The Chemical Biology of Phosphoinositide 3-Kinases

Since its discovery in the late 1980s, phosphoinositide 3‐kinase (PI3K), and its isoforms have arguably reached the forefront of signal transduction research. Regulation of this lipid kinase, its functions, its effectors, in short its entire signaling network, has been extensively studied. PI3K inhibitors are frequently used in biochemistry and cell biology. In addition, many pharmaceutical companies have launched drug‐discovery programs to identify modulators of PI3Ks. Despite these efforts and a fairly good knowledge of the PI3K signaling network, we still have only a rudimentary picture of the signaling dynamics of PI3K and its lipid products in space and time. It is therefore essential to create and use novel biological and chemical tools to manipulate the phosphoinositide signaling network with spatial and temporal resolution. In this review, we discuss the current and potential future tools that are available and necessary to unravel the various functions of PI3K and its isoforms. PIK your battles: Phosphatidylinositol 3‐kinases (PI3Ks) are a central signaling hub in mammalian cells. Here, we summarize the state of the art for studying PI3K activity and the innovative tools chemistry provides to facilitate these investigations. These range from synthetic phosphoinositols via fluorescent lipid binding domains and chemical dimerizers to membrane‐permeable, photoactivatable lipid derivatives.