Evidence continues to accumulate that so-called nuclear receptors need not be nuclear to cause signaling events. Haynes et al. and Razandi et al. report rapid effects of estrogen apparently mediated by the traditional receptor that are more characteristic of signals initiated by transmembrane receptors. Within minutes of treating endothelial cells with estrogen, Haynes et al. found the estrogen receptor in complexes with the p85 regulatory subunit of phosphatidylinositol 3-kinase and the tryrosine kinase Src. Estrogen caused phosphorylation of Src on a site consistent with activation of the kinase, and a pharmacological inhibitor of Src blocked estrogen-induced activation of the kinase Akt and synthesis of nitric oxide. Phosphorylation of Akt in response to estrogen was absent in cells lacking Src and in the related kinases Fyn and Yes. Razandi et al. also report activation of Src in response to estrogen in endothelial cells and breast cancer cells. However, they propose that Src acts to stimulate matrix metalloproteinases, which in turn release heparin-binding epidermal growth factor that can then activate the EGF receptor (EGFR). They also found that dominant-negative minigenes for heterotrimeric guanine nucleotide-binding protein α subunits Gαq and Gαi blocked activation of mitogen-activated protein kinases that resulted from EGFR-dependent signals initiated by treatment of cells with estrogen.
M. P. Haynes, L. Li, D. Sinha, K. S. Russell, K. Hisamoto, R. Baron, M. Collinge, W. C. Sessa, J. R. Bender, Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen. J. Biol. Chem. 278, 2118-2123 (2003). [Abstract] [Full Text]