Lipid regulation of cellular signaling and protein-protein interactions

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PROJECT SUMMARY/ABSTRACT Lipid regulation of cellular signaling and protein-protein interactions Eukaryotic cells can be regarded as a vast, extensively compartmentalized and hierarchic protein- protein interaction (PPI) network. Characterizing PPI is therefore a crucial step in gaining an understanding of how cells function. PPI has also emerged as an attractive target space for drug development since PPI regulates numerous cellular processes, such as cell signaling. Despite the wealth of PPI data, however, the mechanisms by which complex cellular PPIs are coordinated and regulated with high spatiotemporal specificity are still poorly understood. This makes it difficult to understand the mechanisms of cell regulation on a systems level and also hampers development of specific drugs targeting PPI. Many PPI networks and protein complexes are formed on or near the cell membranes, the plasma membrane in particular. However, direct involvement of membrane lipids in coordination and modulation of PPI has not been explored. We have recently made breakthroughs in this line of research and revolutionized the PPI research by establishing that lipids directly and specifically regulate cellular PPI. This important new discovery as well as our innovative in situ quantitative lipid imaging technology give us a unique and unparalleled opportunity to systematically investigate how various lipids modulate PPI. We will study the mechanisms by which various lipids, including cholesterol and phosphoinositides, regulate a wide variety of cellular processes by spatiotemporally coordinating and modulating PPI through their specific interaction with protein interaction domains, including PDZ and SH2 domains. We will also develop new small molecule modulators of lipid-dependent PPI as drug candidates for various human diseases, including cancer. Given the general and fundamental importance of PPI, our pioneering, innovative research should have high potential impact on broad areas of biology and medicine.