Direct Modification and Activation of a Nuclear Receptor-PIP2 Complex by the Inositol Lipid Kinase IPMK

Phosphatidylinositol 4,5-bisphosphate (PIP2) is best known as a plasma membrane-bound regulatory lipid. Although PIP2 and phosphoinositide-modifying enzymes coexist in the nucleus, their nuclear roles remain unclear. We showed that inositol polyphosphate multikinase (IPMK), which functions both as an inositol kinase and as a phosphoinositide 3-kinase (PI3K), interacts with the nuclear receptor steroidogenic factor 1 (SF-1) and phosphorylates its bound ligand, PIP2. In vitro studies showed that PIP2 was not phosphorylated by IPMK if PIP2 was displaced or blocked from binding to the large hydrophobic pocket of SF-1 and that the ability to phosphorylate PIP2 bound to SF-1 was specific to IPMK and did not occur with type 1 p110 PI3Ks. IPMK-generated SF-1-PIP3 (phosphatidylinositol 3,4,5-trisphosphate) was de-phosphorylated by the lipid phosphatase PTEN. Consistent with the in vitro activities of IPMK and PTEN on SF-1-PIPn, SF-1 transcriptional activity was reduced by silencing IPMK or overexpressing PTEN. This ability of lipid kinases and phosphatases to directly remodel and alter the activity of a non-membrane protein-lipid complex establishes a previously unappreciated pathway for promoting lipid-mediated signaling in the nucleus.