Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation
Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation
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DOI：
10.1038/sj.onc.1202680
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发表时间：
1999-06-03
期刊：
影响因子：
8
通讯作者：
Claesson-Welsh, L
中科院分区：
文献类型：
--
作者：
Klint, P;Kanda, S;Claesson-Welsh, L
我们研究了成纤维细胞生长因子（FGF）受体1介导的内皮细胞（EC）分化的信号转导。活化的FGFR-1通过两个衔接蛋白FRS2和Shc与Ras偶联。在FGF-2处理的增殖EC中，FRS2以及She被酪氨酸磷酸化并与Grb 2相互作用。相反，在FGF-2处理的分化细胞中，Shc而不是FRS2参与Grb 2相互作用。在FGF刺激的增殖和分化的内皮细胞中，MAP激酶Erk2以持续的方式被激活。通过PD98059处理细胞抑制MEK和MAP激酶活性，仍然允许EC管形成。FGFR-1通过直接结合和激活磷脂酶C-γ（PLC-γ）介导蛋白激酶C（PKC）的激活，并且还显示激活细胞质酪氨酸激酶Src。用PKC抑制剂bisindolylmaleimide处理细胞不能阻止管形成。相比之下，Src激酶活性是EC分化的先决条件，因为用PP1（Src家族特异性抑制剂）处理细胞消除了管形成。在分化EC中，FGF-2诱导Src和粘着斑激酶（FAK）之间的复合物形成。这些数据表明Ras途径通过She或FRS2启动。依赖于细胞程序。阻断Src家族激酶的功能，减弱分化。
We have examined fibroblast growth factor (FGF) receptor-1 mediated signal transduction in differentiation of endothelial cells (EC). The activated FGFR-1 couples to Ras through two adaptor proteins, FRS2 and Shc. In FGF-2 treated proliferating EC, FRS2 as well as She are tyrosine phosphorylated and interact with Grb2, In contrast, in FGF-2 treated differentiating cells, Shc, but not FRS2, is engaged in Grb2-interactions, Sustained MAP kinase activity has previously been implicated in differentiation. In FGF stimulated proliferating and differentiating endothelial cells, the MAP kinase Erk2 is activated in a sustained manner. Inhibition of MEK and MAP kinase activity by PD98059 treatment of cells, still allows EC tube formation, The FGFR-1 mediates activation of protein kinase C (PKC) through direct binding and activation of phospholipase C-gamma (PLC-gamma), and has also been shown to activate the cytoplasmic tyrosine kinase Src. Treatment of the cells with the PKC inhibitor bisindolylmaleimide does not prevent tube formation. In contrast, Src kinase activity is prerequisite for EC differentiation, since treatment of the cells with PP1, a Src family specific inhibitor, abrogates tube formation. In differentiating EC, FGF-2 induces complex formation between Src and focal adhesion kinase (FAK). These data indicate that the Ras pathway is initiated via She or FRS2. dependent on the cellular program. Blocking the function of Src family kinases, attenuates differentiation.