Direct modification and regulation of the nuclear protein-lipid complex NR5A1- PIP2 by the PI3-kinase IPMK

Phosphatidylinositol (4,5)-diphosphate (PIP2) is a critical component for generating intracellular lipid signals. While PIP2 and other phosphoinositides exist in non-membrane nuclear compartments, their role in nuclear events remains largely undefined. Here, we discovered that PIP2 bound to the endocrine transcription factor SF-1 (NR5A1) is an excellent substrate for inositol polyphosphate multikinase (IPMK/Ipk2), a PI3-kinase previously linked to transcriptional responses. By stark contrast, SF-1/PIP2 is unrecognized by classic p110 PI3-kinases. Cellular studies revealed that maximal SF-1 activity depends on a full complement of IPMK. Furthermore, the lipid phosphatase PTEN dephosphorylated SF-1/PIP3 and when expressed in PTEN-negative cells dampened SF-1 activity. Thus, the ability of lipid- modifying enzymes to directly remodel and reprogram protein/lipid complexes such as SF-1/PIP2 establishes an essential role for nuclear lipid signaling in gene expression.