Apoptosis leads to immediate removal of cells from the body during development, tissue remodeling, maturation of the immune system or resolution of cancer. Surface changes on the apoptotic cell are recognized by neighboring cells or professional phagocytes such as macrophages and result in its engulfment and digestion. In this proposal the mechanisms by which apoptotic cells are phagocytosed will be investigated. We hypothesize that there are specific pathways of engulfment, involving in particular, a newly identified and cloned receptor (PSR) for the phosphatidylserine that is expressed in the outer membrane leaflet of apoptotic cells. The uptake mechanisms are predicted: 1) to be similar in macrophages and non-professional phagocytes such as fibroblasts and epithelial cells, 2) to be different from those involving the Fc receptor, 3) to initiate unique signal transduction pathways and, as we have shown previously, 4) to initiate an anti- rather than pro-inflammatory phenotype in the phagocytosing cell. All of these would help explain the extreme efficiency and rapidity of apoptotic cell removal in vivo as well as its non-inflammatory nature. Apoptotic cells or surrogate particles (erythrocytes with surface-bound ligands for specific apoptotic cell recognition receptors) will be examined for mechanisms of uptake. This is suggested to involve a version of macropinocytosis (stimulated or triggered phagocytosis) initiated via ligation of the PS receptor rather than the classical """"""""zipper"""""""" process. In particular, we will examine the requirement for an ATP cassette protein transporter, ABC1, and suggest that, by exporting cholesterol, it modulates the cholesterol-rich membrane domains leading to altered intracellular signaling and changes in membrane phospholipid distribution in the phagocyte. Additional elements of the signaling pathway that will be examined in detail involve DOCK1 80 signaling through CrkII-p130(Cas) complexes to induce low molecular weight G protein-mediated membrane ruffling and particle internalization.
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