Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling
Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling
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DOI：
10.1038/nn1237
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发表时间：
2004-05-01
影响因子：
25
通讯作者：
Nikolov, DB
中科院分区：
文献类型：
--
作者：
Himanen, JP;Chumley, MJ;Nikolov, DB
Eph受体酪氨酸激酶和它们的ephrin配体之间的相互作用调节细胞迁移和轴突寻路。通常认为EphA受体被肝配蛋白-A配体激活，而EphB受体与肝配蛋白-B配体相互作用。在这里，我们表明，这些分子中最广泛研究的两个，EphB 2和ephrin-A5，从未被描述为相互作用，实际上以高亲和力相互结合。EphB 2表达细胞暴露于肝配蛋白-A5导致受体聚集、自磷酸化和下游信号传导的启动。Ephrin-A5在模型系统中诱导EphB 2介导的生长锥塌陷和神经突收缩。我们进一步表明，使用X-射线晶体学，肝配蛋白A5-EphB 2复合物是一个异二聚体，是建筑上不同的四聚体EphB 2-肝配蛋白-B2结构。结构数据揭示了EphB 2-肝配蛋白-A5信号传导的分子基础，并为理解A-和B-亚类Eph受体和肝配蛋白之间的功能相互作用和串扰的复杂性提供了框架。
The interactions between Eph receptor tyrosine kinases and their ephrin ligands regulate cell migration and axon pathfinding. The EphA receptors are generally thought to become activated by ephrin-A ligands, whereas the EphB receptors interact with ephrin-B ligands. Here we show that two of the most widely studied of these molecules, EphB2 and ephrin-A5, which have never been described to interact with each other, do in fact bind one another with high affinity. Exposure of EphB2-expressing cells to ephrin-A5 leads to receptor clustering, autophosphorylation and initiation of downstream signaling. Ephrin-A5 induces EphB2-mediated growth cone collapse and neurite retraction in a model system. We further show, using X-ray crystallography, that the ephrin-A5-EphB2 complex is a heterodimer and is architecturally distinct from the tetrameric EphB2-ephrin-B2 structure. The structural data reveal the molecular basis for EphB2-ephrin-A5 signaling and provide a framework for understanding the complexities of functional interactions and crosstalk between A- and B-subclass Eph receptors and ephrins.