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Submitted on April 27, 2004
Accepted on July 16, 2004
Departments of Medicine and Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425; Department of Medicine, Duke University Medical Center, Durham, NC 27710; The Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401
* To whom correspondence should be addressed. E-mail: luttrell{at}musc.edu.
Diverse extracellular stimuli activate the ERK1/2 mitogen-activated protein (MAP) kinase cascade by transactivating epidermal growth factor (EGF) receptors. Here, we have examined the role of EGF receptors in insulin-like growth factor type 1 (IGF-I)-stimulated ERK1/2 activation in several cultured cell lines. In HEK-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 GFP-tagged ERK2 in co-cultured 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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