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-Shc Association and Shc Pathway Activation
Departments of Internal Medicine (R.X.-D.S., R.A.M., M.S., R.J.S.) and Biomolecular Research Facility (Y.B.), University of Virginia School of Medicine, Charlottesville, Virginia 22908; and Department of Molecular & Cellular Oncology (L.A., R.K.), University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030
Address all correspondence and requests for reprints to: Dr. Robert X. Song, Division of Hematology and Oncology, University of Virginia Health Science Center, Charlottesville, Virginia 22901. E-mail: rs5wf{at}virginia.edu
E2 rapidly activates MAPK in breast cancer cells, and the
mechanism for this effect has not been fully identified. Since growth
factor-induced MAPK activation involves signaling via the adapter
protein Shc (Src-homology and collagen homology) and its association
with membrane receptors, we hypothesized that breast cancer cells
utilize similar signaling mechanisms in response to E2. In the present
study, we demonstrated that E2 rapidly induced Shc
phosphorylation and Shc-Grb2 (growth factor receptor binding
protein 2)-Sos (son of sevenless) complex formation in MCF-7 cells.
Overexpression of dominant negative Shc blocked the effect of E2 on
MAPK, indicating a critical role of Shc in E2 action. Using selective
inhibitors, we also demonstrated that ER
and Src are upstream
regulators of Shc. A rapid physical association between ER and Shc
upon E2 stimulation further evidenced the role of ER on Shc
activation. Mutagenesis studies showed that the phosphotyrosine binding
and SH2 domains of Shc are required to interact with the activation
function 1, but not activation function 2, domain of
ER. Using a glutathione-S-transferanse-Shc
pull-down assay, we demonstrated that this ER-Shc association was
direct. Biological consequences of this pathway were further
investigated at the genomic and nongenomic levels. E2 stimulated
MAPK-mediated Elk-1 transcriptional activity. Confocal microscopy
studies showed that E2 rapidly induced formation of membrane ruffles,
pseudopodia, and ER membrane translocation. The E2-induced
morphological changes were prevented by antiestrogen. Together
our results demonstrate that ER can mediate the rapid effects of E2
on Shc, MAPK, Elk-1, and morphological changes in breast cancer
cells
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R. I. Fernando and J. Wimalasena Estradiol Abrogates Apoptosis in Breast Cancer Cells through Inactivation of BAD: Ras-dependent Nongenomic Pathways Requiring Signaling through ERK and Akt Mol. Biol. Cell, July 1, 2004; 15(7): 3266 - 3284. [Abstract] [Full Text] [PDF]
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Z. Yang, C. J. Barnes, and R. Kumar Human Epidermal Growth Factor Receptor 2 Status Modulates Subcellular Localization of and Interaction with Estrogen Receptor {alpha} in Breast Cancer Cells Clin. Cancer Res., June 1, 2004; 10(11): 3621 - 3628. [Abstract] [Full Text] [PDF]
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 S. Cabodi, L. Moro, G. Baj, M. Smeriglio, P. Di Stefano, S. Gippone, N. Surico, L. Silengo, E. Turco, G. Tarone, et al. p130Cas interacts with estrogen receptor {alpha} and modulates non-genomic estrogen signaling in breast cancer cells J. Cell Sci., March 15, 2004; 117(8): 1603 - 1611. [Abstract] [Full Text] [PDF]
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R. X. Song, C. J. Barnes, Z. Zhang, Y. Bao, R. Kumar, and R. J. Santen The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor {alpha} to the plasma membrane PNAS, February 17, 2004; 101(7): 2076 - 2081. [Abstract] [Full Text] [PDF]
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 A. M. FOWLER, N. SOLODIN, M. T. PREISLER-MASHEK, P. ZHANG, A. V. LEE, and E. T. ALARID 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 FASEB J, January 1, 2004; 18(1): 81 - 93. [Abstract] [Full Text] [PDF]
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 C. S. Watson and B. Gametchu Proteins of Multiple Classes May Participate in Nongenomic Steroid Actions Experimental Biology and Medicine, December 1, 2003; 228(11): 1272 - 1281. [Abstract] [Full Text] [PDF]
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Y. Kinoshita and S. Chen Induction of Aromatase (CYP19) Expression in Breast Cancer Cells through a Nongenomic Action of Estrogen Receptor {alpha} Cancer Res., July 1, 2003; 63(13): 3546 - 3555. [Abstract] [Full Text] [PDF]
