It is now well accepted that an important aspect of leukocyte interaction with extracellular matrix is that matrix proteins induce cell activation. The rationale for this project is to understand the molecular mechanisms involved in this mechanism of leukocyte activation. Several years ago we found that in addition to integrins, a non-integrin protein of the phagocyte plasma membrane was required for extracellular matrix induced activation. We called this IgV superfamily member with multiple transmembrane segments Integrin-associated Protein (lAP) because of its physical and functional association with phagocyte integrins. Subsequently, we showed that this protein is identical to CD47. Now it is clear from our work and others that CD47 has roles in several important processes in inflammation and immunity, including activation of phagocytosis, respiratory burst, and integrin-mediated adhesion; leukocyte transendothelial and transepithelial migration; synergy with TCR in lymphocyte activation; and even regulation of lymphocyte apoptosis. Recently, we have focused on understanding the molecular mechanisms by which CD47 affects this panoply of functions in diverse cell types. We have demonstrated CD47 association with heterotrimeric G proteins and shown that both these G proteins and rho family G proteins regulate CD47 function. We also have shown that CD47 associates with p21-activated kinase (pak) and with a novel cytoplasmic protein that regulates heterotrimeric G protein signaling, PLIC-1. These data suggest the hypothesis that a fundamental role for CD47 is to act as both an effector and a regulator of G protein signaling. The next funding period will be devoted to testing this hypothesis and its implications for how CD47 regulates leukocyte activation. ? Specifically, I propose to determine :1. What are the structural requirements in CD47 for GTPase ? regulation?; 2. What are the roles for rho family GTPases and pak in CD47 functions?; and 3) How does the CD47-associated cytosolic protein PLIC-1 regulate Gi signaling? These studies will contribute greatly to the understanding and ultimately the control of inflammatory and immune responses. ? ? ? ?
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