EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF.
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.
Prenzel
N
N
Department of Molecular Biology, Max-Planck-Institut für Biochemie, Martinsried, Germany.
Zwick
E
E
Daub
H
H
Leserer
M
M
Abraham
R
R
Wallasch
C
C
Ullrich
A
A
D051722:ADAM Proteins; D000818:Animals; D001426:Bacterial Proteins / Q000494:pharmacology; D019556:COS Cells; D002460:Cell Line; D019483:Disintegrins / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000378:metabolism*; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D001426:Bacterial Proteins; D019483:Disintegrins; C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011498:Protein Precursors; D011976:Receptors, Muscarinic; C028581:CRM197 (non-toxic variant of diphtheria toxin); D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D051722:ADAM Proteins; C098339:ADAM9 protein, human; D008666:Metalloendopeptidases; D019204:GTP-Binding Proteins