Ephrin-A1 binding to CD4+ T lymphocytes stimulates migration and induces tyrosine phosphorylation of PYK2
Ephrin-A1 binding to CD4+ T lymphocytes stimulates migration and induces tyrosine phosphorylation of PYK2
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DOI：
10.1182/blood-2004-08-2981
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发表时间：
2005-04-01
期刊：
影响因子：
20.3
通讯作者：
Finne, EF
中科院分区：
文献类型：
--
作者：
Aasheim, HC;Delabie, J;Finne, EF
Eph 受体是受体酪氨酸激酶的最大亚家族，其肝配蛋白配体是调节细胞附着、形状和移动性的细胞间通讯的重要介质。在这里，我们证明CD4（+）T淋巴细胞表达EphA1和EphA4受体，并且这些细胞结合配体ephrinA1。此外，我们还显示了肝配蛋白-A1 在高内皮小静脉 (HEV) 内皮细胞上的体内表达。 Ephrin-A1 与 CD4(+) T 细胞结合可刺激基质细胞衍生因子 1 α (SDF-1 α) 和巨噬细胞炎症蛋白 3 β (MIP3 β) 介导的趋化性。与趋化反应增加一致，观察到肌动蛋白聚合增加，尤其是肝配蛋白-A1 和 SDF-1 α 的组合。通过 EphA 受体的信号传导诱导细胞内酪氨酸磷酸化。特别是，富含脯氨酸的酪氨酸激酶 2 (PYK2) 在酪氨酸残基 402 和 580 上被磷酸化。Ephrin-A1 诱导的趋化性和细胞内酪氨酸磷酸化（包括 EphA1 和 Pyk2）被 Tyrphostin-Ag 抑制。总之，CD4+T细胞上EphA受体的配体结合刺激趋化性，诱导细胞内酪氨酸磷酸化，并影响肌动蛋白聚合。这与我们发现 HEV 内皮细胞表达 ephrin-A1 一起表明 Eph 受体在跨内皮迁移中的作用。
Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell-cell communication regulating cell attachment, shape, and mobility. Here we demonstrate that CD4(+) T lymphocytes express the EphA1 and EphA4 receptors and that these cells bind the ligand ephrinA1. Further we show ephrin-A1 expression in vivo on high endothelial venule (HEV) endothelial cells. Ephrin-A1 binding to CD4(+) T cells stimulates both stromal cell-derived factor 1 alpha (SDF-1 alpha)- and macrophage inflammatory protein 3 beta (MIP3 beta)-mediated chemotaxis. In line with the increased chemotactic response, increased actin polymerization is observed in particular with the combination of ephrin-A1 and SDF-1 alpha.. Signaling through EphA receptors induces intracellular tyrosine phosphorylation. In particular, proline-rich tyrosine kinase 2 (PYK2) is phosphorylated on tyrosine residues 402 and 580. Ephrin-A1-induced chemotaxis and intracellular tyrosine phosphorylation, including EphA1 and Pyk2, was inhibited by Tyrphostin-Ag. In conclusion, ligand engagement of EphA receptors on CD4(+) T cells stimulates chemotaxis, induces intracellular tyrosine phosphorylation, and affects actin polymerization. This, together with our finding that ephrin-A1 is expressed by HEV endothelial cells, suggests a role for Eph receptors in transendothelial migration.