Ena/VASP proteins mediate repulsion from ephrin ligands
Ena/VASP proteins mediate repulsion from ephrin ligands
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DOI：
10.1242/jcs.03333
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发表时间：
2007-01-15
影响因子：
4
通讯作者：
Nobes, Catherine D.
中科院分区：
文献类型：
--
作者：
Evans, Iwan R.;Renne, Thomas;Nobes, Catherine D.
Ena/VASP蛋白负调节细胞运动性，并有助于从几个指导线索排斥;然而，目前没有证据表明Eph受体下游的作用。Eph受体介导的排斥从ephrin在网站的细胞间接触在几个发展的迁移。例如，ephrin-Bs在体节后半部分的表达限制了神经嵴细胞向前半部分的迁移。在这里，我们表明，肝配蛋白-B2不稳定神经嵴细胞板状伪足时，在基板结合或可溶性形式。我们的时间推移的研究表明，排斥事件与向后崩溃和随后的损失板状伪足膜皱褶。我们假设Ena/VASP蛋白通过破坏细胞突起的稳定性来促进来自肝配蛋白的排斥，并且表明与野生型对照相比，Ena/VASP缺陷的成纤维细胞表现出来自肝配蛋白-A和肝配蛋白-B条纹的排斥减少。此外，当EphB 4和肝配蛋白-B2在邻近的Swiss 3 T3成纤维细胞中表达时，VASP和Mena与活化的Eph受体在由EphB 4表达细胞形成的突起处共积累。隔离Ena/VASP蛋白远离这些细胞的外周抑制Eph受体内化，这是一个促进排斥的过程。我们的研究结果表明，Ena/VASP蛋白调节肝配蛋白诱导的Eph受体信号转导事件，可能是通过破坏板状突起的稳定。
Ena/VASP proteins negatively regulate cell motility and contribute to repulsion from several guidance cues; however, there is currently no evidence for a role downstream of Eph receptors. Eph receptors mediate repulsion from ephrins at sites of intercellular contact during several developmental migrations. For example, the expression of ephrin-Bs in posterior halves of somites restricts neural crest cell migration to the anterior halves. Here we show that ephrin-B2 destabilises neural crest cell lamellipodia when presented in a substrate-bound or soluble form. Our timelapse studies show that repulsive events are associated with the rearward collapse and subsequent loss of lamellipodia as membrane ruffles. We hypothesise that Ena/VASP proteins contribute to repulsion from ephrins by destabilising cellular protrusions and show that Ena/VASP-deficient fibroblasts exhibit reduced repulsion from both ephrin-A and ephrin-B stripes compared to wild-type controls. Moreover, when EphB4 and ephrin-B2 were expressed in neighbouring Swiss 3T3 fibroblasts, VASP and Mena co-accumulated with activated Eph receptors at protrusions formed by EphB4-expressing cells. Sequestration of Ena/VASP proteins away from the periphery of these cells inhibited Eph receptor internalisation, a process that facilitates repulsion. Our results suggest that Ena/VASP proteins regulate ephrin-induced Eph receptor signalling events, possibly by destabilising lamellipodial protrusions.