selected from a list of 1365 Experts worldwide ranked by ideXlab platform
Kathleen J. Green - One of the best experts on this subject based on the ideXlab platform.
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regulation of intestinal epithelial intercellular adhesion and barrier function by Desmosomal Cadherin desmocollin 2
Molecular Biology of the Cell, 2021Co-Authors: Arturo Rayasandino, Lisa M. Godsel, Kathleen J. Green, Vani Narayanan, Annyclaude Luissint, Dennis H M Kusters, Sven Flemming, Vicky Garciahernandez, Susan J Hagen, Daniel E. ConwayAbstract:The role of Desmosomal Cadherin desmocollin-2 (Dsc2) in regulating barrier function in intestinal epithelial cells (IECs) is not well understood. Here, we report the consequences of silencing Dsc2 on IEC barrier function in vivo using mice with inducible intestinal-epithelial-specific Dsc2 knockdown (KD) (Dsc2ERΔIEC). While the small intestinal gross architecture was maintained, loss of epithelial Dsc2 influenced Desmosomal plaque structure, which was smaller in size and had increased intermembrane space between adjacent epithelial cells. Functional analysis revealed that loss of Dsc2 increased intestinal permeability in vivo, supporting a role for Dsc2 in the regulation of intestinal epithelial barrier function. These results were corroborated in model human IECs in which Dsc2 KD resulted in decreased cell-cell adhesion and impaired barrier function. It is noteworthy that Dsc2 KD cells exhibited delayed recruitment of desmoglein-2 (Dsg2) to the plasma membrane after calcium switch-induced intercellular junction reassembly, while E-Cadherin accumulation was unaffected. Mechanistically, loss of Dsc2 increased desmoplakin (DP I/II) protein expression and promoted intermediate filament interaction with DP I/II and was associated with enhanced tension on desmosomes as measured by a Dsg2-tension sensor. In conclusion, we provide new insights on Dsc2 regulation of mechanical tension, adhesion, and barrier function in IECs.
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Desmosomal Cadherin association with tctex 1 and cortactin arp2 3 drives perijunctional actin polymerization to promote keratinocyte delamination
Nature Communications, 2018Co-Authors: Oxana Nekrasova, Lisa M. Godsel, Jennifer L. Koetsier, Robert M. Harmon, Joshua A. Broussard, Gillian N. Fitz, Margaret L. Gardel, Kathleen J. GreenAbstract:The epidermis is a multi-layered epithelium that serves as a barrier against water loss and environmental insults. Its morphogenesis occurs through a tightly regulated program of biochemical and architectural changes during which basal cells commit to differentiate and move towards the skin’s surface. Here, we reveal an unexpected role for the vertebrate Cadherin desmoglein 1 (Dsg1) in remodeling the actin cytoskeleton to promote the transit of basal cells into the suprabasal layer through a process of delamination, one mechanism of epidermal stratification. Actin remodeling requires the interaction of Dsg1 with the dynein light chain, Tctex-1 and the actin scaffolding protein, cortactin. We demonstrate that Tctex-1 ensures the correct membrane compartmentalization of Dsg1-containing desmosomes, allowing cortactin/Arp2/3-dependent perijunctional actin polymerization and decreasing tension at E-Cadherin junctions to promote keratinocyte delamination. Moreover, Dsg1 is sufficient to enable simple epithelial cells to exit a monolayer to form a second layer, highlighting its morphogenetic potential.
