NGF activates similar intracellular signaling pathways in vascular smooth muscle cells as PDGF-BB but elicits different biological responses
NGF activates similar intracellular signaling pathways in vascular smooth muscle cells as PDGF-BB but elicits different biological responses
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DOI：
10.1161/01.atv.19.4.1041
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发表时间：
1999-04-01
影响因子：
8.7
通讯作者：
Hempstead, B
中科院分区：
文献类型：
--
作者：
Kraemer, R;Nguyen, H;Hempstead, B
调节平滑肌细胞迁移和增殖的信号传导途径还不完全清楚。平滑肌细胞表达至少3个介导细胞迁移的受体酪氨酸激酶家族：血小板衍生生长因子（PDGF）受体、神经营养因子受体trk家族和胰岛素样生长因子1受体。神经营养因子、神经生长因子（NGF）和胰岛素样生长因子1诱导平滑肌细胞的迁移而非增殖，而PDGF-BB刺激这两种反应。为了确定受体酪氨酸激酶下游的不同信号传导途径是否特异性介导平滑肌细胞迁移或增殖，检查了平滑肌细胞中不同信号传导途径的配体诱导的活化。与PDGF-BB相比，NGF诱导Shc/MAP激酶途径和磷脂酶C γ的活化延长。然而，与NGF相比，PDGF-BB对磷脂酰肌醇-3激酶的激活作用要大10倍。胰岛素样生长因子1只激活磷脂酰肌醇-3激酶。磷脂酰肌醇-3激酶的药理学抑制剂Wortmannin和LY 294002抑制PDGF-BB和NGF诱导的迁移，而MAP激酶激酶的抑制剂PD 98059则没有作用。我们的研究结果表明：（1）不同的受体酪氨酸激酶使用相似的信号通路激活模式来介导细胞迁移和增殖的不同生物学结果，（2）NGF激活平滑肌细胞中的信号蛋白，类似于在NGF诱导的神经元分化过程中激活的信号蛋白，不同信号通路的联合作用对平滑肌细胞迁移和增殖的调节是重要的。利用突变型trk受体的进一步研究将有助于确定介导NGF诱导的平滑肌细胞迁移的信号转导途径。
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 gamma 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.