Receptors for the Fc domain of IgG (FcgammaR) and for the third component of complement are critical for pathogen elimination in host defense against infection and in generation of an inflammatory response. In preliminary, we have found that specific functions of both FcgammaRs and the integrin complement receptor aMa2 are lost in dendritic cells and macrophages that lack glycan phosphatidylinositol (GPI) anchored proteins because of a targeted deletion of the enzyme, Pig-a, which is required for synthesis of the GPI anchor. GPI-anchored proteins are not uniformly distributed in the plasma membrane, but are found in lipid rafts, domains enriched in cholesterol and sphingolipids. In unactivated cells raft domains are small patches where, on the cytoplasmic face, some signaling molecules accumulate. Cell activation by a variety of means leads to lipid raft coalescence, which in turn may lead to activation of signaling cascades because of the increased concentration of signaling molecules in the enlarged raft domains. Ligated FcgammaRs and alphaMbeta2 can cluster together with aggregated lipid rafts, suggesting a potential role for GPI-anchored proteins in targeting these receptors to rafts. Raft association may be a critical step in transmembrane signaling by these receptors. The purpose of this application is to understand the molecular basis for the requirement for GPI anchored proteins in the function of FcgammaRs and aMa2, to determine the molecular mechanisms by which these receptors are targeted to lipid rafts, and to test the hypothesis that their targeting to the raft compartment allows communication of the ligated receptors with intracellular tyrosine kinase signaling cascades.
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