Patterns within protein/polyphosphoinositide interactions provide specifictargets for therapeutic intervention

Signaling pathways involving the inositol polyphosphates and the polyphosph oinositides have become intricately linked with a number of disease states. More recently, this has principally involved the 3-phosphorylated products of phosphoinositide S-kinase, an enzyme that itself shows oncogenic activi ty and has hence become of interest in the design of antitumorigenic drugs. The downstream effecters of phosphoinositide 3-kinase are involved in diff erent aspects of cellular signaling and cytoskeleton and trafficking events that are linked to specific polyphosphoinositide binding properties of spe cific protein domains, which themselves have emerging roles in specific dis ease states. Our recent findings have demonstrated that there is a selectiv ity of the intracellular effects of extracellularly applied inositol polyph osphates in their abilities to inhibit a range of growth-related in vivo as say conditions, and that these can themselves be linked to the inhibition o f the membrane localization of a green fluorescent protein (GFP) -tagged PH domain. We propose that GFP fusions of the polyphosphoinositides binding d omains of specific proteins of interest can be used in high-throughput inve stigations of the therapeutic value of specific inositol polyphosphates ana logs. Inhibition of in vivo membrane targeting of these domains from protei ns involved in cell growth and tumorigenesis can thus be used in the search for new anticancer drugs.