Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Sci. Signal., 19 June 2012
Vol. 5, Issue 229, p. ra44
[DOI: 10.1126/scisignal.2003111]

RESEARCH ARTICLES

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

Raymond D. Blind, Miyuki Suzawa, and Holly A. Ingraham*

Department of Cellular and Molecular Pharmacology, Mission Bay Campus, University of California, San Francisco, San Francisco, CA 94158, USA.

Abstract: 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–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.

* To whom correspondence should be addressed. E-mail: holly.ingraham{at}ucsf.edu

Citation: R. D. Blind, M. Suzawa, H. A. Ingraham, Direct Modification and Activation of a Nuclear Receptor–PIP2 Complex by the Inositol Lipid Kinase IPMK. Sci. Signal. 5, ra44 (2012).

Read the Full Text

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Inositol Polyphosphate Multikinase Is a Coactivator of p53-Mediated Transcription and Cell Death.
R. Xu, N. Sen, B. D. Paul, A. M. Snowman, F. Rao, M. S. Vandiver, J. Xu, and S. H. Snyder (2013)
Science Signaling 6, ra22
   Abstract »    Full Text »    PDF »
Arginine Transcriptional Response Does Not Require Inositol Phosphate Synthesis.
D. Bosch and A. Saiardi (2012)
J. Biol. Chem. 287, 38347-38355
   Abstract »    Full Text »    PDF »
Acid Ceramidase (ASAH1) Represses Steroidogenic Factor 1-Dependent Gene Transcription in H295R Human Adrenocortical Cells by Binding to the Receptor.
N. C. Lucki, D. Li, S. Bandyopadhyay, E. Wang, A. H. Merrill, and M. B. Sewer (2012)
Mol. Cell. Biol. 32, 4419-4431
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 19 June 2012.
H. A. Ingraham, R. D. Blind, and A. M. VanHook (2012)
Science Signaling 5, pc13
   Abstract »    Full Text »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882