NGF activates similar intracellular signaling pathways in vascular smooth muscle cells as PDGF-BB but elicits different biological responses

The signaling pathways that regulate smooth muscle cell migration and proli feration are incompletely understood. Smooth muscle cells express at least 3 families of receptor tyrosine kinases that mediate cell migration: platel et-derived growth factor (PDGF) receptors, the trk family of neurotrophin r eceptors, and insulin-like growth factor 1 receptor. The neurotrophin, nerv e growth factor (NGF), and insulin-like growth factor 1 induce the migratio n but not the proliferation of smooth muscle cells, whereas PDGF-BB stimula tes both responses. To determine whether distinct signaling pathways downst ream of receptor tyrosine kinases specifically mediate smooth muscle cell m igration or proliferation, the ligand-induced activation of different signa ling pathways in smooth muscle cells was examined. NGF induces prolonged ac tivation of the Shc/MAP kinase pathway and phospholipase C gamma compared w ith PDGF-BB. The activation of phosphatidylinositol-3 kinase, however, was 10-fold greater in response to PDGF-BB compared with NGF. Insulin-like grow th factor 1 activates only phosphatidylinositol-3 kinase. Pharmacological i nhibitors of phosphatidylinositol-3 kinase, Wortmannin and LY294002, inhibi t PDGF-BB and NGF-induced migration, whereas an inhibitor of MAP kinase kin ase, PD98059, has no effect. Our results suggest that (1) different recepto r tyrosine kinases use similar patterns of activation of signaling pathways to mediate distinct biological outcomes of cell migration and proliferatio n, (2) NGF activates signaling proteins in smooth muscle cells similar to t hose activated during NGF-induced neuronal differentiation, and (3) the com binatorial effects of different signaling pathways are important for the re gulation of smooth muscle cell migration and proliferation. Further studies using mutant trk receptors will help to define the signal transduction pat hways mediating NGF-induced smooth muscle cell migration.