Akt-ing Against a Loss

Mutations in the tumor suppressor protein PTEN occur in a variety of cancers. Its major enzymatic activity is to dephosphorylate phosphoinositides, including phosphoinositide-3,4,5-trisphosphate (PIP3). In the absence of PTEN, cellular levels of PIP3 increase, which result in overgrowth phenotypes and lethality in Drosophila larvae. However, PIP3 binds to numerous signaling molecules, and so it is not clear if there is a specific interaction that loss of PTEN function primarily affects. Stocker et al. show that flies can live in the absence of PTEN if the interaction of PIP3 with the serine-threonine kinase Akt is decreased through a mutation in its PH domain. At least in the fly, Akt appears to be the principal target of PIP3. H. Stocker, M. Andjelkovic, S. Oldham, M. Laffargue, M. P. Wymann, B. A. Hemmings, E. Hafen, Living with lethal PIP3 levels: Viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science 295, 2088-2091 (2002). [Abstract] [Full Text]