Insights into Desmosome Biology from Inherited Human Skin Disease and Cardiocutaneous Syndromes

Nitoiu, Daniela; Etheridge, Sarah; Kelsell, David P.

doi:10.3109/15419061.2014.908854

Cited by 27 publications

(25 citation statements)

References 146 publications

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“…Both isoforms, DSPII and DSPIa, encode for a smaller version of DSPI, as they lack parts of the central alpha-helical rod domain with DSPII missing amino acids 1195-1793 and DSPIa missing amino acids 1351-1793 (Fig. S1c 1 ) (3,12). DSPI is the major isoform expressed in heart tissue, whereas DSPII is absent from the heart and simple epithelia (13), but plays a more significant role than DSPI in maintaining robust adhesion in keratinocytes (14).…”

Section: Discussionmentioning

confidence: 97%

Desmoplakin Mutations with Palmoplantar Keratoderma, Woolly Hair and Cardiomyopathy

Pigors¹,

Schwieger‐Briel²,

Cosgarea³

et al. 2015

Acta Derm Venerol

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Mutations in genes encoding for desmosomal components are associated with a broad spectrum of phenotypes comprising skin and hair abnormalities and account for 45-50% of cases of arrhythmogenic right ventricular cardiomyopathy. Today, more than 120 dominant and recessive desmoplakin (DSP) gene mutations have been reported to be associated with skin, hair and/or heart defects. Here we report on 3 cases with yet unreported DSP mutations, c.7566_7567delAAinsC, p.R2522Sfs*39, c.7756C>T, p.R2586*, c.2131_2132delAG and c.1067C>A, p.T356K, that were associated with variable woolly hair or hypotrichosis, palmoplantar keratoderma, and cardiac manifestations. In addition, we review and summarise the clinical features and DSP mutations of the patients described in the literature, which illustrates the complexity of this group of disorders and of their genotype-phenotype correlations, which cannot be easily predicted. Early diagnosis is crucial and cardiac examinations have to be performed on a regular basis.

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Section: Discussionmentioning

confidence: 97%

Desmoplakin Mutations with Palmoplantar Keratoderma, Woolly Hair and Cardiomyopathy

Pigors¹,

Schwieger‐Briel²,

Cosgarea³

et al. 2015

Acta Derm Venerol

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“…For example, in the skin and mucosae, autoantibodies against desmosome (desmogleins in pemphigous) and hemidesmosome (in pemphigoid) surface proteins, are associated with autoimmune blistering disease 85 . Mutations in desmosomal proteins result in arrhythmogenic cardiomyopathies and in skin syndromes (reviewed by 86 ). The “Ogna type” epidermolysis bullosa simplex is caused by a missense mutation in plectin, which links keratin IF to the hemidesmosome plaque 87 …”

Section: Keratins and Intercellular Bonds In Epithelial Barriers: Is mentioning

confidence: 99%

Multiple roles for keratin intermediate filaments in the regulation of epithelial barrier function and apico-basal polarity

2016

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As multicellular organisms evolved a family of cytoskeletal proteins, the keratins (types I and II) expressed in epithelial cells diversified in more than 20 genes in vertebrates. There is no question that keratin filaments confer mechanical stiffness to cells. However, such a number of genes can hardly be explained by evolutionary advantages in mechanical features. The use of transgenic mouse models has revealed unexpected functional relationships between keratin intermediate filaments and intracellular signaling. Accordingly, loss of keratins or mutations in keratins that cause or predispose to human diseases, result in increased sensitivity to apoptosis, regulation of innate immunity, permeabilization of tight junctions, and mistargeting of apical proteins in different epithelia. Precise mechanistic explanations for these phenomena are still lacking. However, immobilization of membrane or cytoplasmic proteins, including chaperones, on intermediate filaments (“scaffolding”) appear as common molecular mechanisms and may explain the need for so many different keratin genes in vertebrates.

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“…Our systematic evaluation of the phosphoproteome in epidermal progenitor cells during differentiation revealed significant changes in the phosphorylation of desmosomal proteins. In addition to their welldocumented role to provide tissues with the essential mechanical strength, accumulating evidence shows that desmosomes can also act as signaling sensors in response to environmental and cellular cues, and participate in fundamental processes such as cell proliferation, differentiation, and tissue morphogenesis (Green & Gaudry, 2000;Kitajima, 2014;Nitoiu et al, 2014;Broussard et al, 2015). In addition to their welldocumented role to provide tissues with the essential mechanical strength, accumulating evidence shows that desmosomes can also act as signaling sensors in response to environmental and cellular cues, and participate in fundamental processes such as cell proliferation, differentiation, and tissue morphogenesis (Green & Gaudry, 2000;Kitajima, 2014;Nitoiu et al, 2014;Broussard et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis

Lee

Jiang

et al. 2017

The EMBO Journal

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Tissue homeostasis of skin is sustained by epidermal progenitor cells localized within the basal layer of the skin epithelium. Post-translational modification of the proteome, such as protein phosphorylation, plays a fundamental role in the regulation of stemness and differentiation of somatic stem cells. However, it remains unclear how phosphoproteomic changes occur and contribute to epidermal differentiation. In this study, we survey the epidermal cell differentiation in a systematic manner by combining quantitative phosphoproteomics with mammalian kinome cDNA library screen. This approach identified a key signaling event, phosphorylation of a desmosome component, PKP1 (plakophilin-1) by RIPK4 (receptor-interacting serine-threonine kinase 4) during epidermal differentiation. With genome-editing and mouse genetics approach, we show that loss of function of either or impairs skin differentiation and enhances epidermal carcinogenesis Phosphorylation of PKP1's N-terminal domain by RIPK4 is essential for their role in epidermal differentiation. Taken together, our study presents a global view of phosphoproteomic changes that occur during epidermal differentiation, and identifies RIPK-PKP1 signaling as novel axis involved in skin stratification and tumorigenesis.

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Insights into Desmosome Biology from Inherited Human Skin Disease and Cardiocutaneous Syndromes

Cited by 27 publications

References 146 publications

Desmoplakin Mutations with Palmoplantar Keratoderma, Woolly Hair and Cardiomyopathy

Desmoplakin Mutations with Palmoplantar Keratoderma, Woolly Hair and Cardiomyopathy

Multiple roles for keratin intermediate filaments in the regulation of epithelial barrier function and apico-basal polarity

Phosphorylation of Pkp1 by RIPK4 regulates epidermal differentiation and skin tumorigenesis

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