IPMK is Indispensable for Activation of AKT: Redefining PI3kinase pathway

Abstract

Inositol polyphosphate multikinase (IPMK) can catalyze production of IP5 and PIP3. Deletion of IPMK abolish AKT phosphorylation at both T 308 and Ser 473 residues even when PI3kinase activity of classical PI3kinase is intact. Akt activation requires its membrane localization followed by phosphorylation by PDK1 and mTORC2. We found that classical PI3kinase exclusively mediates AKT localization to the membrane but dispensable for PDK1 membrane localization and activation of mTORC2. IPMK interacts with both PDK1 and mTORC2 complex. Generation of PIP3 by IPMK promotes membrane localization of PDK1 and also activation of mTORC2, however, shows no effect in AKT localization to the membrane. In summary, PIP3 generated by IPMK exclusively controls PDK1 and mTORC2 functioning, however, classical PI3Kinase only controls AKT localization to the membrane.Support or Funding InformationNIH grant 5R01MH018501‐48