Journal
JOURNAL OF CELL BIOLOGY
Volume 212, Issue 4, Pages 425-438Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.201507018
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Funding
- National Cancer Institute grant [CCSG P30CA060553]
- National Institutes of Health [R01 AR041836, AR43380, NIH-HL106632, NIH-GM057691]
- J.L. Mayberry Endowment
- Fondation Leducq Transatlantic Network grant
- American Heart Association [11POST7380001, 15PRE25560138]
- National Science Foundation
- [CA122151]
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Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor beta 1 (TGF-beta 1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-beta 1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-beta 1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-beta 1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.
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