Symmetry breaking in spreading RAT2 fibroblasts requires the MAPK/ERK pathway scaffold RACK1 that integrates FAK, p190A-RhoGAP and ERK2 signaling
Symmetry breaking in spreading RAT2 fibroblasts requires the MAPK/ERK pathway scaffold RACK1 that integrates FAK, p190A-RhoGAP and ERK2 signaling
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DOI：
10.1016/j.bbamcr.2016.05.013
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发表时间：
2016-09-01
影响因子：
5.1
通讯作者：
Vomastek, Tomas
中科院分区：
文献类型：
--
作者：
Klimova, Zuzana;Braborec, Vojtech;Vomastek, Tomas
贴壁细胞的铺展是一个形态发生过程，细胞打破球状或径向对称性，呈迁移性，细胞前部呈空间分离的突起，后部无突起。这些对称破缺事件的组织和调控既复杂又随机，目前还没有完全了解。在这里，我们表明，在放射状扩散的细胞中，对称性破坏始于离散的非突起区域的发展，其特征是大而稀疏的灶性粘连和长长的外周肌动蛋白束。这一非突起静态区的建立指定了向远端方向突起的细胞前沿，从而决定了细胞迁移的极轴和方向。非突起区域的发育需要ERK2和ERK途径支架蛋白RACK1。RACK1通过减少p190A-RhoGAP的外周定位，促进ERK2黏附介导的激活，进而抑制p190A-RhoGAP信号转导。我们认为，持续的ERK信号在预期的细胞后部诱导p190A-RhoGAP从细胞外围耗尽，导致外围肌动蛋白束和细胞后部形成。由于细胞黏附同时激活ERK和p190A-RhoGAP信号，这构成了一个空间受限的非相干前馈信号通路。(C)2016爱思唯尔B.V.保留所有权利。
The spreading of adhering cells is a morphogenetic process during which cells break spherical or radial symmetry and adopt migratory polarity with spatially segregated protruding cell front and non-protruding cell rear. The organization and regulation of these symmetry-breaking events, which are both complex and stochastic, are not fully understood. Here we show that in radially spreading cells, symmetry breaking commences with the development of discrete non-protruding regions characterized by large but sparse focal adhesions and long peripheral actin bundles. Establishment of this non-protruding static region specifies the distally oriented protruding cell front and thus determines the polarity axis and the direction of cell migration. The development of non-protruding regions requires ERK2 and the ERK pathway scaffold protein RACK1. RACK1 promotes adhesion-mediated activation of ERK2 that in turn inhibits p190A-RhoGAP signaling by reducing the peripheral localization of p190A-RhoGAP. We propose that sustained ERK signaling at the prospective cell rear induces p190A-RhoGAP depletion from the cell periphery resulting in peripheral actin bundles and cell rear formation. Since cell adhesion activates both ERK and p190A-RhoGAP signaling this constitutes a spatially confined incoherent feed-forward signaling circuit. (C) 2016 Elsevier B.V. All rights reserved.