Role of MAP kinase activation in bovine tracheal smooth muscle mitogenesis

Am J Physiol. 1995 Jun;268(6 Pt 1):L894-901. doi: 10.1152/ajplung.1995.268.6.L894.


Abnormal growth of airway smooth muscle may play an important role in the pathogenesis of human airway diseases. Little is known about the proliferative responses of cultured airway smooth muscle cells, nor of the precise pathways responsible for mitogenesis in these cells. We assessed DNA synthesis, cell proliferation, and mitogen-activated protein (MAP) kinase activation in bovine tracheal myocytes after exposure to four potential mitogens: platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and 5-hydroxytryptamine (5-HT). Stimulation with either PDGF or IGF-1 induced substantial increases in DNA synthesis and cell number, as reflected by [3H]thymidine incorporation, flow cytometry, and methylene blue staining. Treatment with EGF or 5-HT, on the other hand, induced only modest DNA synthesis and no increase in cell number. Immunoblots and kinase renaturation assays of cell extracts demonstrated activation of both the 42- and 44-kDa MAP kinases within minutes of either PDGF, IGF-1, EGF, or 5-HT exposure. However, relative to EGF and 5-HT stimulation, late-phase MAP kinase activation was significantly greater after treatment with the mitogens PDGF and IGF-1. We conclude that in cultured bovine tracheal myocytes 1) PDGF and IGF-1 are potent mitogens; 2) MAP kinase may be activated subsequent to stimulation of either receptor tyrosine kinases (PDGF, EGF, IGF-1) or G protein-linked receptors lacking in known tyrosine kinase activity (5-HT); and 3) unsustained MAP kinase activation is insufficient for mitogenesis. Finally, the finding that mitogenicity correlates with the late phase of MAP kinase activation is consistent with the notion that sustained MAP kinase activation is important for bovine tracheal myocyte proliferation.

Publication types

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

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cattle
  • Cell Cycle / drug effects
  • Cell Cycle / physiology*
  • Cell Division*
  • Cells, Cultured
  • DNA / biosynthesis
  • DNA Replication / drug effects
  • Enzyme Activation
  • Epidermal Growth Factor / pharmacology
  • Growth Substances / pharmacology*
  • Insulin-Like Growth Factor I / pharmacology
  • Kinetics
  • Muscle, Smooth / cytology*
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / enzymology
  • Platelet-Derived Growth Factor / pharmacology
  • Serotonin / pharmacology*
  • Thymidine / metabolism
  • Time Factors
  • Trachea / cytology*
  • Trachea / drug effects
  • Trachea / enzymology


  • Growth Substances
  • Platelet-Derived Growth Factor
  • Serotonin
  • Epidermal Growth Factor
  • Insulin-Like Growth Factor I
  • DNA
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Thymidine