Shedding of epidermal transmembrane proteins

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The basement membrane zone (BM) in human skin is an epithelial-mesenchymal interface designed to provide adherence and resistance against outer shearing forces. Specialized supramolecular protein complexes attach the epidermis to the dermis and are critical for the stable connection of the basal cell cytoskeleton with the BM. In the muscle, a very similar supramolecular aggregate, the dystrophin glycoprotein complex, links the inside of muscle cells with the BM. A number of proteins of these complexes are known, and defects in their genes lead to hereditary diseases. A component of the muscle complex, dystroglycan (DG), has recently been shown to occur also in certain epithelia. We demonstrated that both a- und ß-DG subunits are present at the skin BM and synthesized by keratinocytes in vitro. Here we propose molecular characterization of the structure, biosynthesis and regulation of the DG skin isoform, as well as the determinations of its ligands and functions. Using human skin diseases and a transgenic mouse as models, the role of DG in the pathogenetic pathways underlying genetic and inflammatory dermatoses will be determined. In addition to expanding our knowledge on the basic biology of BM proteins, we hope to contribute with this project to the development of novel therapeutic strategies for BM diseases and for other, common medical problems such as wound healing.