Cooperation of distinct Rac-dependent pathways to stabilise E-cadherin adhesion.
Cooperation of distinct Rac-dependent pathways to stabilise E-cadherin adhesion.
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DOI：
10.1016/j.cellsig.2015.04.014
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发表时间：
2015-09
影响因子：
4.8
通讯作者：
Braga VM
中科院分区：
文献类型：
--
作者：
Erasmus JC;Welsh NJ;Braga VM
Rac 1被钙粘蛋白连接激活的确切机制尚不完全清楚。在角质形成细胞中，通过钙粘蛋白连接激活Rac 1需要EGFR信号传导，但EGFR如何做到这一点尚不清楚。为了解决哪种激活剂可以介导E-cadherin信号传导至Rac 1，我们研究了EGFR和两种Rac 1 GEF，SOS 1和DOCK 180。EGFR RNAi阻止了连接诱导的Rac 1激活，并导致钙粘蛋白接触处的E-钙粘蛋白片段化定位。相反，另一个EGFR家族成员ErbB 3的缺失并不干扰这两个过程。DOCK 180 RNAi，而不是SOS 1，阻止E-钙粘蛋白诱导的Rac 1激活。然而，在一个强烈的分歧从EGFR RNAi表型，DOCK 180耗竭没有扰乱肌动蛋白的招聘或钙粘蛋白在连接的本地化。相反，DOCK 180水平降低损害了预形成的细胞聚集体对机械应力的抵抗力。因此，在相同的细胞类型中，EGFR和DOCK 180通过新形成的接触调节Rac 1的激活，但控制单独的细胞事件，这些细胞事件合作以稳定连接。E-cadherin激活Rac 1以稳定连接，但如何触发不同的Rac 1依赖性细胞事件尚不清楚。钙粘蛋白参与通过两种途径激活Rac 1：EGFR或DOCK 180，一种非传统的Rac GEF。EGFR调节F-肌动蛋白募集到钙粘蛋白簇，从而稳定接触。相比之下，DOCK 180提供了对机械应力的抵抗力，这是一种未报道的Rac 1在连接处的功能。Rac 1激活的独特机制驱动单独的事件，这些事件相互合作以稳定角质形成细胞-细胞接触。
The precise mechanisms via which Rac1 is activated by cadherin junctions are not fully known. In keratinocytes Rac1 activation by cadherin junctions requires EGFR signalling, but how EGFR does so is unclear. To address which activator could mediate E-cadherin signalling to Rac1, we investigated EGFR and two Rac1 GEFs, SOS1 and DOCK180. EGFR RNAi prevented junction-induced Rac1 activation and led to fragmented localization of E-cadherin at cadherin contacts. In contrast, depletion of another EGFR family member, ErbB3, did not interfere with either process. DOCK180 RNAi, but not SOS1, prevented E-cadherin-induced Rac1 activation. However, in a strong divergence from EGFR RNAi phenotype, DOCK180 depletion did not perturb actin recruitment or cadherin localisation at junctions. Rather, reduced DOCK180 levels impaired the resistance to mechanical stress of pre-formed cell aggregates. Thus, within the same cell type, EGFR and DOCK180 regulate Rac1 activation by newly-formed contacts, but control separate cellular events that cooperate to stabilise junctions. E-cadherin activates Rac1 to stabilise junctions, but how distinct Rac1-dependent cellular events are triggered is unknown. Cadherin engagement activates Rac1 via two pathways: EGFR or DOCK180, an unconventional Rac GEF. EGFR modulates F-actin recruitment to cadherin clusters, thereby stabilizing contacts. In contrast, DOCK180 provides resistance to mechanical stress, an unreported Rac1 function at junctions. Distinct mechanisms of Rac1 activation drives separate events that cooperate to stabilise keratinocyte cell-cell contacts.