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L. B. Lutz, M. Jamnongjit, W.-H. Yang, D. Jahani, A. Gill, and S. R. Hammes Selective Modulation of Genomic and Nongenomic Androgen Responses by Androgen Receptor Ligands Mol. Endocrinol., June 1, 2003; 17(6): 1106 - 1116. [Abstract] [Full Text] [PDF]
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M. Marino, F. Acconcia, and A. Trentalance Biphasic Estradiol-induced AKT Phosphorylation Is Modulated by PTEN via MAP Kinase in HepG2 Cells Mol. Biol. Cell, June 1, 2003; 14(6): 2583 - 2591. [Abstract] [Full Text] [PDF]
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 G. Castoria, M. Lombardi, M. V. Barone, A. Bilancio, M. Di Domenico, D. Bottero, F. Vitale, A. Migliaccio, and F. Auricchio Androgen-stimulated DNA synthesis and cytoskeletal changes in fibroblasts by a nontranscriptional receptor action J. Cell Biol., May 12, 2003; 161(3): 547 - 556. [Abstract] [Full Text] [PDF]
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G. E. Stoica, T. F. Franke, A. Wellstein, F. Czubayko, H.-J. List, R. Reiter, E. Morgan, M. B. Martin, and A. Stoica Estradiol Rapidly Activates Akt via the ErbB2 Signaling Pathway Mol. Endocrinol., May 1, 2003; 17(5): 818 - 830. [Abstract] [Full Text] [PDF]
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E. R. Levin Bidirectional Signaling between the Estrogen Receptor and the Epidermal Growth Factor Receptor Mol. Endocrinol., March 1, 2003; 17(3): 309 - 317. [Abstract] [Full Text] [PDF]
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 D. P. Edwards and V. Boonyaratanakornkit Rapid Extranuclear Signaling by the Estrogen Receptor (ER): MNAR Couples ER and Src to the MAP Kinase Signaling Pathway Mol. Interv., February 1, 2003; 3(1): 12 - 15. [Abstract] [Full Text] [PDF]
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M. Razandi, A. Pedram, S. T. Park, and E. R. Levin Proximal Events in Signaling by Plasma Membrane Estrogen Receptors J. Biol. Chem., January 17, 2003; 278(4): 2701 - 2712. [Abstract] [Full Text] [PDF]
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D. W. Singleton, Y. Feng, C. J. Burd, and S. A. Khan Nongenomic Activity and Subsequent c-fos Induction by Estrogen Receptor Ligands Are Not Sufficient to Promote Deoxyribonucleic Acid Synthesis in Human Endometrial Adenocarcinoma Cells Endocrinology, January 1, 2003; 144(1): 121 - 128. [Abstract] [Full Text] [PDF]
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 K. J. Ho and J. K. Liao Nonnuclear Actions of Estrogen Arterioscler Thromb Vasc Biol, December 1, 2002; 22(12): 1952 - 1961. [Abstract] [Full Text] [PDF]
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C.-W. Wong, C. McNally, E. Nickbarg, B. S. Komm, and B. J. Cheskis Estrogen receptor-interacting protein that modulates its nongenomic activity-crosstalk with Src/Erk phosphorylation cascade PNAS, November 12, 2002; 99(23): 14783 - 14788. [Abstract] [Full Text] [PDF]
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 D. M. Brownson, N. G. Azios, B. K. Fuqua, S. F. Dharmawardhane, and T. J. Mabry Flavonoid Effects Relevant to Cancer J. Nutr., November 1, 2002; 132(11): 3482S - 3489. [Abstract] [Full Text] [PDF]
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M. Marino, F. Acconcia, F. Bresciani, A. Weisz, and A. Trentalance Distinct Nongenomic Signal Transduction Pathways Controlled by 17beta -Estradiol Regulate DNA Synthesis and Cyclin D1 Gene Transcription in HepG2 Cells Mol. Biol. Cell, October 1, 2002; 13(10): 3720 - 3729. [Abstract] [Full Text] [PDF]
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W. Yue, J.-P. Wang, M. Conaway, S. Masamura, Y. Li, and R. J. Santen Activation of the MAPK Pathway Enhances Sensitivity of MCF-7 Breast Cancer Cells to the Mitogenic Effect of Estradiol Endocrinology, September 1, 2002; 143(9): 3221 - 3229. [Abstract] [Full Text] [PDF]
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K. J. Ho and J. K. Liao Non-nuclear Actions of Estrogen: New Targets for Prevention and Treatment of Cardiovascular Disease Mol. Interv., July 1, 2002; 2(4): 219 - 228. [Abstract] [Full Text] [PDF]
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 A. C. B. Cato, A. Nestl, and S. Mink Rapid Actions of Steroid Receptors in Cellular Signaling Pathways Sci. Signal., June 25, 2002; 2002(138): re9 - re9. [Abstract] [Full Text] [PDF]
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V. G. Keshamouni, R. R. Mattingly, and K. B. Reddy Mechanism of 17-beta -Estradiol-induced Erk1/2 Activation in Breast Cancer Cells. A ROLE FOR HER2 AND PKC-delta J. Biol. Chem., June 14, 2002; 277(25): 22558 - 22565. [Abstract] [Full Text] [PDF]
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