s of oral presentations A 1 — Desmosomal molecules in and out of junctions Kathleen J. Green, Adi Dubash, Lisa M. Godsel Departments of Pathology and Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA kgreen@northwestern.edu Desmosomes are intercellular junctions that anchor the intermediate filament (IF) cytoskeleton to sites of strong intercellular adhesion, and play a critical role in ensuring mechanical integrity of the skin and the heart. Desmosome building blocks come primarily from three protein families. Transmembrane members of the cadherin family, the desmogleins and desmocollins, cooperate to form the adhesive interface. Within the junctional plaque, the cytoplasmic tails of the cadherins provide a scaffold for armadillo family members including plakoglobin and plakophilins (PKPs) 1-3 and the IF-binding protein, desmoplakin (DP), which in turn anchors the strain-bearing IF cytoskeleton to the plaque. In cardiac muscle, desmosome molecules are major architectural components of the intercalated discs, highly organized regions of the plasma membrane comprising components of adherens junctions, gap junctions, and desmosomes that together coordinate mechanical and electrochemical signaling between adjacent cardiac myocytes. In vertebrates, postnatal remodeling of these specialized regions of the plasma membrane occurs, giving rise to the area composita in which desmosomal building blocks are intermixed with components of adherens junctions. The crucial functions of desmosome molecules in epithelial and cardiac tissues are highlighted by the discovery of mutations that cause skin and heart disease. While interference with the architectural roles of desmosome molecules has been assumed to make an important contribution to tissue responses that lead to disease pathogenesis, functions that transcend their well-established roles in adhesion and IF-anchorage are emerging. Desmosome molecules have recently been shown to guide the remodeling of microtubules during epidermal morphogenesis, and also govern actin remodeling by regulating Rho GTPases during junction assembly. Of particular interest is the desmosomal armadillo protein plakophilin 2 (PKP2), which is reported as the most frequent target for mutation in arrhythmogenic right ventricular cardiomyopathy (ARVC), a leading cause of sudden cardiac death in the young. We previously showed that in epithelial cells, PKP2 regulates the localization and activity of RhoA to locally control actomyosin contractile signaling important for cell junction formation, while keeping global RhoA signaling in check. In the heart, signaling through RhoA and its downstream effectors is critical for normal cardiac development and physiology. Indeed, our data show that PKP2 silencing results in elevated RhoA and disruption of actin organization in cardiac myocytes. Further, loss of PKP2 or its fellow armadillo protein plakoglobin leads to elevated expression of target genes of the transcriptional regulator SRF (serum response factor), which is activated in a RhoA-dependent fashion, and along with Rho plays essential roles in cardiac development, hypertrophy and fibrosis. These data suggest a new cellular pathway through which desmosome deficiency could contribute to pathogen-
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Apr 5, 2014
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