EGF activates ErbB-2 and stimulates phosphatidylinositol 3-kinase in humanairway smooth muscle cells

The epidermal growth factor (EGF)receptor (EGFR) family includes four homol ogous transmembrane receptor protein tyrosine kinases, EGFR, ErbB-2, ErbB-3 , and ErbB-4. This receptor family plays a pivotal role in regulating cell proliferation, differentiation, and transformation. Ligand-induced activati on of these receptors results in formation of homo- and heterodimers, which undergo transphosphorylation and transactivation. The aim of this study wa s to characterize the role of EGFR family members in signaling EGF-induced human airway smooth muscle (HASM) cell proliferation. Here, we show that EG F stimulates activation of EGFR and transactivation of ErbB-2 in quiescent HASM cells. Phosphatidylinositol (PI) S-kinase, a critical signaling enzyme that modulates HASM cell growth, is preferentially associated with ErbB-2, and EGF-stimulated transactivation of ErbB-2 induces PI S-kinase activatio n. ErbB-3 and ErbB-4 are present in HASM cells; however, EGF has no effect on their activation. Betacellulin, a ligand for EGFR, ErbB-3, and ErbB-4, i nduced DNA synthesis of HASM cells and stimulated signaling through the act ivation of EGFR and ErbB-2 but not of ErbB-3 and ErbB-4. Heregulin, a speci fic ligand for ErbB-3 and ErbB-4, did not effect DNA synthesis and did not activate its specific receptors. These data suggest that EGF imparts signal s that involve activation of ErbB-2 and are associated with ErbB-2 PI 3-kin ase activation. Despite the mRNA and protein expression of all members of t he EGFR family, ligand-stimulated signaling induced activation of EGFR and ErbB-2 but not of ErbB-3 and ErbB-4.