Direct modification and activation of a nuclear receptor-PIP₂ complex by the inositol lipid kinase IPMK.

Blind RD, Suzawa M, Ingraham HA
Sci Signal. 2012 5 (229): ra44

PMID: 22715467 · PMCID: PMC3395721 · DOI:10.1126/scisignal.2003111

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 dephosphorylated by the lipid phosphatase PTEN. Consistent with the in vitro activities of IPMK and PTEN on SF-1-PIP(n), 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.

MeSH Terms (22)

Binding Sites Blotting, Western Cell Nucleus Chromatin Immunoprecipitation HEK293 Cells Humans Kinetics Models, Molecular Molecular Structure Mutation Phosphatidylinositol 3-Kinases Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositol Phosphates Phosphorylation Phosphotransferases (Alcohol Group Acceptor) Protein Binding Protein Structure, Tertiary PTEN Phosphohydrolase RNA Interference Signal Transduction Steroidogenic Factor 1 Substrate Specificity

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