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Desmosomal Cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination
Nature Publishing Group, 2018Co-Authors: Oxana Nekrasova, Lisa M. Godsel, Jennifer L. Koetsier, Robert M. Harmon, Joshua A. Broussard, Gillian N. Fitz, Margaret L. Gardel, Kathleen J. GreenAbstract:The epidermis is a multi-layered epithelium formed by the differentiation of basal cells and movement into suprabasal layers. Here the authors define a role for the Desmosomal Cadherin desmoglein-1 in promoting the delamination of basal cells by remodeling the actin cytoskeleton through interactions with the dynein light chain Tctex-1 and cortactin
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isoform specific differences in the size of Desmosomal Cadherin catenin complexes
Journal of Investigative Dermatology, 2001Co-Authors: Leslie J Bannon, Betty L Cabrera, M S Stack, Kathleen J. GreenAbstract:Via their integration of the intermediate filament cytoskeleton into the cell membrane, desmosomes facilitate the maintenance of cell shape and tissue integrity as well as intercellular communication. The transmembrane components of the desmosome, the desmogleins and desmocollins, are members of the Cadherin family of cell–cell adhesion molecules. Each of these proteins exists as three distinct isoforms, which are the products of individual genes and expressed in a cell-type and differentiation-specific manner. Previous work has suggested that desmoglein 1 binds to its catenin partner, plakoglobin, in an approximately 6:1 stoichiometry. In this study, the molecular organization of complexes formed by plakoglobin and desmoglein 1, 2, or 3 are further examined through immunoprecipitation, size exclusion chromatography and sucrose density sedimentation analysis. It is shown that the complex formed between plakoglobin and desmoglein 1 has an overall molecular weight greater than that of plakoglobin/desmoglein 2 or plakoglobin/desmoglein 3; however, the stoichiometry of the plakoglobin/desmoglein 1 complex does not appear to exceed 2:1.
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the amino terminal domain of desmoplakin binds to plakoglobin and clusters Desmosomal Cadherin plakoglobin complexes
Journal of Cell Biology, 1997Co-Authors: Andrew P. Kowalczyk, Helena L. Palka, Elayne A. Bornslaeger, Jeffrey E. Borgwardt, Avninder S. Dhaliwal, Connie M. Corcoran, Mitchell F. Denning, Kathleen J. GreenAbstract:The desmosome is a highly organized plasma membrane domain that couples intermediate filaments to the plasma membrane at regions of cell–cell adhesion. Desmosomes contain two classes of Cadherins, desmogleins, and desmocollins, that bind to the cytoplasmic protein plakoglobin. Desmoplakin is a Desmosomal component that plays a critical role in linking intermediate filament networks to the Desmosomal plaque, and the amino-terminal domain of desmoplakin targets desmoplakin to the desmosome. However, the Desmosomal protein(s) that bind the amino-terminal domain of desmoplakin have not been identified. To determine if the Desmosomal Cadherins and plakoglobin interact with the amino-terminal domain of desmoplakin, these proteins were co-expressed in L-cell fibroblasts, cells that do not normally express Desmosomal components. When expressed in L-cells, the Desmosomal Cadherins and plakoglobin exhibited a diffuse distribution. However, in the presence of an amino-terminal desmoplakin polypeptide (DP-NTP), the Desmosomal Cadherins and plakoglobin were observed in punctate clusters that also contained DP-NTP. In addition, plakoglobin and DP-NTP were recruited to cell–cell interfaces in L-cells co-expressing a chimeric Cadherin with the E-Cadherin extracellular domain and the desmoglein-1 cytoplasmic domain, and these cells formed structures that were ultrastructurally similar to the outer plaque of the desmosome. In transient expression experiments in COS cells, the recruitment of DP-NTP to cell borders by the chimera required co-expression of plakoglobin. Plakoglobin and DP-NTP co-immunoprecipitated when extracted from L-cells, and yeast two hybrid analysis indicated that DP-NTP binds directly to plakoglobin but not Dsg1. These results identify a role for desmoplakin in organizing the Desmosomal Cadherin–plakoglobin complex and provide new insights into the hierarchy of protein interactions that occur in the Desmosomal plaque.
Robert M. Harmon - One of the best experts on this subject based on the ideXlab platform.
