Semaphorin 4D/Plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway
Semaphorin 4D/Plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway
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DOI：
10.1128/mcb.25.16.6889-6898.2005
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发表时间：
2005-08-01
影响因子：
5.3
通讯作者：
Gutkind, JS
中科院分区：
文献类型：
--
作者：
Basile, JR;Afkhami, T;Gutkind, JS
脑信号蛋白是细胞表面和分泌的蛋白质，在神经元组织中提供轴突引导并调节许多细胞类型中的细胞运动。它们通过结合称为丛蛋白的跨膜受体家族而起作用，丛蛋白属于散射因子受体的c-Met家族，但缺乏内在酪氨酸激酶结构域。有趣的是，我们最近发现丛蛋白-B1在内皮细胞中高度表达，并且它被脑信号蛋白4D激活后产生了有效的促血管生成反应（J. R. Basile，A. Barac，T. Zhu，K. L. Guan和J.S. Gutkind，Cancer Res. 64：5212-5224，2004）。在寻找潜在的分子机制中，我们观察到脑信号蛋白4D刺激的内皮细胞迁移需要激活磷脂酰肌醇3-激酶（PI 3 K）-Akt通路。令人惊讶的是，我们发现丛蛋白-B1通过激活细胞内酪氨酸激酶级联反应刺激PI 3 K-Akt，该级联反应涉及PYK 2和Src的顺序激活。这导致丛蛋白-B1的酪氨酸磷酸化，包括PYK 2、Src和PI 3 K的多聚体信号传导复合物快速募集到丛蛋白-B1，并激活Akt。这些发现表明丛蛋白-B1可能通过直接激活细胞内酪氨酸激酶级联来实现其众多的生理功能。
Semaphorins are cell surface and secreted proteins that provide axonal guidance in neuronal tissues and regulate cell motility in many cell types. They act by binding a family of transmembrane receptors known as plexins, which belong to the c-Met family of scatter factor receptors but lack an intrinsic tyrosine kinase domain. Interestingly, we have recently shown that Plexin-B1 is highly expressed in endothelial cells and that its activation by Semaphorin 4D elicits a potent proangiogenic response (J. R. Basile, A. Barac, T. Zhu, K. L. Guan, and J. S. Gutkind, Cancer Res. 64:5212-5224, 2004). In searches for the underlying molecular mechanism, we observed that Semaphorin 4D-stimulated endothelial cell migration requires the activation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Surprisingly, we found that Plexin-B1 stimulates PI3K-Akt through the activation of an intracellular tyrosine kinase cascade that involves the sequential activation of PYK2 and Src. This results in the tyrosine phosphorylation of Plexin-B1, the rapid recruitment of a multimeric signaling complex that includes PYK2, Src, and PI3K to Plexin-B1 and the activation of Akt. These findings suggest that Plexin-B1 may achieve its numerous physiological functions through the direct activation of intracellular tyrosine kinase cascades.