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

Adi D. Dubash, Chen Y. Kam, Brian A. Aguado, Dipal M. Patel, Mario Delmar, Lonnie D. Shea, Kathleen J. Green*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


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 β1 (TGF-β1) 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-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/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-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)425-438
Number of pages14
JournalJournal of Cell Biology
Issue number4
StatePublished - 2016

ASJC Scopus subject areas

  • Cell Biology


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