Role of epidermal growth factor receptor activation in regulating mucin synthesis

Abstract

commentary review reports primary research COPD = chronic obstructive pulmonary disease; EGF(R) = epidermal growth factor (receptor); MAPK = mitogen-activated protein kinase; TGF = transforming growth factor; TNF = tumor necrosis factor. Available online http://respiratory-research.com/content/2/2/085 IntroductionEpidermal growth factor (EGF) was discovered by Cohen, and he and his colleagues subsequently extended our knowledge of the mechanisms of action of EGF and its receptor EGFR [1]. EGFR is a 170 kDa membrane glycoprotein, which is activated by ligands such as EGF, transforming growth factor (TGF)-α, heparin-binding EGF, amphiregulin, betacellulin, and epiregulin. These proteins are synthesized as transmembrane precursors and are cleaved proteolytically by metalloproteases to release the mature growth factor, which can interact with EGFR and cause its activation. Epidermal growth factor expression and activation causes goblet-cell metaplasia in airwaysThe discovery that a human epidermoid (A-431) cancer cell line contains high concentrations of EGFR led to extensive investigation into the role of the EGFR cascade in epithelial cell multiplication (cancer). Although growth factors can act as transforming proteins, it was recently hypothesized that EGFR activation may also be involved in epithelial differentiation into mucin-containing goblet cells by specific inflammatory mediators. The hypothesis was supported by the following observations. First, mucosubstances can be detected in dysplastic lesions and in foci of carcinoma in situ in human airways, and in tracheal lesions induced by carcinogens in animals [2]. The coexistence of mucin-containing cells and cancer cells suggests the possibility of a common progenitor. Second, Clara cells (also called 'nongranulated secretory cells') are believed to be the progenitor cells for bronchiolar carcinoma AbstractHealthy individuals have few goblet cells in their airways, but in patients with hypersecretory diseases goblet-cell upregulation results in mucus hypersecretion, airway plugging, and death. Multiple stimuli produce hypersecretion via epidermal growth factor receptor (EGFR) expression and activation, causing goblet-cell metaplasia from Clara cells by a process of cell differentiation. These cells are also believed to be the cells of origin of non-small-cell lung cancer, but this occurs via cell multiplication. The mechanisms that determine which pathway is chosen are critical but largely unknown. Although no effective therapy exists for hypersecretion at present, the EGFR cascade suggests methods for effective therapeutic intervention.

Tumor Necrosis Factor-α Triggers Mucus Production in Airway Epithelium through an IκB Kinase β-dependent Mechanism

“…Moreover, pharmacological inhibition with specific tyrosine kinase inhibitors suggested that tyrosine phosphorylation events downstream of EGFR engagement were necessary for TGF-␣-induced mucin up-regulation. These studies also suggested that TNF-␣ triggered this response presumably by upregulating the expression of EGFR (19,26). However, in vivo evidence of this proposed pathway is not firmly established, and the actual signal transduction pathway presumably engaged by tyrosine phosphorylation and leading to mucus production remains unknown.…”

Acidic Mammalian Chitinase Is Secreted via an ADAM17/Epidermal Growth Factor Receptor-dependent Pathway and Stimulates Chemokine Production by Pulmonary Epithelial Cells

“…EGFR has been strongly implicated in the pathogenesis of Th2 tissue inflammation via its ability to regulate goblet cell metaplasia, mucin synthesis, and epithelial cell proliferation, differentiation, and survival (12,(27)(28)(29). Recent studies demonstrated that EGFR signaling mediates allergen-induced chemokine (TARC/CCL17) release by lung epithelial cells (30).…”

Interleukin-1β and Tumor Necrosis Factor-α Induce MUC5AC Overexpression through a Mechanism Involving ERK/p38 Mitogen-activated Protein Kinases-MSK1-CREB Activation in Human Airway Epithelial Cells

“…Mucin hypersecretion is commonly observed in many respiratory diseases, such as rhinitis, sinusitis, otitis media, nasal allergy, chronic bronchitis, and cystic fibrosis (1)(2)(3)(4). Eighteen types of mucin genes have been discovered to date: MUC1 (5), MUC2 (6), MUC3 (7), MUC4 (8), MUC5AC (9), MUC5B (10), MUC6 (11), MUC7 (12), MUC8 (13), MUC9 (14), MUC10 (15), MUC11 (16), MUC12 (16), MUC13 (17), MUC15 (18), MUC16 (19), MUC17 (20), and MUC18 (21).…”