Mucous hypersecretion is a serious feature of chronic airway diseases such as asthma, COPD, and cystic fibrosis. Although mucins are produced via activation of an EGF receptor (EGFR) signaling cascade, the mechanisms leading to exaggerated mucin production in mucous hypersecretory diseases are unknown. Because expression of ICAM-1 and of the ICAM-1 ligand, fibrinogen, is increased in the airways of subjects with mucous hypersecretory diseases, we hypothesized that fibrinogen binding to ICAM-1 could increase EGFR-dependent mucin production in human airway (NCI-H292) epithelial cells. Consistent with this hypothesis, we found that an ICAM-1 neutralizing antibody and an ICAM-1 (8-22) peptide that binds fibrinogen decreased mucin production induced by the EGFR ligand TGF-alpha dose-dependently. Exogenous fibrinogen and a fibrinogen (117-133) peptide that binds ICAM-1 rescued mucin production in cells treated with the ICAM-1 (8-22) peptide. Surprisingly, the ICAM-1 (8-22) peptide increased EGFR phosphotyrosine and phospho-ERK1,2 in cells treated with TGF-alpha. The ICAM-1 (8-22) peptide-induced increases in EGFR phosphotyrosine and phospho-ERK1,2 were prevented by exogenous fibrinogen and by the fibrinogen (117-133) peptide, and by selective inhibitors of phospholipase C (PLC), protein kinase C (PKC)-alpha/beta, and metalloproteases. These results suggest that fibrinogen binding to ICAM-1 promotes mucin production by decreasing TGF-alpha-induced EGFR and ERK1,2 activation, and that the fibrinogen-ICAM-1-dependent decrease in EGFR and ERK1,2 activation occurs via inhibition of an early positive feedback pathway involving PLC- and PKC-alpha/beta-dependent metalloprotease activation and subsequent metalloprotease-dependent EGFR reactivation.