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Desmosomal Cadherin association with tctex 1 and cortactin arp2 3 drives perijunctional actin polymerization to promote keratinocyte delamination
Nature Communications, 2018Co-Authors: Oxana Nekrasova, Lisa M. Godsel, Jennifer L. Koetsier, Robert M. Harmon, Joshua A. Broussard, Gillian N. Fitz, Margaret L. Gardel, Kathleen J. GreenAbstract:The epidermis is a multi-layered epithelium that serves as a barrier against water loss and environmental insults. Its morphogenesis occurs through a tightly regulated program of biochemical and architectural changes during which basal cells commit to differentiate and move towards the skin’s surface. Here, we reveal an unexpected role for the vertebrate Cadherin desmoglein 1 (Dsg1) in remodeling the actin cytoskeleton to promote the transit of basal cells into the suprabasal layer through a process of delamination, one mechanism of epidermal stratification. Actin remodeling requires the interaction of Dsg1 with the dynein light chain, Tctex-1 and the actin scaffolding protein, cortactin. We demonstrate that Tctex-1 ensures the correct membrane compartmentalization of Dsg1-containing desmosomes, allowing cortactin/Arp2/3-dependent perijunctional actin polymerization and decreasing tension at E-Cadherin junctions to promote keratinocyte delamination. Moreover, Dsg1 is sufficient to enable simple epithelial cells to exit a monolayer to form a second layer, highlighting its morphogenetic potential.
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Desmosomal Cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination
Nature Publishing Group, 2018Co-Authors: Oxana Nekrasova, Lisa M. Godsel, Jennifer L. Koetsier, Robert M. Harmon, Joshua A. Broussard, Gillian N. Fitz, Margaret L. Gardel, Kathleen J. GreenAbstract:The epidermis is a multi-layered epithelium formed by the differentiation of basal cells and movement into suprabasal layers. Here the authors define a role for the Desmosomal Cadherin desmoglein-1 in promoting the delamination of basal cells by remodeling the actin cytoskeleton through interactions with the dynein light chain Tctex-1 and cortactin
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the gef bcr activates rhoa mal signaling to promote keratinocyte differentiation via desmoglein 1
Journal of Cell Biology, 2013Co-Authors: Adi D. Dubash, Jennifer L. Koetsier, Nicole A. Najor, Robert M. HarmonAbstract:Although much is known about signaling factors downstream of Rho GTPases that contribute to epidermal differentiation, little is known about which upstream regulatory proteins (guanine nucleotide exchange factors [GEFs] or GTPase-activating proteins [GAPs]) are involved in coordinating Rho signaling in keratinocytes. Here we identify the GEF breakpoint cluster region (Bcr) as a major upstream regulator of RhoA activity, stress fibers, and focal adhesion formation in keratinocytes. Loss of Bcr reduced expression of multiple markers of differentiation (such as desmoglein-1 [Dsg1], keratin-1, and loricrin) and abrogated MAL/SRF signaling in differentiating keratinocytes. We further demonstrated that loss of Bcr or MAL reduced levels of Dsg1 mRNA in keratinocytes, and ectopic expression of Dsg1 rescued defects in differentiation seen upon loss of Bcr or MAL signaling. Taken together, these data identify the GEF Bcr as a regulator of RhoA/MAL signaling in keratinocytes, which in turn promotes differentiation through the Desmosomal Cadherin Dsg1.
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Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation.
The Journal of clinical investigation, 2013Co-Authors: Robert M. Harmon, Cory L Simpson, Jennifer L. Koetsier, Jodi L. Johnson, Ofer Sarig, Adi D. Dubash, Nicole A. Najor, Eli SprecherAbstract:Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The Desmosomal Cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.
Oxana Nekrasova - One of the best experts on this subject based on the ideXlab platform.
