Cp. Berrie et M. Falasca, Patterns within protein/polyphosphoinositide interactions provide specifictargets for therapeutic intervention, FASEB J, 14(15), 2000, pp. 2618-2622
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.