Crosstalks between the receptors tyrosine kinase EGFR and TrkA and the GPCR, FPR, in human monocytes are essential for receptors-mediated cell activation.
The G-protein coupled receptor (GPCR) fMLP receptor (FPR) and the two receptors tyrosine kinase (RTK), the nerve growth factor (NGF) receptor TrkA and the epidermal growth factor (EGF) receptor (EGFR) are involved in reactive oxygen species (ROS), matrix metalloproteinase-9 (MMP-9) production and CD11b membrane integrin upregulation. We show that in monocytes the three receptors crosstalk each other to modulate these pro-inflammatory mediators. Tyrphostin AG1478, the EGFR inhibitor, inhibits fMLP and NGF-associated ROS production, fMLP-associated CD11b upregulation and NGF-induced TrkA phosphorylation; K252a, the NGF receptor inhibitor, inhibits fMLP or EGF-associated ROS production, CD11b expression and EGF-induced EGFR phosphorylation; cyclosporine H, the FPR inhibitor inhibits EGF or NGF-associated ROS production, EGF-associated CD11b upregulation and prevents EGFR and TrkA phosphorylation by their respective ligand EGF and NGF. In response to fMLP, TrkA phosphorylation is inhibited by the EGFR inhibitor while EGFR phosphorylation is inhibited by the TrkA inhibitor. Receptor crosstalks are Src and ERK dependent. Down-regulation of each receptor by specific siRNA suppresses the ability of the two other receptors to promote ligand-mediated ERK phosphorylation and pro-inflammatory activities including ROS, MMP-9 production and CD11b upregulation. Thus, in monocytes GPCR ligands' activity involves activation of RTK while RTK-ligands activity engages GPCR-signalling molecules.
El Zein
Nabil
N
Pediatric Oncology Laboratory, 1020 Brussels, Belgium. nelzein@ulb.ac.be
D'Hondt
Stéphanie
S
Sariban
Eric
E
D039481:CD11b Antigen / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D020932:Nerve Growth Factor / Q000494:pharmacology; D020239:Receptor Cross-Talk; D020917:Receptor, trkA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044042:Receptors, Formyl Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D039481:CD11b Antigen; D044042:Receptors, Formyl Peptide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D004815:Epidermal Growth Factor; D020932:Nerve Growth Factor; D006861:Hydrogen Peroxide; D066246:ErbB Receptors; D020917:Receptor, trkA; D048049:Extracellular Signal-Regulated MAP Kinases