Muscarinic M2 receptors mediate transactivation of EGF receptor through Fyn kinase and without matrix metalloproteases.
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 PLCgamma1. 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.
Stirnweiss
Jörg
J
Institute of Biochemistry and Biophysics, Biological and Pharmaceutical Faculty, Friedrich-Schiller-University, Philosophenweg 12, D-07743 Jena, Germany.
Valkova
Christina
C
Ziesché
Elisabeth
E
Drube
Sebastian
S
Liebmann
Claus
C
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D051966:Phospholipase C gamma / Q000378:metabolism; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D051575:Proto-Oncogene Proteins c-yes / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D043585:Receptor, Muscarinic M2 / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics*
D043585:Receptor, Muscarinic M2; D066246:ErbB Receptors; D051076:Proto-Oncogene Proteins c-fyn; D051575:Proto-Oncogene Proteins c-yes; D016392:Proto-Oncogene Proteins pp60(c-src); D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma; D020782:Matrix Metalloproteinases