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Review
. 2011 Apr 29;286(17):14737-43.
doi: 10.1074/jbc.R110.191791. Epub 2011 Feb 22.

Non-nuclear estrogen receptor signaling in the endothelium

Qian Wu  1 , Ken Chambliss, Michihisa Umetani, Chieko Mineo, Philip W Shaul
Affiliations
Review

Non-nuclear estrogen receptor signaling in the endothelium

Qian Wu et al. J Biol Chem. .

Abstract

In addition to the classical function of estrogen receptors (ER) as transcription factors, evidence continues to accumulate that they mediate non-nuclear processes in numerous cell types, including the endothelium, in which they activate endothelial NO synthase. Non-nuclear ER signaling entails unique post-translational modifications and protein-protein interactions of the receptor with adaptor molecules, kinases, and G proteins. Recent in vitro and in vivo studies in mice using an estrogen-dendrimer conjugate that is excluded from the nucleus indicate that non-nuclear ER activation underlies the migration and growth responses of endothelial cells to estrogen but not the growth responses of endometrial or breast cancer cells to the hormone. In this minireview, the features of ERα and protein-protein interactions that enable it to invoke extranuclear signaling in the endothelium and the consequences of that signaling are discussed.

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Figures

FIGURE 1.
FIGURE 1.
Post-translational modifications and protein-protein interactions involved in non-nuclear ERα signaling. The structure of ERα is shown in linear fashion, with the N- to C-terminal domains designated A–F. The amino acid spans of the domains are indicated by boxed numbers. The N-terminal A/B domain contains a hormone-independent transcription function (AF-1); the C domain contains the DNA-binding domain (DBD); the D domain contains nuclear localization signals; the E domain contains the ligand-binding domain (LBD), which also possesses hormone-dependent activation function (AF-2); and the F domain, which modulates the ability of ERα to respond to tamoxifen in a cell-specific manner. Post-translational modifications and adaptor proteins that interact directly with ERα are shown above the receptor, and kinases, phosphatases, and G proteins with direct interaction are shown below the receptor, with the relevant residues or regions of ERα that contain the interaction domains indicated numerically. Modifications or interacting proteins that regulate ERα non-nuclear functions in the endothelium are shown in black, and those thus far identified in non-endothelial cells are shown in gray.
FIGURE 2.
FIGURE 2.
Non-nuclear ERα resides in a signaling complex associated with endothelial cell caveolae/lipid rafts. Upon estrogen binding, Gαi and Gβγ disassociate from ERα, and liberated Gβγ activates c-Src. This leads to the activation of PI3K, which activates Akt to phosphorylate eNOS Ser-1177, and to the activation of ERK1/2, which is also required to yield an increase in eNOS enzymatic activity. The resulting NO that is produced has both autocrine and paracrine actions.
FIGURE 3.
FIGURE 3.
Non-nuclear ER activation in mice promotes re-endothelialization and provides protection from neointima formation, but it does not promote uterine or breast cancer growth. Experiments were performed in ovariectomized female mice administered vehicle (Veh), E2, control dendrimer (Dend), or EDC. A, in studies of carotid artery re-endothelialization following perivascular electric injury, the remaining area of endothelial denudation that has incorporated Evans blue dye 3 days post-injury is shown. B, neointima formation was evaluated in ApoE−/− mice 2 weeks following carotid artery endothelial denudation. C, uterotrophic responses to the treatments were also assessed. D, following the establishment of MCF-7 cell tumor xenografts in SCID mice, the growth responses of the tumors to 21 days of treatment were determined. This figure was reprinted with permission (70).
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