This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by El-Shewy, H. M. Articles by Luttrell, L. M. Search for Related Content PubMed PubMed Citation Articles by El-Shewy, H. M. Articles by Luttrell, L. M.

Ectodomain Shedding-Dependent Transactivation of Epidermal Growth Factor Receptors in Response to Insulin-Like Growth Factor Type I

Departments of Medicine and Biochemistry and Molecular Biology (H.M.E.-S., L.M.L.), Medical University of South Carolina, Charleston, South Carolina 29425; Department of Medicine (F.L.K., L.B.-H.), Duke University Medical Center, Durham, North Carolina 27710; and The Ralph H. Johnson Veterans Affairs Medical Center (H.M.E.-S., L.M.L.), Charleston, South Carolina 29401

Address all correspondence and requests for reprints to: Louis M. Luttrell, Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, 816 Clinical Sciences Building, P.O. Box 250624, Charleston, South Carolina 29425. E-mail: luttrell{at}musc.edu.

Diverse extracellular stimuli activate the ERK1/2 MAPK cascade by transactivating epidermal growth factor (EGF) receptors. Here, we have examined the role of EGF receptors in IGF-I-stimulated ERK1/2 activation in several cultured cell lines. In human embryonic kidney 293 cells, IGF-I triggered proteolysis of heparin binding (HB)-EGF, increased tyrosine autophosphorylation of EGF receptors, stimulated EGF receptor inhibitor (AG1478)-sensitive ERK1/2 phosphorylation, and promoted EGF receptor endocytosis. In a mixed culture system that employed IGF-I receptor null murine embryo fibroblasts (MEFs) (R^– cells) to detect paracrine signals produced by MEFs expressing the human IGF-I receptor (R⁺ cells), stimulation of R⁺ cells provoked rapid activation of green fluorescent protein-tagged ERK2 in cocultured R^– cells. The R^– cell response was abolished by either the broad-spectrum matrix metalloprotease inhibitor batimastat or by AG1478, indicating that it resulted from the proteolytic generation of an EGF receptor ligand from adjacent R⁺ cells. These data suggest that the paracrine production of EGF receptor ligands leading to EGF receptor transactivation is a general property of IGF-I receptor signaling. In contrast, the contribution of transactivated EGF receptors to IGF-I-stimulated downstream events, such as ERK1/2 activation, varies in a cell type-dependent manner.

This article has been cited by other articles:

				K. D. Rodland, N. Bollinger, D. Ippolito, L. K. Opresko, R. J. Coffey, R. Zangar, and H. S. Wiley Multiple Mechanisms Are Responsible for Transactivation of the Epidermal Growth Factor Receptor in Mammary Epithelial Cells J. Biol. Chem., November 14, 2008; 283(46): 31477 - 31487. [Abstract] [Full Text] [PDF]

				T. Moore, L. Beltran, S. Carbajal, S. Strom, J. Traag, S. D. Hursting, and J. DiGiovanni Dietary Energy Balance Modulates Signaling through the Akt/Mammalian Target of Rapamycin Pathways in Multiple Epithelial Tissues Cancer Prevention Research, June 1, 2008; 1(1): 65 - 76. [Abstract] [Full Text] [PDF]

				T. Moore, S. Carbajal, L. Beltran, S. N. Perkins, S. Yakar, D. LeRoith, S. D. Hursting, and J. DiGiovanni Reduced Susceptibility to Two-Stage Skin Carcinogenesis in Mice with Low Circulating Insulin-Like Growth Factor I Levels Cancer Res., May 15, 2008; 68(10): 3680 - 3688. [Abstract] [Full Text] [PDF]

				R. X.-D. Song, Z. Zhang, Y. Chen, Y. Bao, and R. J. Santen Estrogen Signaling via a Linear Pathway Involving Insulin-Like Growth Factor I Receptor, Matrix Metalloproteinases, and Epidermal Growth Factor Receptor to Activate Mitogen-Activated Protein Kinase in MCF-7 Breast Cancer Cells Endocrinology, August 1, 2007; 148(8): 4091 - 4101. [Abstract] [Full Text] [PDF]

				K.-P. Xu and F.-S. X. Yu Cross Talk between c-Met and Epidermal Growth Factor Receptor during Retinal Pigment Epithelial Wound Healing Invest. Ophthalmol. Vis. Sci., May 1, 2007; 48(5): 2242 - 2248. [Abstract] [Full Text] [PDF]

				Y. Fang, E. Studer, C. Mitchell, S. Grant, W. M. Pandak, P. B. Hylemon, and P. Dent Conjugated Bile Acids Regulate Hepatocyte Glycogen Synthase Activity In Vitro and In Vivo via G{alpha}i Signaling Mol. Pharmacol., April 1, 2007; 71(4): 1122 - 1128. [Abstract] [Full Text] [PDF]

				A. Yacoub, W. Hawkins, D. Hanna, H. Young, M. A. Park, M. Grant, J. D. Roberts, D. T. Curiel, P. B. Fisher, K. Valerie, et al. Human Chorionic Gonadotropin Modulates Prostate Cancer Cell Survival after Irradiation or HMG CoA Reductase Inhibitor Treatment Mol. Pharmacol., January 1, 2007; 71(1): 259 - 275. [Abstract] [Full Text] [PDF]

				L. Chen, R. R. Hodges, C. Funaki, D. Zoukhri, R. J. Gaivin, D. M. Perez, and D. A. Dartt Effects of {alpha}1D-adrenergic receptors on shedding of biologically active EGF in freshly isolated lacrimal gland epithelial cells Am J Physiol Cell Physiol, November 1, 2006; 291(5): C946 - C956. [Abstract] [Full Text] [PDF]

				H. M. El-Shewy, K. R. Johnson, M.-H. Lee, A. A. Jaffa, L. M. Obeid, and L. M. Luttrell Insulin-like Growth Factors Mediate Heterotrimeric G Protein-dependent ERK1/2 Activation by Transactivating Sphingosine 1-Phosphate Receptors J. Biol. Chem., October 20, 2006; 281(42): 31399 - 31407. [Abstract] [Full Text] [PDF]

				J. Dong, L. K. Opresko, W. Chrisler, G. Orr, R. D. Quesenberry, D. A. Lauffenburger, and H. S. Wiley The Membrane-anchoring Domain of Epidermal Growth Factor Receptor Ligands Dictates Their Ability to Operate in Juxtacrine Mode Mol. Biol. Cell, June 1, 2005; 16(6): 2984 - 2998. [Abstract] [Full Text] [PDF]