Pemphigus vulgaris autoimmune globulin induces Src-dependent tyrosine-phosphorylation of plakophilin 3 and its detachment from desmoglein 3

Cirillo, Nicola; AlShwaimi, Emad; McCullough, Michael; Prime, Stephen S.

doi:10.3109/08916934.2013.866100

Cited by 26 publications

(28 citation statements)

References 38 publications

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“…Mutations in plakophilin 1 and 2 also disrupt desmosome assembly and stability resulting in skin fragility and blistering (McGrath et al 1997; McGrath and Mellerio 2010; Hall 2009). Src inhibition prevented phosphorylation of plakophilin-3, which reduced the disruptive effects of Pemphigus Vulgaris autoimmune antibodies (Cirillo et al 2014). Genetic loss of desmoplakin causes the loss of skin integrity due to intercellular separation and loss of desmosomal linkages to the cytokeratin intermediate filaments (Vasioukhin et al 2001b), and desmoplakin mutations have been found in cases of palmoplantar keratoderma, woolly hair syndrome, and cardiomyopathy (Pigors et al 2015).…”

Section: Epidermis Organization and Regulation Of Homeostasismentioning

confidence: 99%

Cell–Cell Junctions Organize Structural and Signaling Networks

García

Nelson

Chavez

2017

Cold Spring Harb Perspect Biol

341

253

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Cell-cell junctions link cells to each other in tissues, and regulate tissue homeostasis in critical cell processes that include tissue barrier function, cell proliferation and migration. Defects in cell-cell junctions give rise to a wide range of tissue abnormalities that disrupt homeostasis and are common in genetic abnormalities and cancers. Here, we discuss the organization and function of cell-cell junctions primarily involved in adhesion (Tight Junction, Adherens Junction, and Desmosomes) in two different epithelial tissues: a simple epithelium (intestine) and a stratified epithelium (epidermis). Studies in these tissues reveal similarities and differences in the organization and functions of different cell-cell junctions that meet the requirements for the specialized functions of each tissue. We discuss cell-cell junction responses to genetic and environmental perturbations that provide further insights into their roles in maintaining tissue homeostasis.

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Section: Epidermis Organization and Regulation Of Homeostasismentioning

confidence: 99%

Cell–Cell Junctions Organize Structural and Signaling Networks

García

Nelson

Chavez

2017

Cold Spring Harb Perspect Biol

341

253

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“…A recent study provided evidence that non-desmosomal Dsg3 regulates Src activity, whereby PV IgG reduces the expression of Dsg3 and is associated with a decrease in active Src (Tsang et al 2012). However, another study found that, under some conditions, Src activity promotes PV acantholysis (Cirillo et al 2014). Here, PKP3 is phosphorylated in response to PV IgG leading to dissociation from Dsg3 (Cirillo et al 2014).…”

Section: Desmosomal Cadherinsmentioning

confidence: 99%

Desmosome regulation and signaling in disease

2015

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Desmosomes are cell-cell adhesive organelles with a well-known role in forming strong intercellular adhesion during embryogenesis and in adult tissues subject to mechanical stress, such as the heart and skin. More recently, desmosome components have also emerged as cell signaling regulators. Loss of expression or interference with the function of desmosome molecules results in diseases of the heart and skin and contributes to cancer progression. However, the underlying molecular mechanisms that result in inherited and acquired disorders remain poorly understood. To address this question, researchers are directing their studies towards determining the functions that occur inside and outside of the junctions and the extent to which functions are adhesion-dependent or independent. This review focuses on recent discoveries that provide insights into the role of desmosomes and desmosome components in cell signaling and disease; wherever possible, we address molecular functions within and outside of the adhesive structure.

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“…Extradesmosomal Dsg3 was shown to associate with the cytoskeleton [56] and with E-cadherin, thereby facilitating the activation of Src [57,58], the latter of which is involved in the turnover of AJs [10,38,43] and was implicated in the pathogenesis of PV [12,13,45,64]. Nevertheless, the precise role of E-cadherin in the turnover of desmosomal cadherins and in the disease pemphigus is still not fully understood.…”

Section: Introductionmentioning

confidence: 99%

E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion

Rötzer

Hartlieb

Vielmuth

et al. 2015

Cell. Mol. Life Sci.

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Desmosomes provide strong intercellular cohesion essential for the integrity of cells and tissues exposed to continuous mechanical stress. For desmosome assembly, constitutively synthesized desmosomal cadherins translocate to the cell-cell border, cluster and mature in the presence of Ca(2+) to stable cell contacts. As adherens junctions precede the formation of desmosomes, we investigated in this study the relationship between the classical cadherin E-cadherin and the desmosomal cadherin Desmoglein 3 (Dsg3), the latter of which is indispensable for cell-cell adhesion in keratinocytes. By using autoantibodies from patients with the blistering skin disease pemphigus vulgaris (PV), we showed in loss of function studies that E-cadherin compensates for effects of desmosomal disassembly. Overexpression of E-cadherin reduced the loss of cell cohesion induced by PV autoantibodies and attenuated activation of p38 MAPK. Silencing of E-cadherin abolished the localization of Dsg3 at the membrane and resulted in a shift of Dsg3 from the cytoskeletal to the non-cytoskeletal protein pool which conforms to the notion that E-cadherin regulates desmosome assembly. Mechanistically, we identified a complex consisting of extradesmosomal Dsg3, E-cadherin, β-catenin and Src and that the stability of this complex is regulated by Src. Moreover, Dsg3 and E-cadherin are phosphorylated on tyrosine residues in a Src-dependent manner and Src activity is required for recruiting Dsg3 to the cytoskeletal pool as well as for desmosome maturation towards a Ca(2+)-insensitive state. Our data provide new insights into the role of E-cadherin and the contribution of Src signaling for formation and maintenance of desmosomal junctions.

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Pemphigus vulgaris autoimmune globulin induces Src-dependent tyrosine-phosphorylation of plakophilin 3 and its detachment from desmoglein 3

Cited by 26 publications

References 38 publications

Cell–Cell Junctions Organize Structural and Signaling Networks

Cell–Cell Junctions Organize Structural and Signaling Networks

Desmosome regulation and signaling in disease

E-cadherin and Src associate with extradesmosomal Dsg3 and modulate desmosome assembly and adhesion

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