PI(3,4,5)P3 regulates the interaction between Akt and B23 in the nucleus

Phosphatidylinositol (3,4,5)-triphosphate (PIP(3)) is a lipid second messenger that employs a wide range of downstream effector proteins for the regulation of cellular processes, including cell survival, polarization and proliferation. One of the most well characterized cytoplasmic targets of PIP(3), serine/threonine protein kinase B (PKB)/Akt, promotes cell survival by directly interacting with nucleophosmin (NPM)/B23, the nuclear target of PIP(3). Here, we report that nuclear PIP(3) competes with Akt to preferentially bind B23 in the nucleoplasm. Mutation of Arg23 and Arg25 in the PH domain of Akt prevents binding to PIP(3), but does not disrupt the Akt/B23 interaction. However, treatment with phosphatases PTEN or SHIP abrogates the association between Akt and B23, indicating that nuclear PIP(3) regulates the Akt/B23 interaction by controlling the concentration and subcellular dynamics of these two proteins.