Mechanisms by which gram-positive bacteria and tobacco smoke stimulate mucin induction through the epidermal growth factor receptor (EGFR).
Mucin, the major macromolecular component of mucus, is generally considered to be a protective substance. When overproduced in a variety of lung diseases, however, mucin gives rise to clinical problems such as airway obstruction and recurrent infection. Our approach to identifying drug targets for the control of mucin overproduction is the analysis of cellular signalling pathways linking stimuli in the diseased lung to mucin transcription. Here we show that mucin transcription in response to both gram-positive bacteria and tobacco smoke is mediated through activation of the epidermal growth factor receptor (EGFR). The mode of activation of EGFR in response to bacterial lipoteichoic acid involves cleavage of the transmembrane ligand HBEGF by ADAM 10, whereas the activation of EGFR in response to smoke involves cleavage of amphiregulin by ADAM 17.
Basbaum
Carol
C
Biomedical Sciences Program, Department of Anatomy, University of California, San Francisco, CA 94143-0452, USA.
Li
Daizong
D
Gensch
Erin
E
Gallup
Marianne
M
Lemjabbar
Hassan
H
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D066258:Amphiregulin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D066255:EGF Family of Proteins; D010450:Endopeptidases / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006023:Glycoproteins / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000502:physiology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000502:physiology; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011956:Receptors, Cell Surface; D015398:Signal Transduction; D012906:Smoke; D013682:Teichoic Acids / Q000494:pharmacology; D014158:Transcription, Genetic; D018909:src Homology Domains
C587848:AREG protein, human; D066258:Amphiregulin; D066255:EGF Family of Proteins; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008070:Lipopolysaccharides; D009077:Mucins; D011956:Receptors, Cell Surface; D012906:Smoke; D013682:Teichoic Acids; C009900:lipoteichoic acid; D066246:ErbB Receptors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human