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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: ellis.levin@med.va.gov.

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

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Plasma Membrane Estrogen Receptors Exist and Functions as Dimers.
M. Razandi, A. Pedram, I. Merchenthaler, G. L. Greene, and E. R. Levin (2004)
Mol. Endocrinol. 18, 2854-2865
   Abstract »    Full Text »    PDF »
Mitogenic Activity of Estrogens in Human Breast Cancer Cells Does Not Rely on Direct Induction of Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase or Phosphatidylinositol 3-Kinase.
A.-M. Gaben, C. Saucier, M. Bedin, G. Redeuilh, and J. Mester (2004)
Mol. Endocrinol. 18, 2700-2713
   Abstract »    Full Text »    PDF »
Estrogen Regulation of Growth Hormone Action.
K.-C. Leung, G. Johannsson, G. M. Leong, and K. K. Y. Ho (2004)
Endocr. Rev. 25, 693-721
   Abstract »    Full Text »    PDF »
Src Family Kinases Mediate Epidermal Growth Factor Receptor Ligand Cleavage, Proliferation, and Invasion of Head and Neck Cancer Cells.
Q. Zhang, S. M. Thomas, S. Xi, T. E. Smithgall, J. M. Siegfried, J. Kamens, W. E. Gooding, and J. R. Grandis (2004)
Cancer Res. 64, 6166-6173
   Abstract »    Full Text »    PDF »
A Membrane Estrogen Receptor Mediates Intracellular Calcium Release in Astrocytes.
V. V. Chaban, A. J. Lakhter, and P. Micevych (2004)
Endocrinology 145, 3788-3795
   Abstract »    Full Text »    PDF »
Requirement of matrix metalloproteinase-9 for the transformation of human mammary epithelial cells by Stat3-C.
T. N. Dechow, L. Pedranzini, A. Leitch, K. Leslie, W. L. Gerald, I. Linkov, and J. F. Bromberg (2004)
PNAS 101, 10602-10607
   Abstract »    Full Text »    PDF »
BRCA1 Inhibits Membrane Estrogen and Growth Factor Receptor Signaling to Cell Proliferation in Breast Cancer.
M. Razandi, A. Pedram, E. M. Rosen, and E. R. Levin (2004)
Mol. Cell. Biol. 24, 5900-5913
   Abstract »    Full Text »    PDF »
The G Protein-coupled Receptor GPR30 Mediates c-fos Up-regulation by 17{beta}-Estradiol and Phytoestrogens in Breast Cancer Cells.
M. Maggiolini, A. Vivacqua, G. Fasanella, A. G. Recchia, D. Sisci, V. Pezzi, D. Montanaro, A. M. Musti, D. Picard, and S. Ando (2004)
J. Biol. Chem. 279, 27008-27016
   Abstract »    Full Text »    PDF »
Mechanisms of Tamoxifen Resistance: Increased Estrogen Receptor-HER2/neu Cross-Talk in ER/HER2-Positive Breast Cancer.
J. Shou, S. Massarweh, C. K. Osborne, A. E. Wakeling, S. Ali, H. Weiss, and R. Schiff (2004)
J Natl Cancer Inst 96, 926-935
   Abstract »    Full Text »    PDF »
Molecular Cues to Implantation.
S. K. Dey, H. Lim, S. K. Das, J. Reese, B. C. Paria, T. Daikoku, and H. Wang (2004)
Endocr. Rev. 25, 341-373
   Abstract »    Full Text »    PDF »
Heparin-Binding Epidermal Growth Factor Cleavage Mediates Zinc-Induced Epidermal Growth Factor Receptor Phosphorylation.
W. Wu, J. M. Samet, R. Silbajoris, L. A. Dailey, D. Sheppard, P. A. Bromberg, and L. M. Graves (2004)
30, 540-547
   Abstract »    Full Text »    PDF »
Thombospondin-1 Disrupts Estrogen-Induced Endothelial Cell Proliferation and Migration and Its Expression Is Suppressed by Estradiol.
K. Sengupta, S. Banerjee, N. K. Saxena, and S. K. Banerjee (2004)
Mol. Cancer Res. 2, 150-158
   Abstract »    Full Text »    PDF »
Interleukin 1{beta} Enhances Invasive Ability of Gastric Carcinoma through Nuclear Factor-{kappa}B Activation.
N. Yamanaka, T. Morisaki, H. Nakashima, A. Tasaki, M. Kubo, H. Kuga, C. Nakahara, K. Nakamura, H. Noshiro, T. Yao, et al. (2004)
Clin. Cancer Res. 10, 1853-1859
   Abstract »    Full Text »    PDF »
The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor {alpha} to the plasma membrane.
R. X. Song, C. J. Barnes, Z. Zhang, Y. Bao, R. Kumar, and R. J. Santen (2004)
PNAS 101, 2076-2081
   Abstract »    Full Text »    PDF »
Estrogen Elicits Cytochrome P450--Mediated Flow-Induced Dilation of Arterioles in NO Deficiency: Role of PI3K-Akt Phosphorylation in Genomic Regulation.
A. Huang, D. Sun, Z. Wu, C. Yan, M. A. Carroll, H. Jiang, J. R. Falck, and G. Kaley (2004)
Circ. Res. 94, 245-252
   Abstract »    Full Text »    PDF »
Agonist-Induced Activation of Matrix Metalloproteinase-7 Promotes Vasoconstriction Through the Epidermal Growth Factor-Receptor Pathway.
L. Hao, M. Du, A. Lopez-Campistrous, and C. Fernandez-Patron (2004)
Circ. Res. 94, 68-76
   Abstract »    Full Text »    PDF »
Increases in estrogen receptor-{alpha} concentration in breast cancer cells promote serine 118/104/106-independent AF-1 transactivation and growth in the absence of estrogen.
A. M. FOWLER, N. SOLODIN, M. T. PREISLER-MASHEK, P. ZHANG, A. V. LEE, and E. T. ALARID (2004)
FASEB J 18, 81-93
   Abstract »    Full Text »    PDF »
Dependence of Peroxisome Proliferator-activated Receptor Ligand-induced Mitogen-activated Protein Kinase Signaling on Epidermal Growth Factor Receptor Transactivation.
O. S. Gardner, B. J. Dewar, H. S. Earp, J. M. Samet, and L. M. Graves (2003)
J. Biol. Chem. 278, 46261-46269
   Abstract »    Full Text »    PDF »
Activation of Phosphatidylinositol 3-Kinase/Akt Pathway by Androgen through Interaction of p85{alpha}, Androgen Receptor, and Src.
M. Sun, L. Yang, R. I. Feldman, X.-m. Sun, K. N. Bhalla, R. Jove, S. V. Nicosia, and J. Q. Cheng (2003)
J. Biol. Chem. 278, 42992-43000
   Abstract »    Full Text »    PDF »
Sphingosine Kinase Transmits Estrogen Signaling in Human Breast Cancer Cells.
O. A. Sukocheva, L. Wang, N. Albanese, S. M. Pitson, M. A. Vadas, and P. Xia (2003)
Mol. Endocrinol. 17, 2002-2012
   Abstract »    Full Text »    PDF »
Bidirectional Signaling between the Estrogen Receptor and the Epidermal Growth Factor Receptor.
E. R. Levin (2003)
Mol. Endocrinol. 17, 309-317
   Abstract »    Full Text »    PDF »

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