Programmed cell death occurs in many tissues of our bodies throughout life. The quick and efficient removal of dying cells is a critical step that protects neighboring cells. The failure to remove apoptotic bodies has been implicated as a cause for certain types of chronic inflammation and autoimmune disorder. Clearance of apoptotic cells also has important implications for clearance of tumor cells after anti-cancer therapies. While several surface receptors that participate in the recognition of apoptotic cells have been identified, relatively little is known about the intracellular signaling events that regulate the cytoskeleton of the phagocyte and facilitate the uptake. This is largely because the signaling proteins involved have remained elusive. The recent identification of seven genes involved in apoptotic cell clearance in the nematode C. elegans, and the existence of their mammalian homologues have provided an exciting opportunity to delineate molecular events that regulate engulfment. Recent work from several laboratories, including ours, suggest that four of these genes in the worm and their mammalian homologues, CrkII, Dock180, ELMO and Rac, regulate cytoskeletal reorganization during engulfment of apoptotic cells, as well as cell migration. We have recently identified ELMO proteins (homologue of worm CED- 12) as novel members that can form a biochemical complex with Dock 180 and CrkII, as well as functionally regulate engulfment, at a step upstream of Rac activation. We have also identified that Dock180 has a novel guanine nucleotide exchange factor domain (Docker), which mediates Rac-GTP loading, and that Dock180 and ELMO function together in this process. Using a combination of biochemical, genetic and functional studies, this proposal will attempt to delineate the molecular details of signaling via ELMO 1, and how the synergy between ELMO 1 and Dock180 leads to Rac activation and cytoskeletal changes. Taken together, these studies may reveal some of the signaling events during engulfment and begin to provide a better molecular understanding of this important biological process. Given the numerous disease states that have been associated with impaired signaling through the Rho-family GTPases, including tumor cell migration, our studies would also have implications for cancer progression and metastasis.
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