Ligand-independent and EGF receptor-supported transactivation:: Lessons from β2-adrenergic receptor signalling

Transactivation of epidermal growth factor receptor (EGFR) by G protein-coupled receptors (GPCRs) is currently understood to be mediated by matrix metalloproteases (MMPs) and the release of EGF-like ligands. This ligand-mediated process also suggests that downstream of EGFR the signalling in response to GPCR ligands or EGF appears to be indistinguishable. Here we provide evidence that transactivation of EGFR by the beta 2-adrenergic receptor (beta 2-AR) is independent of MMPs and results in an incomplete downstream signalling involving extracellular signal-activated kinase (ERK) but not PLC-gamma 1 and Akt. In contrast, beta 2-AR has the ability to activate PLC gamma 1 when the EGFR is primed either by co-stimulation with EGF or by increased basal activity due to over-expression. In that way but not via the beta 2-AR-mediated transactivation the EGFR docking sites pY992 and pY1173 may be generated which are critical for PLC gamma 1. This EGFR-supported transactivation is strongly dependent on EGFR tyrosine kinase, c-Src, and the c-Src-specific EGFR tyrosine residue 845 and represents a novel paradigm of EGFR transactivation. (c) 2006 Elsevier Inc. All rights reserved.