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desmoglein 1 regulates invadopodia by suppressing egfr erk signaling in an erbin dependent manner
Molecular Cancer Research, 2019Co-Authors: Alejandra Valenzuelaiglesias, Oxana Nekrasova, Christopher Arnette, Hope E. Burks, Amulya Yalamanchili, Lisa M. GodselAbstract:Loss of the Desmosomal cell-cell adhesion molecule, Desmoglein 1 (Dsg1), has been reported as an indicator of poor prognosis in head and neck squamous cell carcinomas (HNSCC) overexpressing epidermal growth factor receptor (EGFR). It has been well established that EGFR signaling promotes the formation of invadopodia, actin-based protrusions formed by cancer cells to facilitate invasion and metastasis, by activating pathways leading to actin polymerization and ultimately matrix degradation. We previously showed that Dsg1 downregulates EGFR/Erk signaling by interacting with the ErbB2-binding protein Erbin (ErbB2 Interacting Protein) to promote keratinocyte differentiation. Here, we provide evidence that restoring Dsg1 expression in cells derived from HNSCC suppresses invasion by decreasing the number of invadopodia and matrix degradation. Moreover, Dsg1 requires Erbin to downregulate EGFR/Erk signaling and to fully suppress invadopodia formation. Our findings indicate a novel role for Dsg1 in the regulation of invadopodia signaling and provide potential new targets for development of therapies to prevent invadopodia formation and therefore cancer invasion and metastasis. IMPLICATIONS: Our work exposes a new pathway by which a Desmosomal Cadherin called Dsg1, which is lost early in head and neck cancer progression, suppresses cancer cell invadopodia formation by scaffolding ErbB2 Interacting Protein and consequent attenuation of EGF/Erk signaling.
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Desmosomal Cadherin association with tctex 1 and cortactin arp2 3 drives perijunctional actin polymerization to promote keratinocyte delamination
Nature Communications, 2018Co-Authors: Oxana Nekrasova, Lisa M. Godsel, Jennifer L. Koetsier, Robert M. Harmon, Joshua A. Broussard, Gillian N. Fitz, Margaret L. Gardel, Kathleen J. GreenAbstract:The epidermis is a multi-layered epithelium that serves as a barrier against water loss and environmental insults. Its morphogenesis occurs through a tightly regulated program of biochemical and architectural changes during which basal cells commit to differentiate and move towards the skin’s surface. Here, we reveal an unexpected role for the vertebrate Cadherin desmoglein 1 (Dsg1) in remodeling the actin cytoskeleton to promote the transit of basal cells into the suprabasal layer through a process of delamination, one mechanism of epidermal stratification. Actin remodeling requires the interaction of Dsg1 with the dynein light chain, Tctex-1 and the actin scaffolding protein, cortactin. We demonstrate that Tctex-1 ensures the correct membrane compartmentalization of Dsg1-containing desmosomes, allowing cortactin/Arp2/3-dependent perijunctional actin polymerization and decreasing tension at E-Cadherin junctions to promote keratinocyte delamination. Moreover, Dsg1 is sufficient to enable simple epithelial cells to exit a monolayer to form a second layer, highlighting its morphogenetic potential.
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Desmosomal Cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination
Nature Publishing Group, 2018Co-Authors: Oxana Nekrasova, Lisa M. Godsel, Jennifer L. Koetsier, Robert M. Harmon, Joshua A. Broussard, Gillian N. Fitz, Margaret L. Gardel, Kathleen J. GreenAbstract:The epidermis is a multi-layered epithelium formed by the differentiation of basal cells and movement into suprabasal layers. Here the authors define a role for the Desmosomal Cadherin desmoglein-1 in promoting the delamination of basal cells by remodeling the actin cytoskeleton through interactions with the dynein light chain Tctex-1 and cortactin
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Desmosomal Cadherins utilize distinct kinesins for assembly into desmosomes
Journal of Cell Biology, 2011Co-Authors: Oxana Nekrasova, William O. Smith, Evangeline V Amargo, Jing Chen, Geri KreitzerAbstract:The Desmosomal Cadherins, desmogleins (Dsgs) and desmocollins (Dscs), comprise the adhesive core of intercellular junctions known as desmosomes. Although these adhesion molecules are known to be critical for tissue integrity, mechanisms that coordinate their trafficking into intercellular junctions to regulate their proper ratio and distribution are unknown. We demonstrate that Dsg2 and Dsc2 both exhibit microtubule-dependent transport in epithelial cells but use distinct motors to traffic to the plasma membrane. Functional interference with kinesin-1 blocked Dsg2 transport, resulting in the assembly of Dsg2-deficient junctions with minimal impact on distribution of Dsc2 or Desmosomal plaque components. In contrast, inhibiting kinesin-2 prevented Dsc2 movement and decreased its plasma membrane accumulation without affecting Dsg2 trafficking. Either kinesin-1 or -2 deficiency weakened intercellular adhesion, despite the maintenance of adherens junctions and other desmosome components at the plasma membrane. Differential regulation of Desmosomal Cadherin transport could provide a mechanism to tailor adhesion strength during tissue morphogenesis and remodeling.
