Muscarinic M2 receptors mediate transactivation of EGF receptor through Fyn kinase and without matrix metalloproteases

• Published in: Cellular signalling 2006-08, Vol.18 (8), p.1338-1349
• Main Authors: Stirnweiss, Jörg, Valkova, Christina, Ziesché, Elisabeth, Drube, Sebastian, Liebmann, Claus
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Cercopithecus aethiops; COS Cells; COS-7 cells; EGFR transactivation; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases - metabolism; Fyn; Humans; M2 receptor; Matrix metalloproteases; Matrix Metalloproteinases - metabolism; Mice; Phospholipase C gamma - metabolism; Protein Binding; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-fyn - metabolism; Proto-Oncogene Proteins c-yes - metabolism; Proto-Oncogene Proteins pp60(c-src) - metabolism; Receptor, Epidermal Growth Factor - genetics; Receptor, Muscarinic M2 - metabolism; SH-SY5Y cells; Signal Transduction; SYF cells; Transcriptional Activation - genetics
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2005.10.018

Transactivation of epidermal growth factor receptor (EGFR) by G protein-coupled receptors (GPCRs) has been attributed to the activation of matrix metalloproteases (MMPs) and the release of EGF family ligands such as HB-EGF. This mode of transactivation leads to signalling downstream of EGFR which is indistinguishable from that induced by the ligand. Here we provide evidence that in the COS-7 cell model EGFR transactivation via the muscarinic M2 receptor (M2R) is independent of MMPs and results in an incomplete EGFR signalling including ERK and Akt but not PLCγ1. Using dominant-negative mutants of c-Src and Fyn and Src-deficient SYF cells as well as by co-immunoprecipitation studies, we can demonstrate that the M2R-mediated transactivation of EGFR specifically involves Fyn but not c-Src or Yes. This specific role of Fyn can be verified in SH-SY5Y human neuroblastoma cells with endogenously expressed M2 receptors.