© 1999 American Heart Association, Inc.
Original Contributions |
NGF Activates Similar Intracellular Signaling Pathways in Vascular Smooth Muscle Cells as PDGF-BB But Elicits Different Biological Responses
From the Departments of Pathology (R.K., H.N.) and Medicine (B.H.), Cornell University Medical College, New York, NY, and Krannert Institute of Cardiology and Richard L. Roudebush Veterans Administration Medical Center (K.L.M.), Indiana University School of Medicine, Indianapolis, Ind.
Abstract—The signaling pathways
that regulate smooth muscle cell migration and proliferation are
incompletely understood. Smooth muscle cells express at least 3
families of receptor tyrosine kinases that mediate cell migration:
platelet-derived growth factor (PDGF) receptors, the trk family of
neurotrophin receptors, and insulin-like growth factor 1 receptor. The
neurotrophin, nerve growth factor (NGF), and insulin-like growth factor
1 induce the migration but not the proliferation of smooth muscle
cells, whereas PDGF-BB stimulates both responses. To determine whether
distinct signaling pathways downstream of receptor tyrosine kinases
specifically mediate smooth muscle cell migration or proliferation, the
ligand-induced activation of different signaling pathways in smooth
muscle cells was examined. NGF induces prolonged activation of the
Shc/MAP kinase pathway and phospholipase C
compared with PDGF-BB.
The activation of phosphatidylinositol-3 kinase, however, was 10-fold
greater in response to PDGF-BB compared with NGF. Insulin-like growth
factor 1 activates only phosphatidylinositol-3 kinase.
Pharmacological inhibitors of phosphatidylinositol-3
kinase, Wortmannin and LY294002, inhibit PDGF-BB and NGF-induced
migration, whereas an inhibitor of MAP kinase kinase,
PD98059, has no effect. Our results suggest that (1) different receptor
tyrosine kinases use similar patterns of activation of signaling
pathways to mediate distinct biological outcomes of cell migration and
proliferation, (2) NGF activates signaling proteins in smooth
muscle cells similar to those activated during NGF-induced
neuronal differentiation, and (3) the combinatorial effects of
different signaling pathways are important for the regulation of smooth
muscle cell migration and proliferation. Further studies using mutant
trk receptors will help to define the signal transduction pathways
mediating NGF-induced smooth muscle cell migration.
Key Words: trk • smooth muscle cells • migration • proliferation • signal transduction
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