Neuropilin-1 Signaling through p130Cas Tyrosine Phosphorylation Is Essential for Growth Factor-Dependent Migration of Glioma and Endothelial Cells
Neuropilin-1 Signaling through p130Cas Tyrosine Phosphorylation Is Essential for Growth Factor-Dependent Migration of Glioma and Endothelial Cells
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DOI：
10.1128/mcb.00903-10
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发表时间：
2011-03-01
影响因子：
5.3
通讯作者：
Frankel, Paul
中科院分区：
文献类型：
--
作者：
Evans, Ian M.;Yamaji, Maiko;Frankel, Paul
神经纤毛蛋白-1（NRP 1）是血管内皮生长因子（VEGF）的受体，在介导细胞运动中起重要作用。然而，NRP 1信号通路对细胞运动的重要性知之甚少。在这里，我们报告说，p130（Cas）酪氨酸磷酸化刺激肝细胞生长因子和血小板衍生生长因子在U87 MG胶质瘤细胞和血管内皮细胞生长因子，并依赖于NRP 1通过其胞内域。在内皮细胞中，NRP 1沉默减少但不阻止VEGF受体2（VEGFR 2）磷酸化，而缺乏胞内结构域的NRP 1突变形式（NRP 1 Δ C）的表达不影响U87 MG细胞或人脐静脉内皮细胞（HUVEC）中的受体磷酸化。在HUVECs中，NRP 1也是VEGF诱导的富含脯氨酸的酪氨酸激酶2磷酸化所必需的，这是p130（Cas）磷酸化所必需的。重要的是，NRP 1或p130（Cas）的敲低或NRP 1 Delta C或非酪氨酸磷酸化底物结构域突变蛋白（p130（Cas 15 F））的表达足以抑制生长因子介导的胶质瘤和内皮细胞迁移。这些数据首次证明了NRP 1胞内结构域在介导几种受体酪氨酸激酶下游的特定信号传导途径中的重要性，并确定了一种新的NRP 1-p130（Cas）途径在趋化性调节中的关键作用。
Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor (VEGF) and plays an important role in mediating cell motility. However, the NRP1 signaling pathways important for cell motility are poorly understood. Here we report that p130(Cas) tyrosine phosphorylation is stimulated by hepatocyte growth factor and platelet-derived growth factor in U87MG glioma cells and VEGF in endothelial cells and is dependent on NRP1 via its intracellular domain. In endothelial cells, NRP1 silencing reduced, but did not prevent, VEGF receptor 2 (VEGFR2) phosphorylation, while expression of a mutant form of NRP1 lacking the intracellular domain (NRP1 Delta C) did not affect receptor phosphorylation in U87MG cells or human umbilical vein endothelial cells (HUVECs). In HUVECs, NRP1 was also required for VEGF-induced phosphorylation of proline-rich tyrosine kinase 2, which was necessary for p130(Cas) phosphorylation. Importantly, knockdown of NRP1 or p130(Cas) or expression of either NRP1 Delta C or a non-tyrosine-phosphorylatable substrate domain mutant protein (p130(Cas15F)) was sufficient to inhibit growth factor-mediated migration of glioma and endothelial cells. These data demonstrate for the first time the importance of the NRP1 intracellular domain in mediating a specific signaling pathway downstream of several receptor tyrosine kinases and identify a critical role for a novel NRP1-p130(Cas) pathway in the regulation of chemotaxis.