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

Am J Physiol. 1999 Feb;276(2):L246-55. doi: 10.1152/ajplung.1999.276.2.L246.


The epidermal growth factor (EGF)-receptor (EGFR) family includes four homologous 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 activation of these receptors results in formation of homo- and heterodimers, which undergo transphosphorylation and transactivation. The aim of this study was to characterize the role of EGFR family members in signaling EGF-induced human airway smooth muscle (HASM) cell proliferation. Here, we show that EGF stimulates activation of EGFR and transactivation of ErbB-2 in quiescent HASM cells. Phosphatidylinositol (PI) 3-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 3-kinase activation. 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, induced DNA synthesis of HASM cells and stimulated signaling through the activation of EGFR and ErbB-2 but not of ErbB-3 and ErbB-4. Heregulin, a specific 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 signals that involve activation of ErbB-2 and are associated with ErbB-2 PI 3-kinase activation. Despite the mRNA and protein expression of all members of the EGFR family, ligand-stimulated signaling induced activation of EGFR and ErbB-2 but not of ErbB-3 and ErbB-4.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cells, Cultured
  • Enzyme Activation / physiology
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / metabolism
  • ErbB Receptors / physiology
  • Humans
  • Muscle, Smooth / cytology
  • Muscle, Smooth / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology
  • Receptor, ErbB-2 / physiology*
  • Receptor, ErbB-3
  • Receptor, ErbB-4
  • Trachea / cytology
  • Trachea / metabolism*
  • Tyrosine / metabolism


  • Proto-Oncogene Proteins
  • Tyrosine
  • Epidermal Growth Factor
  • Phosphatidylinositol 3-Kinases
  • ERBB4 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Receptor, ErbB-4