Structural Basis for Regulation of Phosphoinositide Kinases and Their Involvement in Human Disease

Abstract

Lipid phosphoinositides play fundamental roles in virtually all pathways that control a cell's decision to grow, move, divide, and die. Because of this, kinases that phosphorylate phosphoinositide lipids are critically involved in myriad essential functions including growth, development, and membrane trafficking. The misregulation of phosphoinositide kinases is critical in human diseases, including cancer, primary immunodeficiencies, and developmental disorders. Phosphoinositide kinases also play a role in mediating bacterial and viral infections for many potent human pathogens. Furthermore, inhibitors of parasite phosphoinositide kinases are in development as therapies for both malaria and cryptosporidiosis. Therefore, understanding how phosphoinositide kinases are regulated has implications for the treatment of many devastating human diseases. Recent structures of phosphoinositide kinases have revealed unique molecular insight into their regulation. This review will summarize our current molecular knowledge on phosphoinositide kinase regulation, and how this information is being used to generate novel small molecule inhibitors as potential therapeutics.

Keywords: PI3K; PI4KA; PI4KB; PI4P5KA; PI5P4KB; PI5P4KC; PIK3CA; PIK3CD; X-ray crystallography; autophagy; cancer; kinase inhibitors; lipid signaling; oncogenes; phosphatidylinositol 4 kinase; phosphoinositide 3 kinase; phosphoinositides; primary immunodeficiency.