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J. Biol. Chem. 278 (4): 2701-2712

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Proximal Events in Signaling by Plasma Membrane Estrogen Receptors*

Mahnaz RazandiDagger , Ali PedramDagger , Steven T. ParkDagger , and Ellis R. LevinDagger §

From the Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, Long Beach, California 90822 and the Departments of Dagger  Medicine and § Pharmacology, University of California, Irvine, California 92717

Estradiol (E2) rapidly stimulates signal transduction from plasma membrane estrogen receptors (ER) that are G protein-coupled. This is reported to occur through the transactivation of the epidermal growth factor receptor (EGFR) or insulin-like growth factor-1 receptor, similar to other G protein-coupled receptors. Here, we define the signaling events that result in EGFR and ERK activation. E2-stimulated ERK required ER in breast cancer and endothelial cells and was substantially prevented by expression of a dominant negative EGFR or by tyrphostin AG1478, a specific inhibitor for EGFR tyrosine kinase activity. Transactivation/phosphorylation of EGFR by E2 was dependent on the rapid liberation of heparin-binding EGF (HB-EGF) from cultured MCF-7 cells and was blocked by antibodies to this ligand for EGFR. Expression of dominant negative mini-genes for Galpha q and Galpha i blocked E2-induced, EGFR-dependent ERK activation, and Gbeta gamma also contributed. G protein activation led to activation of matrix metalloproteinases (MMP)-2 and -9. This resulted from Src-induced MMP activation, implicated using PP2 (Src family kinase inhibitor) or the expression of a dominant negative Src protein. Antisense oligonucleotides to MMP-2 and MMP-9 or ICI 182780 (ER antagonist) each prevented E2-induced HB-EGF liberation and ERK activation. E2 also induced AKT up-regulation in MCF-7 cells and p38beta MAP kinase activity in endothelial cells, blocked by an MMP inhibitor, GM6001, and tyrphostin AG1478. Targeting of only the E domain of ERalpha to the plasma membrane resulted in MMP activation and EGFR transactivation. Thus, specific G proteins mediate the ability of E2 to activate MMP-2 and MMP-9 via Src. This leads to HB-EGF transactivation of EGFR and signaling to multiple kinase cascades in several target cells for E2. The E domain is sufficient to enact these events, defining additional details of the important cross-talk between membrane ER and EGFR in breast cancer.

* This work was supported by a grant from the Research Service of the Department of Veteran's Affairs, a grant from the Avon Products Breast Cancer Research Foundation, Department of Defense Breast Cancer Research Program Grant BC990915, and National Institutes of Health Grant HL-59890 (to E. R. L.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Medical Service (111-I), Long Beach VA Medical Center/UC-Irvine, 5901 E. 7th St., Long Beach, CA 90822. Tel.: 562-826-5748; Fax: 562-826-5515; E-mail:

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

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