Patterns within protein/polyphosphoinositide interactions provide specific targets for therapeutic intervention

Signaling pathways involving the inositol polyphosphates and the polyphosphoinositides have become intricately linked with a number of disease states. More recently, this has principally involved the 3-phosphorylated products of phosphoinositide 3-kinase, an enzyme that itself shows oncogenic activity and has hence become of interest in the design of antitumorigenic drugs. The downstream effectors of phosphoinositide 3-kinase are involved in different aspects of cellular signaling and cytoskeleton and trafficking events that are linked to specific polyphosphoinositide binding properties of specific protein domains, which themselves have emerging roles in specific disease states. Our recent findings have demonstrated that there is a selectivity of the intracellular effects of extracellularly applied inositol polyphosphates in their abilities to inhibit a range of growth-related in vivo assay conditions, and that these can themselves be linked to the inhibition of the membrane localization of a green fluorescent protein (GFP) -tagged PH domain. We propose that GFP fusions of the polyphosphoinositides binding domains of specific proteins of interest can be used in high-throughput investigations of the therapeutic value of specific inositol polyphosphates analogs. Inhibition of in vivo membrane targeting of these domains from proteins involved in cell growth and tumorigenesis can thus be used in the search for new anticancer drugs.