Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase

T. Simoncini, A. Hafezl-Moghadam, Derek Brazil, K. Ley, W.W. Chin, J.K. Liao

Research output: Contribution to journalArticle

1161 Citations (Scopus)

Abstract

Oestrogen produces diverse biological effects through binding to the oestrogen receptor (ER)(1). The ER is a steroid hormone nuclear receptor, which, when bound to oestrogen, modulates the transcriptional activity of target genes(2). Controversy exists, however, concerning whether ER has a role outside the nucleus(3), particularly in mediating the cardiovascular protective effects of oestrogen(4). Here we show that the ER isoform, ER alpha, binds in a ligand-dependent manner to the p85 alpha regulatory subunit of phosphatidylinositol-3-OH kinase (PI(3)K). Stimulation with oestrogen increases ER alpha-associated PI(3)K activity, leading to the activation of protein kinase B/Akt and endothelial nitric oxide synthase (eNOS). Recruitment and activation of PI(3)K by ligand-bound ERa are independent of gene transcription, do not involve phosphotyrosine adapter molecules or src-homology domains of p85 alpha, and extend to other steroid hormone receptors. Mice treated with oestrogen show increased eNOS activity and decreased vascular leukocyte accumulation after ischaemia and reperfusion injury. This vascular protective effect of oestrogen was abolished in the presence of PI(3)K or eNOS inhibitors. Our findings define a physiologically important non-nuclear oestrogen-signalling pathway involving the direct interaction of ERa with PI(3)K.
Original languageEnglish
Pages (from-to)538-541
Number of pages4
JournalNature
Volume407
Issue number6803
Publication statusPublished - 28 Sep 2000

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase'. Together they form a unique fingerprint.

  • Cite this

    Simoncini, T., Hafezl-Moghadam, A., Brazil, D., Ley, K., Chin, W. W., & Liao, J. K. (2000). Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature, 407(6803), 538-541.