Support is requested to analyze the interaction between the actin crosslinking protein filamin and integrin beta subunit cytoplasmic tails; the effect this interaction has on integrin signaling; the mechanisms by which integrin-filamin interactions inhibit cell migration; and how the interaction is regulated in cells. Heterodimeric integrin adhesion receptors mediate cell-extracellular matrix and cell-cell adhesion events throughout development, during hemostasis and in the response to injury and infection. The binding of specific signaling and cytoskeletal proteins to integrin beta tails controls cell adhesion, bidirectional integrin signaling and regulates cell motility. Integrin-mediated cell migration is essential for development, the immune response, and for tissue remodeling and wound healing. Integrin-mediated cell migration also contributes to a number of disease states and is required for tumor metastasis, inflammation and the formation of atherosclerotic plaques. The increased association of filamin with integrin beta tails inhibits cell migration. The applicant hypothesizes that regulated association of filamin with integrin beta tails mediates distinct integrin functions and acts as a brake on cell migration. To test this hypothesis he aims to map the integrin binding site in filamin and identify mutations that selectively inhibit integrin binding. He will use these mutants and previously identified integrin mutants that up- or down-regulate filamin binding to characterize the effect of integrin-filamin interactions on integrin-mediated signal transduction. He will then investigate whether the inhibition of cell migration following increased filamin binding to integrins is due to the observed effects on integrin signaling, to local filamin-mediated effects on actin filament crosslinking or to a combination of both processes. Finally he will assess effect of filamin proteolysis, filamin or integrin phosphorylation and competition between integrins and other filamin-binding proteins on the association of filamin with integrin beta tails. These studies will characterize the regulation and mechanism of action of a pathway that controls cell migration. Cell migration is a tightly controlled process that plays a central role in many biological phenomena. Therefore these studies will provide insight into a process essential during health and disease and may identify novel therapeutic targets for treatment of cancers, arthritis and atherosclerosis.
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