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

Oestrogen produces diverse biological effects through binding to the oestro gen receptor (ER)(1). The ER is a steroid hormone nuclear receptor, which, when bound to oestrogen, modulates the transcriptional activity of target g enes(2). Controversy exists, however, concerning whether ER has a role outs ide 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 phosph atidylinositol-3-OH kinase (PI(3)K). Stimulation with oestrogen increases E R alpha-associated PI(3)K activity, leading to the activation of protein ki nase B/Akt and endothelial nitric oxide synthase (eNOS). Recruitment and ac tivation of PI(3)K by ligand-bound ERa are independent of gene transcriptio n, 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 leukocyt e accumulation after ischaemia and reperfusion injury. This vascular protec tive effect of oestrogen was abolished in the presence of PI(3)K or eNOS in hibitors. Our findings define a physiologically important non-nuclear oestr ogen-signalling pathway involving the direct interaction of ERa with PI(3)K .