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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AR043380-16
Application #
8110868
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
1996-02-20
Project End
2016-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
16
Fiscal Year
2011
Total Cost
$465,076
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Maruthappu, T; Posafalvi, A; Castelletti, S et al. (2018) Loss-of-function desmoplakin I and II mutations underlie dominant arrhythmogenic cardiomyopathy with a hair and skin phenotype. Br J Dermatol :
Nekrasova, Oxana; Harmon, Robert M; Broussard, Joshua A et al. (2018) Desmosomal cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination. Nat Commun 9:1053
Mohamad, Janan; Sarig, Ofer; Godsel, Lisa M et al. (2018) Filaggrin 2 Deficiency Results in Abnormal Cell-Cell Adhesion in the Cornified Cell Layers and Causes Peeling Skin Syndrome Type A. J Invest Dermatol 138:1736-1743
Kam, Chen Yuan; Dubash, Adi D; Magistrati, Elisa et al. (2018) Desmoplakin maintains gap junctions by inhibiting Ras/MAPK and lysosomal degradation of connexin-43. J Cell Biol 217:3219-3235
Yang, Ruiguo; Broussard, Joshua A; Green, Kathleen J et al. (2018) Techniques to stimulate and interrogate cell-cell adhesion mechanics. Extreme Mech Lett 20:125-139
Quinlan, Roy A; Schwarz, Nicole; Windoffer, Reinhard et al. (2017) A rim-and-spoke hypothesis to explain the biomechanical roles for cytoplasmic intermediate filament networks. J Cell Sci 130:3437-3445
Broussard, Joshua A; Yang, Ruiguo; Huang, Changjin et al. (2017) The desmoplakin-intermediate filament linkage regulates cell mechanics. Mol Biol Cell 28:3156-3164
Samuelov, Liat; Li, Qiaoli; Bochner, Ron et al. (2017) SVEP1 plays a crucial role in epidermal differentiation. Exp Dermatol 26:423-430
Jones, Jonathan C R; Kam, Chen Yuan; Harmon, Robert M et al. (2017) Intermediate Filaments and the Plasma Membrane. Cold Spring Harb Perspect Biol 9:
Broussard, Joshua A; Green, Kathleen J (2017) Research Techniques Made Simple: Methodology and Applications of Förster Resonance Energy Transfer (FRET) Microscopy. J Invest Dermatol 137:e185-e191

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