INTEGRIN aMb2:STRUCTURE AND ATHEROTHROMBOTIC FUNCTIONS

Cleveland Clinic Lerner Com-Cwru, Cleveland OH

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Abstract

Alpha-M-beta2, a member of the beta2 subfamily of integrins, regulates a wide variety of leukocyte-mediated responses, including transendothelial migration, oxidative responses, reperfusion injury and formation of cell-conjugates, resonses that are relevent to atherosclerosis, thrombosis, restenosis and stroke. These responses depend upon the capacity of alpha-M-beta2 to undergo activation and function as a receptor for an extremely broad spectrum of ligands. Included within the ligand repertoire of alpha-M-beta2 is ICAM-1, which is expressed and participates in the firm adhesion and transmigration of leukocytes across inflamed endothelial, and fibrinogen (Fg);which participates in thrombus formation, innate immunity and leukocyte-platelet conjugation. A mosaic model has been hypothesized to explain the diversity of ligand recognition by. Alpha-M-beta2 in which different ligands use different sets of amino acid residues in the alpha-M-l-domain to engage the receptor. Moreover, the alpha-M and beta2 subunits of the receptor contribute differently to adhesive and migratory functions of alpha-M-beta2-bearing cells. In Aim 1, the mosaic model will be tested by comparing the recognition interface of ICAM-1 with Fg and other alpha-M-beta2 and to test the corollary that igands which engage different residues can induce different signaling events within the cells. The recognition of ICAM-1 and Fg requires activation of the receptor, which depends upon transmission of a signal from the cytoplasmic tails of the subunits to the extracellular domain. This mechanism has been examined structurally for alpha-IIb-beta3. In Aim 2, the hypothesis will be tested that the structural differences between the cytoplasmic tails of alpha-M-2 and alpha-IIb-beta3 will lead to distinct mechanisms of activation, cytoskeletal interconnections and intracellular signaling. Leukocyte interaction with platelets and release of microparticles are processes that are important in atherosclerosis and thrombosis. In Aim 3, the role of alpha-M-beta2 and its multiple ligands, Fg, GPIbalpha and JAM-3, in forming and targeting these leukocyte derivatives will be examined in vitro and in vivo. Unique insights, data sets, functional assays and mutant receptors have been developed and will be used to address these hypotheses. The proposed studies will provide an understanding of the molecular mechanisms that govern alpha-M-beta2 activation, ligand recognition and its consequences that regulate the participation of leukocytes in thrombosis and cardiovascular pathologies.