EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF

• Published in: Nature (London) 1999-12, Vol.402 (6764), p.884-888
• Main Authors: Ullrich, Axel, Prenzel, Norbert, Zwick, Esther, Daub, Henrik, Leserer, Michael, Abraham, Reimar, Wallasch, Christian
• Format: Article
• Language: English
• Subjects: ADAM Proteins; Animals; Bacterial Proteins - pharmacology; Biological and medical sciences; Cancer; Cell Line; Cell physiology; Cells; COS Cells; Disintegrins - metabolism; Epidermal Growth Factor - metabolism; Fundamental and applied biological sciences. Psychology; Genes; GTP-Binding Proteins - metabolism; Heparin-binding EGF-like Growth Factor; Hormones; Humanities and Social Sciences; Humans; Intercellular Signaling Peptides and Proteins; letter; Membrane Proteins; Metalloendopeptidases - metabolism; Molecular and cellular biology; Molecular biology; multidisciplinary; Neurology; Phosphorylation; Physiology; Protein Precursors - metabolism; Protein Processing, Post-Translational; Rats; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Receptors, Muscarinic - genetics; Receptors, Muscarinic - metabolism; Receptors, Platelet-Derived Growth Factor - metabolism; Responses to growth factors, tumor promotors, other factors; Science; Science (multidisciplinary); Signal Transduction; Transcriptional Activation; Tumor Cells, Cultured
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/47260

Cross-communication between different signalling systems allows the integration of the great diversity of stimuli that a cell receives under varying physiological situations. The transactivation of epidermal growth factor receptor (EGFR)-dependent signalling pathways upon stimulation of G-protein-coupled receptors (GPCRs), which are critical for the mitogenic activity of ligands such as lysophosphatidic acid, endothelin, thrombin, bombesin and carbachol, provides evidence for such an interconnected communication network. Here we show that EGFR transactivation upon GPCR stimulation involves proHB-EGF and a metalloproteinase activity that is rapidly induced upon GPCR-ligand interaction. We show that inhibition of proHB-EGF processing blocks GPCR-induced EGFR transactivation and downstream signals. The pathophysiological significance of this mechanism is demonstrated by inhibition of constitutive EGFR activity upon treatment of PC3 prostate carcinoma cells with the metalloproteinase inhibitor batimastat. Together, our results establish a new mechanistic concept for cross-communication among different signalling systems.