A heterotrimeric GTPase-regulated isoform of PI3K and the regulation of its potential effectors

We have purified two forms of phosphoinositide 3-kinase (PI3K) that are activated by heterotrimeric G-protein beta gamma-subunits. These novel isoforms of PI3K are structurally distinct to those forms of PI3K which have already been cloned. They are both heterodimers made up of a p120 and a p101 and a p117 and a p101 protein. The p101 species in both heterodimers are identical and show no substantial homology with any other proteins or DNA sequences. The p117 and p120 are highly related. The p101 and p120 species have been cloned from a pig neutrophil mRNA library. The p120 has similarities with other known PI3K catalytic subunits. They may be responsible for conferring cells with the capacity to produce phosphatidylinositol (3,4,5)-trisphosphate in response to activation of G-protein-coupled receptors. Activation of both the monomeric G-protein rac and PI3K(s) have been implicated in receptor-stimulated membrane-ruffling. We have observed that agonist-stimulated guanine nucleotide exchange on rac can be inhibited by a variety of PI3K inhibitors. This suggests PI3K may lie upstream of rac in receptor-driven pathways regulating cell movement.