Platelet-derived growth factor-BB and thrombin activate phosphoinositide 3-kinase and protein kinase B: Role in mediating airway smooth muscle proliferation

Trevor R. Walker, Sarah M. Moore, Mark F. Lawson, Reynold A. Panettieri, Edwin R. Chilvers

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Proliferation of airway smooth muscle results from persistent inflammatory cytokine and growth factor stimulation and is a critical component of airway luminal narrowing in chronic asthma. Using primary cultures of bovine tracheal smooth muscle (BTSM) cells to examine the signaling basis of cell proliferation, platelet-derived growth factor (PDGF)- BB and thrombin (which act through distinct receptor types) were found to induce DNA synthesis in BTSM cells. Mitogen-induced DNA synthesis could be completely inhibited by LY294002, a selective phosphoinositide 3-kinase (PtdIns 3-kinase) inhibitor. Exposure of BTSM cells to PDGF-BB or thrombin resulted in rapid activation of PtdIns 3-kinase and accumulation of phosphoinositide-3,4,5-trisphosphate. Protein kinase B, a novel signaling protein kinase, was identified in BTSM cells and was activated by PDGF-BB and thrombin in a PtdIns 3-kinase-dependent manner; this may underlie mitogen- stimulated activation of p70(s6k), PD98059, a mitogen-activated protein kinase kinase 1 inhibitor, also partially inhibited PDGF-BB- and thrombin- stimulated DNA synthesis, indicating a modulatory role for mitogen-activated protein kinase in proliferation. GF109203X, Ro 318220, calphostin C, and chelerythrine (selective protein kinase C inhibitors) had no effect on PDGF- BB- or thrombin-stimulated DNA synthesis, suggesting that, despite abolishment of mitogen-stimulated protein kinase C activity, cell proliferation stimulated by PDGF-BB and thrombin is protein kinase C- independent. These data demonstrate that the PtdIns 3-kinase/protein kinase B pathway represents a key signaling route in airway smooth muscle proliferation, with the mitogen-activated protein kinase kinase 1/mitogen- activated protein kinase cascade providing a complementary signal required for the full mitogenic response.

Original languageEnglish (US)
Pages (from-to)1007-1015
Number of pages9
JournalMolecular pharmacology
Volume54
Issue number6
DOIs
StatePublished - 1998
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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