Ligand-independent and EGF receptor-supported transactivation: lessons from beta2-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 beta2-adrenergic receptor (beta2-AR) is independent of MMPs and results in an incomplete downstream signalling involving extracellular signal-activated kinase (ERK) but not PLCgamma1 and Akt. In contrast, beta2-AR has the ability to activate PLCgamma1 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 beta2-AR-mediated transactivation the EGFR docking sites pY992 and pY1173 may be generated which are critical for PLCgamma1. 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.
Drube
Sebastian
S
Institute of Biochemistry and Biophysics, Biological and Pharmaceutical Faculty, Friedrich-Schiller-University Jena, Philosophenweg 12, D-07743 Jena, Germany.
Stirnweiss
Jörg
J
Valkova
Christina
C
Liebmann
Claus
C
D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D019000:Phosphotyrosine; D066246:ErbB Receptors; D016392:Proto-Oncogene Proteins pp60(c-src); D048049:Extracellular Signal-Regulated MAP Kinases; D051966:Phospholipase C gamma; D020782:Matrix Metalloproteinases