Lisa M. Godsel - One of the best experts on this subject based on the ideXlab platform.
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regulation of intestinal epithelial intercellular adhesion and barrier function by Desmosomal Cadherin desmocollin 2
Molecular Biology of the Cell, 2021Co-Authors: Arturo Rayasandino, Lisa M. Godsel, Kathleen J. Green, Vani Narayanan, Annyclaude Luissint, Dennis H M Kusters, Sven Flemming, Vicky Garciahernandez, Susan J Hagen, Daniel E. ConwayAbstract:The role of Desmosomal Cadherin desmocollin-2 (Dsc2) in regulating barrier function in intestinal epithelial cells (IECs) is not well understood. Here, we report the consequences of silencing Dsc2 on IEC barrier function in vivo using mice with inducible intestinal-epithelial-specific Dsc2 knockdown (KD) (Dsc2ERΔIEC). While the small intestinal gross architecture was maintained, loss of epithelial Dsc2 influenced Desmosomal plaque structure, which was smaller in size and had increased intermembrane space between adjacent epithelial cells. Functional analysis revealed that loss of Dsc2 increased intestinal permeability in vivo, supporting a role for Dsc2 in the regulation of intestinal epithelial barrier function. These results were corroborated in model human IECs in which Dsc2 KD resulted in decreased cell-cell adhesion and impaired barrier function. It is noteworthy that Dsc2 KD cells exhibited delayed recruitment of desmoglein-2 (Dsg2) to the plasma membrane after calcium switch-induced intercellular junction reassembly, while E-Cadherin accumulation was unaffected. Mechanistically, loss of Dsc2 increased desmoplakin (DP I/II) protein expression and promoted intermediate filament interaction with DP I/II and was associated with enhanced tension on desmosomes as measured by a Dsg2-tension sensor. In conclusion, we provide new insights on Dsc2 regulation of mechanical tension, adhesion, and barrier function in IECs.
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desmoglein 1 regulates invadopodia by suppressing egfr erk signaling in an erbin dependent manner
Molecular Cancer Research, 2019Co-Authors: Alejandra Valenzuelaiglesias, Oxana Nekrasova, Christopher Arnette, Hope E. Burks, Amulya Yalamanchili, Lisa M. GodselAbstract:Loss of the Desmosomal cell-cell adhesion molecule, Desmoglein 1 (Dsg1), has been reported as an indicator of poor prognosis in head and neck squamous cell carcinomas (HNSCC) overexpressing epidermal growth factor receptor (EGFR). It has been well established that EGFR signaling promotes the formation of invadopodia, actin-based protrusions formed by cancer cells to facilitate invasion and metastasis, by activating pathways leading to actin polymerization and ultimately matrix degradation. We previously showed that Dsg1 downregulates EGFR/Erk signaling by interacting with the ErbB2-binding protein Erbin (ErbB2 Interacting Protein) to promote keratinocyte differentiation. Here, we provide evidence that restoring Dsg1 expression in cells derived from HNSCC suppresses invasion by decreasing the number of invadopodia and matrix degradation. Moreover, Dsg1 requires Erbin to downregulate EGFR/Erk signaling and to fully suppress invadopodia formation. Our findings indicate a novel role for Dsg1 in the regulation of invadopodia signaling and provide potential new targets for development of therapies to prevent invadopodia formation and therefore cancer invasion and metastasis. IMPLICATIONS: Our work exposes a new pathway by which a Desmosomal Cadherin called Dsg1, which is lost early in head and neck cancer progression, suppresses cancer cell invadopodia formation by scaffolding ErbB2 Interacting Protein and consequent attenuation of EGF/Erk signaling.
