Metalloprotease-mediated ligand release regulates autocrine signaling through the epidermal growth factor receptor

• DOI: 10.1073/pnas.96.11.6235
• Publication Date: 2002-07-26T14:35:07Z
• Authors: Jianying Dong; Lee K. Opresko; Peter J. Dempsey; Douglas A. Lauffe...; Robert J. Coffey; H. Steven Wiley
• Keywords: 0301 basic medicine; Epidermal Growth Factor; Transcription, Genetic; Antibodies, Monoclonal; Metalloendopeptidases; Epithelial Cells; Transforming Growth Factor alpha; Hydroxamic Acids; Ligands; Cell Line; ErbB Receptors; 03 medical and health sciences; Cell Movement; Humans; Protease Inhibitors; Phosphorylation; Cell Division; Signal Transduction

Ligands that activate the epidermal growth factor receptor (EGFR) are synthesized as membrane-anchored precursors appear to be proteolytically released by members of ADAM family metalloproteases. Because EGFR ligands thought biologically active, role ligand release in regulation signaling is unclear. To investigate this question, we used metalloprotease inhibitors block from human mammary epithelial cells. These cells express both transforming α and amphiregulin require autocrine through for proliferation migration. We found reduced cell direct proportion their effect on release. Metalloprotease also EGF-responsive tumorigenic lines were synergistic with inhibitory effects antagonistic antibodies. Blocking strongly inhibited activation rate persistence The could reversed either adding exogenous EGF or expressing an artificial gene lacked a membrane-anchoring domain. Our results indicate soluble rather than forms mediate most biological ligands. have shown promise preventing spread metastatic disease. Many antimetastatic result ability inhibit EGFR.