title: The protein kinases TPL2 and EGFR contribute to ERK1/ERK2 hyperactivation in CFTRΔF508-expressing airway epithelial cells exposed to Pseudomonas aeruginosa.
abstract: Excessive inflammation and Pseudomonas aeruginosa infection are two major characteristics of cysticfibrosis (CF) lung disease. In this manuscript, we describe a novel mechanism of ERK1/ERK2 activationand CXCL8 expression in airway epithelial cells (AECs) lacking functional CFTR. In both non-CF and CFAECs, the protein kinase TPL2 is required for ERK1/ERK2 MAPK activation. However, we have found that EGFR is strongly phosphorylated in the airway epithelium of CF lung and contributes to ERK1/ERK2 MAPK activation in CF AECs exposed to P. aeruginosa diffusible material (PsaDM). Moreover, PsaDM stimulates the expression of the EGFR pro-ligand HB-EGF more strongly, and in a sustained manner, in CF AECs compared to non-CF cells. Finally, although both non-CF and CF AECs expresses CXCL8 in response to PsaDM, the levels of CXCL8 are higher and EGFR plays a more important role in regulating CXCL8 synthesis in CF AECs. Together, our finding shows that in addition to the TLR-mediated TPL2 activation of ERK1/ERK2, an additional pathway contributing to ERK1/ERK2 activation is triggered by infection of CF AECs: the EGFR signaling pathway. This second pathway may contribute to excessive inflammation observed in CF.
authors.forename: Guy
authors.initials: G
authors.lastname: Martel
authors.forename: Lucie
authors.initials: L
authors.lastname: Roussel
authors.forename: Simon
authors.initials: S
authors.lastname: Rousseau
mesh_terms: D002460:Cell Line; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011552:Pseudomonas Infections / Q000201:enzymology* / Q000235:genetics; D011550:Pseudomonas aeruginosa; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000382:microbiology; D017384:Sequence Deletion
chemical_list: D011518:Proto-Oncogene Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C512478:EGFR protein, human; D066246:ErbB Receptors; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human