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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.

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