Transactivation of the EGF Receptor Mediates IGF-1-stimulated Shc Phosphorylation and ERK1/2 Activation in COS-7 Cells^*

Francine L. Roudabush, Kristen L. Pierce, Stuart Maudsley, Khuda Dad Khan, and Louis M. Luttrell

From the Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710

The receptor for insulin-like growth factor 1 (IGF-1) mediates multiple cellular responses, including stimulation of both proliferative and anti-apoptotic pathways. We have examined the role of cross talk between the IGF-1 receptor (IGF-1R) and the epidermal growth factor receptor (EGFR) in mediating responses to IGF-1. In COS-7 cells, IGF-1 stimulation causes tyrosine phosphorylation of the IGF-1R  subunit, the EGFR, insulin receptor substrate-1 (IRS-1), and the Shc adapter protein. Shc immunoprecipitates performed after IGF-1 stimulation contain coprecipitated EGFR, suggesting that IGF-1R activation induces the assembly of EGFR·Shc complexes. Tyrphostin AG1478, an inhibitor of the EGFR kinase, markedly attenuates IGF-1-stimulated phosphorylation of EGFR, Shc, and ERK1/2 but has no effect on phosphorylation of IGF-1R, IRS-1, and protein kinase B (Akt). Cross talk between IGF-1 and EGF receptors is mediated through an autocrine mechanism involving matrix metalloprotease-dependent release of heparin-binding EGF (HB-EGF), because IGF-1-mediated ERK activation is inhibited both by [Glu⁵²]Diphtheria toxin, a specific inhibitor of HB-EGF, and the metalloprotease inhibitor 1,10-phenanthroline. These data demonstrate that IGF-1 stimulation of the IRS-1/PI3K/Akt pathway and the EGFR/Shc/ERK1/2 pathway occurs by distinct mechanisms and suggest that IGF-1-mediated "transactivation" of EGFR accounts for the majority of IGF-1-stimulated Shc phosphorylation and subsequent activation of the ERK cascade.

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^* This work was supported by National Institutes of Health Grants DK02352 and DK55524 (to L. M. 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: Dept. of Medicine, Box 3821, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-2974; Fax: 919-684-8875; E-mail: Luttrell@receptor-biol.duke.edu.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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S. J. DiCamillo, I. Carreras, M. V. Panchenko, P. J. Stone, M. A. Nugent, J. A. Foster, and M. P. Panchenko (2002)
J. Biol. Chem. 277, 18938-18946
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Heparin-binding EGF-like growth factor mediates the biological effects of P450 arachidonate epoxygenase metabolites in epithelial cells.

J.-K. Chen, J. Capdevila, and R. C. Harris (2002)
PNAS 99, 6029-6034
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Early Placenta Insulin-like Growth Factor (pro-EPIL) Is Overexpressed and Secreted by c-erbB-2-positive Cells with High Invasion Potential.

B. Brandt, A. Roetger, J.-M. Bidart, J. Packeisen, K. Schier, J.-H. Mikesch, D. Kemming, W. Boecker, D. Yu, and H. Buerger (2002)
Cancer Res. 62, 1020-1024
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The p40phox and p47phox PX Domains of NADPH Oxidase Target Cell Membranes via Direct and Indirect Recruitment by Phosphoinositides.

Y. Zhan, J. V. Virbasius, X. Song, D. P. Pomerleau, and G. W. Zhou (2002)
J. Biol. Chem. 277, 4512-4518
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Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition on Epithelial Proliferation in Normal and Premalignant Breast.

K. C. Chan, W. F. Knox, J. M. Gee, J. Morris, R. I. Nicholson, C. S. Potten, and N. J. Bundred (2002)
Cancer Res. 62, 122-128
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cag+ Helicobacter pylori Induce Transactivation of the Epidermal Growth Factor Receptor in AGS Gastric Epithelial Cells.

S. Keates, S. Sougioultzis, A. C. Keates, D. Zhao, R. M. Peek Jr., L. M. Shaw, and C. P. Kelly (2001)
J. Biol. Chem. 276, 48127-48134
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Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate.

J. V. Virbasius, X. Song, D. P. Pomerleau, Y. Zhan, G. W. Zhou, and M. P. Czech (2001)
PNAS 98, 12908-12913
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Src Family Tyrosine Kinases Participate in Insulin-like Growth Factor I Mitogenic Signaling in 3T3-L1 Cells.

C. M. Boney, H. Sekimoto, P. A. Gruppuso, and A. R. Frackelton Jr. (2001)
Cell Growth Differ. 12, 379-386
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Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors.

B. C. Paria, W.-g. Ma, J. Tan, S. Raja, S. K. Das, S. K. Dey, and B. L. M. Hogan (2001)
PNAS 98, 1047-1052
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beta 2-Adrenergic Receptor-induced p38 MAPK Activation Is Mediated by Protein Kinase A Rather than by Gi or Gbeta gamma in Adult Mouse Cardiomyocytes.

M. Zheng, S.-J. Zhang, W.-Z. Zhu, B. Ziman, B. K. Kobilka, and R.-P. Xiao (2000)
J. Biol. Chem. 275, 40635-40640
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Activation of MAPKs by Angiotensin II in Vascular Smooth Muscle Cells. METALLOPROTEASE-DEPENDENT EGF RECEPTOR ACTIVATION IS REQUIRED FOR ACTIVATION OF ERK AND p38 MAPK BUT NOT FOR JNK.

S. Eguchi, P. J. Dempsey, G. D. Frank, E. D. Motley, and T. Inagami (2001)
J. Biol. Chem. 276, 7957-7962
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{micro}-Opioid Receptor-mediated ERK Activation Involves Calmodulin-dependent Epidermal Growth Factor Receptor Transactivation.

M. M. Belcheva, M. Szucs, D. Wang, W. Sadee, and C. J. Coscia (2001)
J. Biol. Chem. 276, 33847-33853
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A Dual Signaling Cascade That Regulates the Ectodomain Shedding of Heparin-binding Epidermal Growth Factor-like Growth Factor.

T. Umata, M. Hirata, T. Takahashi, F. Ryu, S. Shida, Y. Takahashi, M. Tsuneoka, Y. Miura, M. Masuda, Y. Horiguchi, et al. (2001)
J. Biol. Chem. 276, 30475-30482
 |  Abstract »  |  Full Text »  |  PDF »

Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate.

J. V. Virbasius, X. Song, D. P. Pomerleau, Y. Zhan, G. W. Zhou, and M. P. Czech (2001)
PNAS 98, 12908-12913
 |  Abstract »  |  Full Text »  |  PDF »