Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion
Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion
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DOI：
10.1038/ncb1044
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发表时间：
2003-10-01
影响因子：
21.3
通讯作者：
Nobes, CD
中科院分区：
文献类型：
--
作者：
Marston, DJ;Dickinson, S;Nobes, CD
在胚胎发育的组织构型过程中，Eph受体-eaffin信号对于控制排斥和吸引细胞的运动是重要的。然而，在细胞-细胞接触部位对这些信号的动态细胞反应还知之甚少。为了检测这些事件，我们使用细胞显微注射在相邻的瑞士3T3成纤维细胞中表达EphB4和ePhinB2，并使用时间推移显微镜研究了注射细胞之间的相互作用。我们发现，在相邻细胞接触的任何地方，Eph受体都被局部激活。这会在Eph-ephin接触部位触发动态的、由RAC调节的膜褶皱。随后，受体和配基细胞相互收缩，伴随着激活的Eph受体及其结合的全长ephinB配体的内吞作用。受体-配体复合体的内化和随后的细胞收缩事件都依赖于肌动蛋白聚合，而肌动蛋白聚合又依赖于受体表达细胞内的Rac信号。类似的情况也发生在原代人内皮细胞中。我们的发现提示了一种新的细胞排斥机制，在这种机制中，表达Eph的细胞和表达eaffin的细胞之间的接触是不稳定的，因为表达受体的细胞对表达配体的细胞膜进行了局部吞噬。
Eph receptor-ephrin signals are important for controlling repulsive and attractive cell movements during tissue patterning in embryonic development. However, the dynamic cellular responses to these signals at cell - cell contact sites are poorly understood. To examine these events we have used cell microinjection to express EphB4 and ephrinB2 in adjacent Swiss 3T3 fibroblasts and have studied the interaction of the injected cells using time-lapse microscopy. We show that Eph receptors are locally activated wherever neighbouring cells make contact. This triggers dynamic, Rac-regulated membrane ruffles at the Eph - ephrin contact sites. Subsequently, the receptor and ligand cells retract from one another, concomitantly with the endocytosis of the activated Eph receptors and their bound, full-length ephrinB ligands. Both the internalization of the receptor - ligand complexes and the subsequent cell retraction events are dependent on actin polymerization, which in turn is dependent on Rac signalling within the receptor- expressing cells. Similar events occur in primary human endothelial cells. Our findings suggest a novel mechanism for cell repulsion, in which the contact between Eph- expressing and ephrin- expressing cells is destabilized by the localized phagocytosis of the ligand-expressing cell plasma membrane by the receptor- expressing cell.