Ectodomain sheading-dependent transactivation of epidermal growth factor receptors in response to insulin-like growth factor type I

Hesham M. El-Shewy, Francine L. Kelly, Liza Barki-Harrington, Louis M. Luttrell

Research output: Contribution to journalArticlepeer-review

Abstract

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 down-stream events, such as ERK1/2 activation, varies in a cell type-dependent manner.

Original languageEnglish
Pages (from-to)2727-2739
Number of pages13
JournalMolecular Endocrinology
Volume18
Issue number11
DOIs
StatePublished - Nov 2004
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology
  • Molecular Biology

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