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Desmosomal Cadherin association with tctex 1 and cortactin arp2 3 drives perijunctional actin polymerization to promote keratinocyte delamination
Nature Communications, 2018Co-Authors: Oxana Nekrasova, Lisa M. Godsel, Jennifer L. Koetsier, Robert M. Harmon, Joshua A. Broussard, Gillian N. Fitz, Margaret L. Gardel, Kathleen J. GreenAbstract:The epidermis is a multi-layered epithelium that serves as a barrier against water loss and environmental insults. Its morphogenesis occurs through a tightly regulated program of biochemical and architectural changes during which basal cells commit to differentiate and move towards the skin’s surface. Here, we reveal an unexpected role for the vertebrate Cadherin desmoglein 1 (Dsg1) in remodeling the actin cytoskeleton to promote the transit of basal cells into the suprabasal layer through a process of delamination, one mechanism of epidermal stratification. Actin remodeling requires the interaction of Dsg1 with the dynein light chain, Tctex-1 and the actin scaffolding protein, cortactin. We demonstrate that Tctex-1 ensures the correct membrane compartmentalization of Dsg1-containing desmosomes, allowing cortactin/Arp2/3-dependent perijunctional actin polymerization and decreasing tension at E-Cadherin junctions to promote keratinocyte delamination. Moreover, Dsg1 is sufficient to enable simple epithelial cells to exit a monolayer to form a second layer, highlighting its morphogenetic potential.
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Desmosomal Cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination
Nature Publishing Group, 2018Co-Authors: Oxana Nekrasova, Lisa M. Godsel, Jennifer L. Koetsier, Robert M. Harmon, Joshua A. Broussard, Gillian N. Fitz, Margaret L. Gardel, Kathleen J. GreenAbstract:The epidermis is a multi-layered epithelium formed by the differentiation of basal cells and movement into suprabasal layers. Here the authors define a role for the Desmosomal Cadherin desmoglein-1 in promoting the delamination of basal cells by remodeling the actin cytoskeleton through interactions with the dynein light chain Tctex-1 and cortactin
Robinaj Eady - One of the best experts on this subject based on the ideXlab platform.
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frameshift mutation in the v2 domain of human keratin 1 results in striate palmoplantar keratoderma
Journal of Investigative Dermatology, 2002Co-Authors: Neilv Whittock, Robinaj Eady, Patriciajc Doppinghepenstal, Frances J D Smith, W Irwin H Mclean, Hong Wan, R Mallipeddi, Andrew W D Griffiths, Gabrielle H S Ashton, John A McgrathAbstract:The striate form of palmoplantar keratoderma is a rare autosomal dominant disorder affecting palm and sole skin. Genetic heterogeneity of striate palmoplantar keratoderma has been demonstrated with pathogenic mutations in the Desmosomal proteins desmoplakin and desmoglein 1. We have studied a four-generation family of British descent with striate palmoplantar keratoderma. Ultrastructural studies show that intermediate filaments of suprabasal keratinocytes are finer than those of the basal layer. In addition, desmosome numbers are normal, but their inner plaques and midline structures are attenuated. Microsatellite markers were used to screen candidate loci including the epidermal differentiation complex on 1q, the desmoplakin locus on 6p, the type I and II keratin gene clusters on chromosomes 12q and 17q, and the Desmosomal Cadherin gene cluster on chromosome 18q. Significant genetic linkage to chromosome 12q was observed using marker D12S368, with a maximum two-point lod score of 3.496 at a recombination fraction of 0. Direct sequencing of the keratin 1 gene revealed a frameshift mutation in exon 9 that leads to the partial loss of the glycine loop motif in the V2 domain and the gain of a novel 70 amino acid peptide. Using expression studies we show that the V2 domain is essential for normal function of keratin intermediate filaments.
