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J. Biol. Chem. 275 (29): 22583-22589

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

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{ddagger}

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

ABSTRACT Back to Top

Abstract: 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 β 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.


Received for publication April 6, 2000.

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A Dual Signaling Cascade That Regulates the Ectodomain Shedding of Heparin-binding Epidermal Growth Factor-like Growth Factor.
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Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate.
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PNAS 98, 12908-12913
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