By tethering the intermediate filament (IF) cytoskeleton to the plasma membrane, the desmosome plaque component desmoplakin (DP) strengthens adhesion mediated by the transmembrane desmosomal cadherins. Mutations in DP or its associated armadillo proteins result in potentially lethal disorders of the skin and heart. The loss of mechanical tissue integrity caused by desmosome dysfunction is commonly thought to underlie disease pathogenesis. However, in addition to their mechanical functions, desmosomal molecules provide signaling cues to regulate IF attachment, drive junction assembly, and guide epidermal morphogenesis. The mechanisms by which desmosomes govern signaling pathways to control tissue homeostasis and disease pathogenesis are poorly understood. We propose that the DP N-terminus and associated armadillo proteins in the plakophilin (PKP) family act as scaffolds to harness the activities of signaling mediators when and where they are needed for junction assembly and epidermal differentiation. Our goal is to determine how DP/PKP deficiency and mutations affecting DP-PKP interactions contribute to disease pathogenesis by interfering with structural and signaling functions by: 1) Determining the independent and cooperative roles of DP and PKPs in desmosome assembly and cell- cell adhesion and the effect of human disease mutations that interfere with DP-PKP interactions on these processes, 2) Testing whether DP and PKPs form scaffolds for PKC and small GTPase (RhoA) signaling mediators to integrate effector pathways that control desmosome function and cytoskeletal remodeling, and 3) Elucidating how DP works in conjunction with PKPs to promote epidermal morphogenesis and homeostasis. We will use an shRNA-dependent knock down approach combined with analysis of tissues and cells from mouse models and human patients with DP and PKP deficiencies to establish the respective roles of DP, PKPs and related signaling pathways in differentiation using 2D submerged, 3D in vitro and in vivo transplanted cultures. Desmosome-associated signaling mediators hold promise as targets for the design of small molecule therapies to ameliorate diseases caused by mutations or autoimmune antibodies that co-opt downstream pathways associated with these structural proteins.

Public Health Relevance

This project aims to understand how sticky structures on the surface of skin cells facilitate the formation of cell sheets to provide an essential skin barrier covering the surface of the body. The studies promise to reveal new functions for these molecules, beyond their role in cell coherence, that control normal tissue development and disease processes. These new pathways are predicted to provide novel therapeutic targets for people with inherited, autoimmune and infectious diseases of the skin.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Baker, Carl
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Northwestern University at Chicago
Schools of Medicine
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Arnette, Christopher; Koetsier, Jennifer L; Hoover, Paul et al. (2016) In Vitro Model of the Epidermis: Connecting Protein Function to 3D Structure. Methods Enzymol 569:287-308
Boyden, Lynn M; Kam, Chen Y; Hernández-Martín, Angela et al. (2016) Dominant de novo DSP mutations cause erythrokeratodermia-cardiomyopathy syndrome. Hum Mol Genet 25:348-57
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Johnson, Jodi L; Najor, Nicole A; Green, Kathleen J (2014) Desmosomes: regulators of cellular signaling and adhesion in epidermal health and disease. Cold Spring Harb Perspect Med 4:a015297

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