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spectrum of dominant mutations in the Desmosomal Cadherin desmoglein 1 causing the skin disease striate palmoplantar keratoderma
European Journal of Human Genetics, 2001Co-Authors: Debbiem Hunt, Danijela Simrak, Lisa Rickman, Neilv Whittock, Robinaj Eady, Howardp Stevens, Dkeithb Armstrong, Patriciajc Doppinghepenstal, Hans Christian HenniesAbstract:Spectrum of dominant mutations in the Desmosomal Cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma
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Genomic organization and amplification of the human Desmosomal Cadherin genes DSC1 and DSC3, encoding desmocollin types 1 and 3.
Biochemical and biophysical research communications, 2000Co-Authors: Neilv Whittock, Roger S. Buxton, Debbiem Hunt, Lisa Rickman, Robinaj Eady, Sukhjit Malhi, Artemis P. Vogazianou, Lisa F. Dawson, John A McgrathAbstract:The Desmosomal Cadherins comprise the desmocollins and desmogleins and are involved in epithelial cell-cell adhesion. There are three desmocollins (DSC 1-3) and three desmogleins (DSG 1-3) that are expressed in a tissue- and development-specific manner. Desmosomal proteins have been implicated in a number of disorders characterized by loss of cell-cell adhesion and trauma-induced skin fragility. Therefore, the desmocollins are potential candidates for genodermatoses involving epithelial tissues. In order to screen the entire DSC1 and DSC3 genes, we have characterized their intron-exon organization. The DSC1 gene comprises 17 exons spanning approximately 33 kb on 18q12.1, and the DSC3 gene comprises 17 exons spanning approximately 49 kb on 18q12.1. We have also developed a comprehensive PCR-based mutation detection strategy for desmocollins 1, 2, and 3 using primers placed on flanking introns followed by direct sequencing of the PCR products.
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n terminal deletion in a Desmosomal Cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma
Human Molecular Genetics, 1999Co-Authors: Lisa Rickman, Danijela Simrak, Debbiem Hunt, Robinaj Eady, Howardp Stevens, Ian A King, Stephen P Bryant, I M Leigh, Joachim Arnemann, Anthony I MageeAbstract:The N-terminal extracellular domain of the Cadherins, calcium-dependent cell adhesion molecules, has been shown by X-ray crystallography to be involved in two types of interaction: lateral strand dimers and adhesive dimers. Here we describe the first human mutation in a Cadherin present in desmosome cell junctions that removes a portion of this highly conserved first extracellular domain. The mutation, in the DSG1 gene coding for a desmoglein (Dsg1), results in the deletion of the first and much of the second beta-strand of the first Cadherin repeat and part of the first Ca2+-binding site, and would be expected to compromise strand dimer formation. It causes a dominantly inherited skin disease, striate palmoplantar keratoderma (SPPK), mapping to chromosome 18q12.1, in which affected individuals have marked hyperkeratotic bands on the palms and soles. In a three generation Dutch family with SPPK, we have found a G-->A transition in the 3" splice acceptor site of intron 2 of the DSG1 gene which segregated with the disease phenotype. This causes aberrant splicing of exon 2 to exon 4, which are in-frame, with the consequent removal of exon 3 encoding part of the prosequence, the mature protein cleavage site and part of the first extracellular domain. This mutation emphasizes the importance of this part of the molecule for Cadherin function, and of the Dsg1 protein and hence desmosomes in epidermal function.