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

Norbert Prenzel, Esther Zwick, Henrik Daub, Michael Leserer, Reimar Abraham, Christian Wallasch and Axel Ullrich ()
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Norbert Prenzel: Max-Planck-Institut für Biochemie
Esther Zwick: Max-Planck-Institut für Biochemie
Henrik Daub: Max-Planck-Institut für Biochemie
Michael Leserer: Max-Planck-Institut für Biochemie
Reimar Abraham: Max-Planck-Institut für Biochemie
Christian Wallasch: Max-Planck-Institut für Biochemie
Axel Ullrich: Max-Planck-Institut für Biochemie

Nature, 1999, vol. 402, issue 6764, 884-888

Abstract: Abstract 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 network1,2,3,4. 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.

Date: 1999
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DOI: 10.1038/47260

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