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

Cross-communication between different signalling systems allows the integra tion of the great diversity of stimuli that a cell receives under varying p hysiological situations. The transactivation of epidermal growth factor rec eptor (EGFR)-dependent signalling pathways upon stimulation of G-protein-co upled receptors (GPCRs), which are critical for the mitogenic activity of l igands such as lysophosphatidic acid, endothelin, thrombin, bombesin and ca rbachol, provides evidence for such an interconnected communication network (1-4). Here we show that EGFR transactivation upon GPCR stimulation involve s proHB-EGF and a metalloproteinase activity that is rapidly induced upon G PCR-ligand interaction. We show that inhibition of proHB-EGF processing blo cks GPCR-induced EGFR transactivation and downstream signals, The pathophys iological significance of this mechanism is demonstrated by inhibition of c onstitutive EGFR activity upon treatment of PC3 prostate carcinoma cells wi th the metalloproteinase inhibitor batimastat. Together, our results establ ish a new mechanistic concept for cross-communication among different signa lling systems.