From kinase to cancer

The story of discovering PI3 kinase, and what it means for a fundamental pathway in cancer.

By Lewis Cantley

1 I suspected that this enzyme might be placing a phosphate on the 3 position of the inositol ring to produce phosphatidylinsitol-3-phosphate (PI-3-P), but I realized that this would be heretical to the field and would require rigorous chemical proof, since PI-3-P had not been previously described.

So, at the Cold Spring Harbor meeting I sought out Bob Michel and Peter Downes, two of the most experienced biochemists in this field, and told them of our findings. While both were skeptical that a novel phosphoinositide had been missed after more than 35 years of research in this field, they both offered advice about how to prove the structure and Downes agreed to collaborate in this endeavor. With Downes' help, we were able to unambiguously define...

1. L. Cantley, "A new pathway for inositol," The Scientist, 18(9):14, May 10, 2004.

2. M. Whitman et al., "Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate," Nature, 332:644-6, 1988.

3. H. Streb et al., "Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate," Nature, 306:67-9, 1983.

4. Y. Sugimoto et al., "Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol," Proc Natl Acad Sci, 81:2117-21, 1984.

5. C.L. Carpenter et al., "Purification and characterization of phosphoinositide 3-kinase from rat liver," J Biol Chem, 265:19704-11, 1990.

6. K.R. Auger et al., "PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells," Cell, 57:167-75, 1989.

7. L.A. Serunian et al., "Production of novel polyphosphoinositides in vivo is linked to cell transformation by polyomavirus middle T antigen," J Virol, 64:4718-25, 1990.

8. B.D. Manning et al., Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway," Mol Cell, 10:151-62, 2002

9. A.R. Tee et al., "Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling," Proc Natl Acad Sci, 99:13571-6, 2002.

10. J.A. Engelman et al., "The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism," Nat Rev Genet, 7:606-19, 2006.

11. T. Shioi et al., "The conserved phosphoinositide 3-kinase pathway determines heart size in mice," EMBO J, 19:2537-48, 2000.

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From kinase to cancer