Phosphoinositide Signaling: From Affinity Probes to Pharmaceutical Targets Review Article

Lipid signaling by phosphoinositides (PIPns) involves an array of proteins with lipid recognition, kinase, phosphatase, and phospholipase functions. Understanding PIPn pathway signaling requires identification and characterization of PIPn-interacting proteins. Moreover, spatiotemporal localization and physiological function of PIPn-protein complexes must be elucidated in cellular and organismal contexts. For protein discovery to functional elucidation, reporter-linked phosphoinositides or tethered PIPns have been essential. The phosphoinositide 3-kinase (PI 3-K) signaling pathway has recently emerged as an important source of potential “druggable” therapeutic targets in human pathophysiology in both academic and pharmaceutical environments. This review summarizes the chemistry of PIPn affinity probes and their use in identifying macromolecular targets. The process of target validation will be described, i.e., the use of tethered PIPns in determining PIPn selectivity in vitro and in establishing the function of PIPn-protein complexes in living cells.