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 genes2. Controversy exists, however, concerning whether ER has a role outside the nucleus3, particularly in mediating the cardiovascular protective effects of oestrogen4. Here we show that the ER isoform, ERα, binds in a ligand-dependent manner to the p85α regulatory subunit of phosphatidylinositol-3-OH kinase (PI(3)K). Stimulation with oestrogen increases ERα-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 ERα are independent of gene transcription, do not involve phosphotyrosine adapter molecules or src-homology domains of p85α, 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 ERα with PI(3)K.
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We thank T. Uchida, A. J. Prorock and K. L. Thomas for technical assistance; M. White for providing IRS-1/2 antibodies; M. Brown for ERα antibody; D. Fruman and L. Cantley for murine p85α-/- fibroblasts, GST–p85α and sub-domains; M. Kasuga for wild-type and dominant-negative p85α cDNAs; and K. Walsh for adenovirus Akt mutants. This work was supported by grants from the National Institutes of Health, the Mary Horrigan Connors Center for Women's Health, the American Heart Association and the Scuola Superiore di Studi e di Perfezionamento “S. Anna”.
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Simoncini, T., Hafezi-Moghadam, A., Brazil, D. et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407, 538–541 (2000). https://doi.org/10.1038/35035131
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