Specific inhibitor of FGF receptor signaling: FGF-2-mediated effects on proliferation, differentiation, and MAPK activation are inhibited by PD173074 in oligodendrocyte-lineage cells
Specific inhibitor of FGF receptor signaling: FGF-2-mediated effects on proliferation, differentiation, and MAPK activation are inhibited by PD173074 in oligodendrocyte-lineage cells
复制标题
DOI：
10.1002/jnr.10773
复制
发表时间：
2003-11-15
影响因子：
4.2
通讯作者：
Winkler, S
中科院分区：
文献类型：
--
作者：
Bansal, R;Magge, S;Winkler, S
多项研究表明，少突胶质细胞（OL）谱系细胞的迁移、增殖和分化受到成纤维细胞生长因子-2（FGF-2）通过其受体（FGFR）FGFR-1、FGFR-2和FGFR-3信号传导的影响。我们报告了一种独特的抑制剂PD 173074在OL系细胞中抑制FGF受体信号传导的有效性和特异性。通过免疫荧光显微镜和免疫印迹检查了三种FGF介导的OL祖细胞和两种分化的OL的反应。PD 173074能有效拮抗FGF-2对OL祖细胞增殖和分化的影响。一剂纳摩尔浓度的PD 173074足以以无毒、剂量依赖性方式长时间抑制正在进行的FGF-2介导的增殖。相反，血小板衍生生长因子（PDGF）诱导的增殖不受PD 173074的影响。类似地，丝裂原活化蛋白激酶（MAPK）活化，FGFR或PDGFR活化后的下游事件，也被PD 173074在用FGF-2而不是PDGF刺激的OL祖细胞中阻断。然而，一般的酪氨酸激酶抑制剂（PD 166285），拮抗FGF-2和PDGF介导的反应。PD 173074还完全拮抗分化的OL的两种表型改变，特别是髓磷脂蛋白的下调，以及它们重新进入细胞周期。我们的结论是，PD 173704是一种有效的和特异性的抑制剂，为多个FGF-2介导的反应的OL祖细胞和分化的OL。这种抑制剂提供了一种鉴定FGF信号传导的重要性的直接方法，其效果与敲除所有FGF受体和所有FGF配体相当，同时使其他途径不受影响。因此，PD 173704是一个很好的工具，用于研究FGF信号在体内其他信号的组合相互作用的背景下的作用。(C)2003 Wiley-Liss，Inc.
Multiple studies have shown that migration, proliferation, and differentiation of oligodendrocyte (OL) lineage cells are influenced by fibroblast growth factor-2 (FGF-2) signaling through its receptors (FGFR) FGFR-1, FGFR-2, and FGFR-3. We report the effectiveness and specificity of a unique inhibitor, PD173074, for inhibiting FGF receptor signaling in OL-lineage cells. Three FGF-mediated responses of OL progenitors and two of differentiated OLs were examined by immunofluorescence microscopy and immunoblotting. PD173074 effectively antagonized the effect of FGF-2 on proliferation and differentiation of OL progenitors in culture. One dose of PD173074 at nanomolar concentrations was sufficient to inhibit ongoing FGF-2 mediated proliferation for prolonged periods; in a non-toxic, dose-dependent manner. In contrast, platelet-derived growth factor (PDGF)-induced proliferation was unaffected by PD173074. Similarly, mitogen-activated protein kinase (MAPK) activation, a downstream event after activation of either FGFR or PDGFR, was also blocked by PD173074 in OL progenitors stimulated with FGF-2 but not PDGF. A general tyrosine kinase inhibitor (PD166285), however, antagonized both FGF-2- and PDGF-mediated responses. PD173074 also completely antagonized two phenotypic alterations of differentiated OLs, specifically downregulation of myelin proteins, and their re-entry into the cell cycle. We conclude that PD173704 is an effective and specific inhibitor for multiple FGF-2-mediated responses of both OL progenitors and differentiated OLs. This inhibitor provides a direct approach for identifying the importance of FGF signaling, comparable in effect to a knockout of all FGF receptors and all FGF ligands, while leaving other pathways unaffected. Thus, PD173704 is an excellent tool for investigating the role of FGF signaling in vivo in the context of combinatorial interactions of other signals. (C) 2003 Wiley-Liss, Inc.