Co-operative Cdc42 and Rho signalling mediates ephrinB-triggered endothelial cell retraction
Co-operative Cdc42 and Rho signalling mediates ephrinB-triggered endothelial cell retraction
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DOI：
10.1042/bj20070146
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发表时间：
2007-05-15
影响因子：
4.1
通讯作者：
Nobes, Catherine D.
中科院分区：
文献类型：
--
作者：
Groeger, Gillian;Nobes, Catherine D.
对Eph受体激活的细胞排斥反应与肌动蛋白细胞骨架的快速重组有关，而细胞骨架重组又部分地由Rho-Rock(Rho激酶)信号介导，驱动肌动蛋白的收缩。在目前的研究中，我们表明Rho本身并不足以产生这种排斥反应。相反，CDC42(细胞分裂周期42)及其效应器MRCK(强直性肌营养不良相关的CDC42结合蛋白激酶)也在ePhinB诱导的细胞回缩中起关键作用。内皮细胞受ewitinB2刺激后，可触发快速但短暂的细胞回缩。我们发现，尽管膜的收缩完全被Bleb-bistatin(一种肌球蛋白-II ATPase抑制剂)阻断，但它只通过抑制Rho-Rock信号而被部分阻断，这表明EphB的肌动肌球蛋白收缩能力下降存在岩石无关的信号。我们发现，CDC42或MRCK抑制与ROCK抑制的组合完全取消了排斥反应。此外，伊弗林-Eph复合体的内吞作用不是细胞最初回缩所必需的，而是随后RAC介导的细胞重新扩散所必需的。我们的数据揭示了Rho、RAC和CDC42在EphB介导的细胞回缩-恢复反应过程中的复杂相互作用。
Cell repulsion responses to Eph receptor activation are linked to rapid actin cytoskeletal reorganizations, which in turn are partially mediated by Rho-ROCK (Rho kinase) signalling, driving actomyosin contractility. In the present study, we show that Rho alone is not sufficient for this repulsion response. Rather, Cdc42 (cell division cycle 42) and its effector MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) are also critical for ephrinB- induced cell retraction. Stimulation of endothelial cells with ephrinB2 triggers rapid, but transient, cell retraction. We show that, although membrane retraction is fully blocked by bleb-bistatin (a myosin-II ATPase inhibitor), it is only partially blocked by inhibiting Rho-ROCK signalling, suggesting that there is ROCK-independent signalling to actomyosin contractility downstrearn of EphBs. We find that a combination of either Cdc42 or MRCK inhibition with ROCK inhibition completely abolishes the repulsion response. Additionally, endocytosis of ephrin-Eph complexes is not required for initial cell retraction, but is essential for subsequent Rac-mediated re-spreading of cells. Our data reveal a complex interplay of Rho, Rac and Cdc42 in the process of EphB-mediated cell retraction-recovery responses.