Desmosomes at a glance

Desai, Bhushan V.; Harmon, Robert M.; Green, Kathleen J.

doi:10.1242/jcs.037457

Cited by 84 publications

(86 citation statements)

References 89 publications

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“…As a result, the monitoring of disease activity and effect of clinical interventions have centered on studying these autoAbs. However, as more targets of autoAbs in PV have been reported, there has been a growing pool of evidence suggesting autoAbs directed against non-Dsg antigens may also play a role in disease (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Current knowledge of non-Dsg autoAbs in PV is segmented and discontinuous, with individual studies focusing on non-Dsg targets individually, providing little insight into their disease relevance as biomarkers or drivers of disease.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of pathogenic autoAbs directed against non-Dsg targets could account for these findings. Early studies established the presence of non-Dsg autoAbs in PV sera by showing that PVIgG depleted of anti-Dsg3 Abs recognized a number of non-Dsg antigens (15), and subsequent work identified several specific non-Dsg proteins as targets of autoAbs in PV (9,(16)(17)(18)(19)(20).Currently, the scope and specificity of non-Dsg autoAbs in PV has not been fully examined, and the genetic factors underlying autoAb generation, including the impact of HLA allele expression on PV autoAb repertoires, are not well understood. Without a detailed understanding of the specificity of the autoimmune response, broad-scale immunosuppression, whose side effects alone can be severe or even life-threatening, remains the mainstay treatment of PV.…”

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Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Sajda

Hazelton

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Patients with pemphigus vulgaris (PV) harbor antibodies reactive against self-antigens expressed at the surface of keratinocytes, primarily desmoglein (Dsg) 3 and, to a lesser extent, Dsg1. Conventionally, only antibodies targeting these molecules have been thought to contribute to disease pathogenesis. This notion has been challenged by a growing pool of evidence that suggests that antibodies toward additional targets may play a role in disease. The aims of this study were to (i) establish high-throughput protein microarray technology as a method to investigate traditional and putative autoantibodies (autoAbs) in PV and (ii) use multiplexed protein array technology to define the scope and specificity of the autoAb response in PV. Our analysis demonstrated significant IgG reactivity in patients with PV toward the muscarinic acetylcholine receptor subtypes 3, 4, and 5 as well as thyroid peroxidase. Furthermore, we found that healthy first-and second-degree relatives of patients with PV express autoAbs toward desmoglein and non-Dsg targets. Our analysis also identified genetic elements, particularly HLA, as key drivers of autoAb expression. Finally, we show that patients with PV exhibit significantly reduced IgM reactivity toward disease-associated antigens relative to controls. The use of protein microarrays to profile the autoAb response in PV advanced the current understanding of disease and provided insight into the complex relationship between genetics and disease development.pemphigus | autoantibody | protein microarray P emphigus vulgaris (PV) is a blistering autoimmune skin disease characterized by the presence of autoantibodies (autoAbs) directed against keratinocyte surface antigens (1, 2). Although early immunofluorescence studies demonstrated the presence of autoAbs in patient sera that bound to the surface of keratinocytes, a direct role of autoAbs in disease pathogenesis was not established until purified patient IgG (PVIgG) was shown to elicit blister formation upon passive transfer in mice (3). The main targets of these autoAbs were identified as Desmoglein (Dsg) 3 and 1, cadherin proteins that constitute key components of desmosomes, protein complexes responsible for maintaining cell-cell adhesion (4-7). Later experiments in which patient sera depleted of anti-Dsg3 Abs failed to produce blisters when passively transferred to mice (8) seemingly cemented the notion that these autoAbs alone were responsible for blister formation. As a result, subsequent research in the field has focused primarily on autoAbs directed against Dsgs.The assertion that anti-Dsg autoAbs alone are pathogenic was first challenged when PVIgG, lacking any anti-Dsg1 autoAbs, produced blisters when passively transferred into Dsg3-null mice (9). Additionally, several studies have shown that anti-Dsg Ab titers do not necessarily correlate with disease activity, and a subset of patients with PV do not harbor any detectable anti-Dsg Abs (10-14). The presence of pathogenic autoAbs directed against non-Dsg targets could account for th...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Sajda

Hazelton

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This may suggest that PKP2 is involved in EGFR signal activation at regions of cell attachment. Desmosome proteins, including PKP2, are intercellular key junctions that confer strong cell-cell adhesion (29,30). They are located at the cell membrane, where they act as anchors for intermediate filaments (29).…”

Section: Discussionmentioning

confidence: 99%

Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation

Arimoto

Burkart

Yan

et al. 2014

Molecular and Cellular Biology

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Epidermal growth factor (EGF) receptor (EGFR) has been implicated in tumor development and invasion. Dimerization and autophosphorylation of EGFR are the critical events for EGFR activation. However, the regulation of EGF-dependent and EGFindependent dimerization and phosphorylation of EGFR has not been fully understood. Here, we report that cytoplasmic protein plakophilin-2 (PKP2) is a novel positive regulator of EGFR signaling. PKP2 specifically interacts with EGFR via its N-terminal head domain. Increased PKP2 expression enhances EGF-dependent and EGF-independent EGFR dimerization and phosphorylation. Moreover, PKP2 knockdown reduces EGFR phosphorylation and attenuates EGFR-mediated signal activation, resulting in a significant decrease in proliferation and migration of cancer cells and tumor development. Our results indicate that PKP2 is a novel activator of the EGFR signaling pathway and a potential new drug target for inhibiting tumor growth.

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“…Those transmembrane structures that connect the cell surface to the intermediate fi lament cytoskeleton consist of heterodimers of desmosomal cadherins, desmogleins (DSG1 -DSG4) and desmocollins (DSC1 -DSC3). The cytoplasmic part of the desmosomal plaque contains a number of associated proteins, such as plakoglobin and plakophilins that associate with DSP and thereby link to the keratin cytoskeleton (Desai et al, 2009). Desmosomal cadherins and their associated proteins play a role in instructing the development and differentiation of complex tissues in vertebrates.…”

Section: Desmosomes and Keratin Network In Skin Inflammationmentioning

confidence: 99%

Junctions and Inflammation in the Skin

Kobielak

Boddupally

2014

Cell Communication & Adhesion

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The skin forms a life-sustaining barrier between the organism and physical environment. The physical barrier of skin is mainly localized in the stratum corneum (SC); however, nucleated epidermis also contributes to the barrier through tight, gap, and adherens junctions (AJs), as well as through desmosomes and cytoskeletal elements. Many infl ammatory diseases, such as atopic dermatitis (AD) and psoriasis, are associated with barrier dysfunction. It is becoming increasingly clear that the skin barrier function is not only affected by infl ammatory signals but that defects in structural components of the barrier may be the initiating event for infl ammatory diseases. This view is supported by fi ndings that mutations in fi laggrin, a key structural epidermal barrier protein, cause the infl ammatory skin disease AD, and that a loss of AJ components, namely epidermal p120 catenin or α -catenin results in skin infl ammation.

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Desmosomes at a glance

Cited by 84 publications

References 89 publications

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Plakophilin-2 Promotes Tumor Development by Enhancing Ligand-Dependent and -Independent Epidermal Growth Factor Receptor Dimerization and Activation

Junctions and Inflammation in the Skin

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