The gp49 family of proteins are members of the immunoglobulin (Ig) superfamily that in the mouse are preferentially expressed by mast cells and mononuclear phagocytes. Two highly homologous genes, gp49A and gp49B, encode at least three transcriptional members of the gp49 family. The gp49A gene encodes gp49A1 transcripts, whereas the gp49B gene encodes gp49B1 and gp49B2 alternate transcripts. gp49B1 protein is expressed on the surface of mast cells, while gp49B2 protein may be secreted. Upon mast cell activation with phorbol myristate acetate or IgE, gp49B1 is serine phosphorylated, consistent with the presence of a protein kinase C phosphorylation site on one serine of the cytoplasmic domain. This domain of gp49B1, but not that of gp49A1, also contains a potentially phosphorylated tyrosine that is an essential part of a consensus sequence required for signal transduction by certain receptors of the Ig superfamily. A potential human member of the gp49 family has been defined by homology cDNA cloning. Over-expression of gp49A1 or gp49B1 protein by transfection in mast cells that express low native levels of gp49 proteins results in a substantial increase in their aggregation with activated T helper (Th) cells. Thus, the gp49 family of proteins likely represents a new class of adhesion molecules expressed by mast cells and mononuclear phagocytes that may facilitate their interaction with Th and perhaps other cells. The broad objective of the proposed research is to understand more about how members of the gp49 family of proteins mediate cell aggregation/adhesion, so as to gain an appreciation of their potential involvement in cell-cell interactions between several populations of mast cells/mononuclear phagocytes and cells that express a counterligand(s). Therefore, the specific aims of the proposed research are: l) to define the participation of gp49A1 and gp49B1 proteins in cell-cell adhesion, and to identify cells that express a counterligand(s) for the gp49 family of proteins; 2) to define the interactions of recombinant soluble gp49B2 protein with counterligand-expressing cells, and to assess the secretion of gp49B2 protein from mammalian cells; 3) to define the expression of specific transcripts and protein for members of the entire mouse gp49 family in mast cell and mononuclear phagocyte populations; and 4) to define the relationship between the mouse gp49 family and a gp49B1-like human cDNA in terms of cell expression, counterligand expression, and possible function. it is anticipated that the successful completion of the proposed studies will accelerate recognition and understanding of the range of functions mediated by the gp49 subfamily of the Ig superfamily. Because both mast cells and T cells have roles in the pathogenesis of bronchial asthma that are firmly established, the proposed studies relate to the overall theme of this program by establishing a new mechanism for their interaction and their possible synergistic contribution to inflammation, including that of the airways.
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