Lipid Mediated Cellular Regulation in Health and Disease

Growth factor signaling is crucial for cellular processes such as cell proliferation, migration, differentiation, and cell death. Growth factor stimulation results in the formation of phosphoinositides (PtdIns) such as phosphatidylinositol-3,4,5,-trisphosphate (PI(3,4,5)P3) and phosphatidylinositol-3,4- bisphosphate (PI(3,4)P2) and triggers a cascade of signaling events which result in biological responses. Improper PtdIns-protein interactions in these signaling networks can lead to the development of different cancer types and other diseases. In this study we identified several PH, PDZ an SH2 domains that binds to (PI(3,4,5)P3) and (PI(3,4)P2), which also has the ability to bind to cholesterol. We demonstrated the ability of cholesterol to bind to AKT1-PH domain, as an example of regulation of cellular function. DVL2-PDZ, is also another cholesterol binding protein which is important for the non-canonical Wnt signaling pathway. We developed small molecules to modulate the DVL2-PDZ cholesterol-mediated cell regulation. Apart from cholesterol, PtdIns are also vital elements in the cellular membranes to initiate the lipid-protein interactions and depending on the distribution of the PtdIns in the subcellular membrane, each form of PtdIns can be targeted by multiple effector protein domains to initiate downstream signaling pathways. In this study we further identified several cytosolic SH2 domain containing proteins which can bind to phosphoinositides. We discovered that Syk cSH2 binds to (PI(3,4,5)P3), a phosphoinositide-protein interaction and showed the importance of the Syk cSH2- PI(3,4,5)P3 interaction in B cell signaling pathway. Small molecules with the ability to specifically inhibit the Syk cSH2 - PI(3,4,5)P3 interaction were identified. Interestingly, these new molecules did not generate any resistance in an Acute Myeloid Leukemia cell line, indicating their usefulness in new treatment strategies to cure B -cell malignancies.