The desmosomal cadherins are cell-cell adhesion molecules that are essential for epidermal integrity. Of the seven desmosomal cadherins expressed in human epidermis, desmoglein 1 (Dsg1) is a particularly prominent disease target. While the existence of inherited, autoimmune and bacterial toxin-mediated skin disease underscores Dsg1's importance in maintaining adhesion in the suprabasal layers, data from the last funding period demonstrate that Dsg1 also engages signaling mediators to promote terminal differentiation. The objective of this work is to identify how Dsg1 is transported to membranes to correctly perform its adhesion and signaling functions, and to determine how Dsg1-mediated signaling scaffolds promote differentiation. We hypothesize that Dsg1 is physically and functionally coupled to the initiation of the suprabasal differentiation through mitogen activated protein kinase (MAPK) and Rho GTPase signaling switches. We will use imaging, biochemistry and genetic interference in vitro in 2D and 3D organotypic cultures and in vivo in human/mouse xenografts, and complement these studies with analysis of material from patients with Dsg1 mutations, to address the following aims: 1) Determine the mechanism of Dsg1 export from the endoplasmic reticulum and transport to the plasma membrane through plus and minus end-directed microtubule motors in the kinesin and dynein families as well as the Dsg1-associated adaptor complex PX-RICS/14-3-3, 2) Determine how Dsg1 dampens mitogen activated protein kinase (MAPK) signaling through its associated protein Erbin to promote epidermal differentiation, and test the importance of this pathway in striate palmar plantar keratoderma (SPPK), and 3) Determine how Dsg1 and its associated protein Erbin regulate RhoGTPase-dependent signaling to promote actin remodeling, control cell shape and regulate serum response factor (SRF)-mediated transcriptional programs necessary for epidermal differentiation. Elucidating how cytoarchitectural scaffolds choreograph chemical signaling to promote differentiation will be essential for treating skin diseases where these pathways are undermined through cadherin gene defects, autoantibodies or bacterial pathogens.

Public Health Relevance

This project aims to understand how sticky molecules 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 focus on 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
Research Project (R01)
Project #
5R01AR041836-22
Application #
8704714
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
1993-08-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
22
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Najor, Nicole Ann; Fitz, Gillian Nicole; Koetsier, Jennifer Leigh et al. (2017) Epidermal Growth Factor Receptor neddylation is regulated by a desmosomal-COP9 (Constitutive Photomorphogenesis 9) signalosome complex. Elife 6:
Samuelov, Liat; Li, Qiaoli; Bochner, Ron et al. (2017) SVEP1 plays a crucial role in epidermal differentiation. Exp Dermatol 26:423-430
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Lowndes, Molly; Rakshit, Sabyasachi; Shafraz, Omer et al. (2014) Different roles of cadherins in the assembly and structural integrity of the desmosome complex. J Cell Sci 127:2339-50

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