Phosphoinositide Signaling in Cytosol and Nucleus

The project focuses on two main areas: agonist-activated PI3Kα signaling in the cytosol and nuclear PI signaling. For cytosolic signaling, the work investigates the spatial and temporal activation of PI3Kα, its incorporation into an IQGAP1 complex, and its regulation by interactions with MAP4 and PI3P, which target PI3Kα to microtubules and endosomes. It also seeks to define mechanisms by which constitutively active PI3Kα mutants stimulate the assembly of these complexes in cancer. For nuclear signaling, the project explores how PIPns are linked (PIPylation) to effector proteins like p53, forming p53-PIP3 complexes that activate nuclear Akt. Key questions include the chemical nature and enzymatic mechanism of PIPn linkage, identification of the cellular 'PIPylome,' regulation of PIPylated proteins by PIPns, and the roles of PI transfer proteins (PITPs) and PI 4-kinase IIα (PI4KIIα) in PIPylation. The functional role of PIP linkage in DNA damage response will also be investigated.