Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes

Dubash, Adi D.; Kam, Chen Yuan; Aguado, Brian A.; Patel, Dipal; Delmar, Mario; Shea, Lonnie D.; Green, Kathleen J.

doi:10.1083/jcb.201507018

Cited by 92 publications

(89 citation statements)

References 82 publications

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“…Importantly, ALK5 inhibition rescued total and membrane-localized desmosomal expression, keratinocyte differentiation marker expression, and cellular adhesive strength. Significantly, PKP2 loss can also stimulate TGF-β signaling, and this reciprocal regulation may reinforce the effects on both noted in our system (85). TGF-β signaling plays a key role in epithelial-mesenchymal transition, in which SLUG-induced desmosomal dissociation is a necessary and initial step (86).…”

Section: Discussionmentioning

confidence: 97%

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

Asrani¹,

Sood²,

Torres³

et al. 2017

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 97%

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

Asrani¹,

Sood²,

Torres³

et al. 2017

Journal of Clinical Investigation

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“…Desmosomes also help localize the actin‐regulatory machinery including Rho‐GTPases, which might further impact the organisation and function of the adherens junctions associated actin cytoskeleton and contractile apparatus. Desmosome components also regulate multiple other signalling pathways including GSK3beta/Wnt, p38/TGFbeta and Ras/Erk2 . Coupling with these pathways regulates multiple endpoints in skin and heart, including cell fate, differentiation, and fibrotic gene expression.…”

Section: What Is the Role Of The Desmosome In Arrhythmogenic Cardiomymentioning

confidence: 99%

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Elliott

Anastasakis

Asimaki

et al. 2019

European J of Heart Fail

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109

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It is 35 years since the first description of arrhythmogenic right ventricular cardiomyopathy (ARVC) and more than 20 years since the first reports establishing desmosomal gene mutations as a major cause of the disease. Early advances in the understanding of the clinical, pathological and genetic architecture of ARVC resulted in consensus diagnostic criteria, which proved to be sensitive but not entirely specific for the disease. In more recent years, clinical and genetic data from families and the recognition of a much broader spectrum of structural disorders affecting both ventricles and associated with a propensity to ventricular arrhythmia have raised many questions about pathogenesis, disease terminology and clinical management. In this paper, we present the conclusions of an expert round table that aimed to summarise the current state of the art in arrhythmogenic cardiomyopathies and to define future research priorities.

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“…Moreover, DSP expression is lost following PKP2 knockdown. Since the restoration of DSP expression rescues the activation of TGFβ1/p38 signaling, DSP acts upstream TGFβ1/p38 and downstream PKP2 (Dubash et al, 2016).…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Fibrosis in Arrhythmogenic Cardiomyopathy: The Phantom Thread in the Fibro-Adipose Tissue

et al. 2020

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Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder, predisposing to malignant ventricular arrhythmias leading to sudden cardiac death, particularly in young and athletic patients. Pathological features include a progressive loss of myocardium with fibrous or fibro-fatty substitution. During the last few decades, different clinical aspects of ACM have been well investigated but still little is known about the molecular mechanisms that underlie ACM pathogenesis, leading to these phenotypes. In about 50% of ACM patients, a genetic mutation, predominantly in genes that encode for desmosomal proteins, has been identified. However, the mutation-associated mechanisms, causing the observed cardiac phenotype are not always clear. Until now, the attention has been principally focused on the study of molecular mechanisms that lead to a prominent myocardium adipose substitution, an uncommon marker for a cardiac disease, thus often recognized as hallmark of ACM. Nonetheless, based on Task Force Criteria for the diagnosis of ACM, cardiomyocytes death associated with fibrous replacement of the ventricular free wall must be considered the main tissue feature in ACM patients. For this reason, it urges to investigate ACM cardiac fibrosis. In this review, we give an overview on the cellular effectors, possible triggers, and molecular mechanisms that could be responsible for the ventricular fibrotic remodeling in ACM patients.

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Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes

Abstract: Loss of the desmosome armadillo protein Plakophilin-2 in neonatal cardiomyocytes results in decreased stability and expression of the cytoskeletal linker protein Desmoplakin, which causes activation of a TGF-β1/p38 MAPK signaling cascade and induces expression of fibrotic genes.

Cited by 92 publications

References 82 publications

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

Definition and treatment of arrhythmogenic cardiomyopathy: an updated expert panel report

Fibrosis in Arrhythmogenic Cardiomyopathy: The Phantom Thread in the Fibro-Adipose Tissue

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