ADHESION JUNCTION REGULATION IN NORMAL AND DISEASED SKIN

University Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

DESCRIPTION: (Verbatim) The human proteins beta catenin and plakoglobin, and the related Drosophila protein Armadillo, have dual roles in keratinocyte cell-cell adhesion and in mediating cellular signaling events. Aberrant regulation of these proteins plays a role in both human cancers and cutaneous autoimmune disease. Beta catenin's signaling function is constitutively activated in a variety of human cancers including colorectal carcinoma and melanoma. In the desmosome, plakoglobin binds desmoglein 3 and 1, the target antigens for autoantibodies produced in the autoimmune blistering diseases pemphigus vulgaris (PV) and pemphigus foliaceus (PF), respectively. Since human beta catenin and plakoglobin and Drosophila Armadillo are phosphoproteins, phosphorylation may represent one mechanism by which these proteins are post-translationally regulated. In addition, we have recently identified O-glycosylation as a second post-translational modification of this family of proteins. We have cloned the Drosphila 0-glycosyltransferase (OGT) gene whose protein product is responsible for catalyzing the addition of this modification in vivo; the Drosophila OGT gene is 80 percent identical to the human counterpart. Over expression of this gene in Drosophila provides us with a tool to explore how this new modification affects the in vivo biology of these proteins. Because of the high degree of identity between (1) the Drosophila and human OGTs and (2) Drosophila Armadillo and human beta catenin and plakoglobin, we can directly apply what we learn from genetic and biochemical studies of the fly to human biology. We test what we learn from the fly by biochemical and cell biologic analyses in a normal human keratinocyte tissue culture system. This proposal details our plan to investigate how the cell-cell adhesion and signal transduction functions of human beta catenin and plakoglobin and Drosophila Annadillo are regulated by (1) phosphorylation and (2) O-glycosylation. Once these processes are disclosed, we believe that we may be able to understand the molecular mechanisms of acantholysis in the human autoimmune blistering diseases pemphigus vulgaris and pemphigus foliaceus.