I didn’t set out to discover a new signaling pathway,” says Lewis Cantley of his identification of phosphatidylinositol (PI) 3-kinase and its targets and activators. He was studying how insulin and growth factors alter ion transport across cell membranes. And he suspected it had something to do with phosphorylated lipids. Since the 1950s, investigators had observed that exposure to hormones and growth factors boosts the phosphorylation of PI in cell membranes. And Cantley found that surrounding the ion pump Na,K-ATPase with phosphorylated PIs in an artificial membrane enhanced its activity. So he set out to isolate the enzyme that phosphorylates this lipid in vivo.
A 1983 paper from Harvard University’s Ray Erikson caught Cantley’s eye. In it, Erikson noted that a frozen-and-thawed preparation of the oncoprotein v-Src was able to phosphorylate the glycerol in which it had been stored. “And I thought, well, inositol looks like two glycerol molecules glued ...
