WONHWA CHO, PH.D. PROJECT SUMMARY/ABSTRACT Lipid regulation of cellular signaling and protein-protein interactions Cellular proteins accomplish their functions through interactions with other proteins, forming complex protein-protein interaction networks. Cellular protein-protein interaction typically involves small modular protein interaction domains, such as Src-homology 2 and PSD95, Dlg1, ZO-1 domains. Physiological significance of protein interaction domain-mediated protein-protein interaction networks has been well supported by a large number of protein interaction domains encoded by human genome and many human diseases, including cancer, caused by dysfunctional protein interaction domain-mediated cellular processes. Interestingly, most protein interaction domains have moderate binding affinity and a significant degree of promiscuity. This may be necessary for reversibility and redundancy of cell signaling pathways but raises a fundamental question as to how high-fidelity cellular function and regulation can be achieved through the protein interaction domain-mediated protein-protein interaction. We have recently shown that membrane lipids, including cholesterol and phosphoinositides, coordinate and regulate protein-protein interaction by directly and specifically interacting with protein interaction domains. This important new discovery and our innovative in situ quantitative lipid imaging technology provide us with a unique and unparalleled opportunity to elucidate the mechanisms by which lipids orchestrate spatiotemporal specificity of protein-protein interaction and cell signaling and develop new strategies to modulate these processes. Given the importance of protein interaction domain-mediated protein-protein interaction and cell signaling in health and disease, our proposed research should have a major impact on broad areas of biology and medicine and lay the foundation for a pioneering and innovative drug discovery strategy for human diseases, most notably cancer.