Activated EGF receptor may balance ERK-inhibitory network signalling pathways.
In the COS-7 cell signalling network high levels of cAMP produced, for example, by co-stimulation of beta2-adrenergic receptor (beta2-AR) and bradykinin B2 receptor (BKR) may affect epidermal growth factor receptor (EGFR)-mediated activation of extracellular signal-stimulated kinase (ERK). In contrast, co-stimulation of either beta2-AR or B2R with EGFR leads to synergistic activation of ERK. Due to triple stimulation of these receptors the synergistic effects on ERK activation as well as cAMP accumulation are diminished. Here we demonstrate that EGF is capable of inducing Src-mediated phosphorylation of the tyrosine residues 177 and 347 of BKR. Their replacement by phenylalanine led to BKR mutants which are unable to activate the cAMP pathway. Using these mutants we can show that EGF attenuates but does not completely inhibit the BKR/cAMP pathway which is counteracting the EGFR signalling to ERK. Our findings suggest that the EGFR may control the cellular network rather by balancing mechanisms then by switch on/off reactions.
Hanke
Sabine
S
Institute of Biochemistry and Biophysics, Biological and Pharmaceutical Faculty, Friedrich-Schiller-University, Philosophenweg 12, D-07743 Jena, Germany.
Valkova
Christina
C
Stirnweiss
Jörg
J
Drube
Sebastian
S
Liebmann
Claus
C
D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000502:physiology; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology; D066246:ErbB Receptors / Q000819:agonists / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D006801:Humans; D009154:Mutation; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000502:physiology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000502:physiology
D043782:Receptor, Bradykinin B2; D018343:Receptors, Adrenergic, beta-2; D014443:Tyrosine; D010649:Phenylalanine; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D066246:ErbB Receptors; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases