Zaoui Kossay, Honoré Stéphane, Isnardon Daniel, Braguer Diane, Badache Ali
French National Institute for Health and Medical Research Unit 891, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France.
J Cell Biol. 2008 Nov 3;183(3):401-8. doi: 10.1083/jcb.200805107. Epub 2008 Oct 27.
Actin assembly at the cell front drives membrane protrusion and initiates the cell migration cycle. Microtubules (MTs) extend within forward protrusions to sustain cell polarity and promote adhesion site turnover. Memo is an effector of the ErbB2 receptor tyrosine kinase involved in breast carcinoma cell migration. However, its mechanism of action remained unknown. We report in this study that Memo controls ErbB2-regulated MT dynamics by altering the transition frequency between MT growth and shortening phases. Moreover, although Memo-depleted cells can assemble the Rac1-dependent actin meshwork and form lamellipodia, they show defective localization of lamellipodial markers such as alpha-actinin-1 and a reduced number of short-lived adhesion sites underlying the advancing edge of migrating cells. Finally, we demonstrate that Memo is required for the localization of the RhoA guanosine triphosphatase and its effector mDia1 to the plasma membrane and that Memo-RhoA-mDia1 signaling coordinates the organization of the lamellipodial actin network, adhesion site formation, and MT outgrowth within the cell leading edge to sustain cell motility.
肌动蛋白在细胞前端的组装驱动膜突出并启动细胞迁移周期。微管（MTs）在向前的突出物中延伸以维持细胞极性并促进黏附位点更新。Memo是参与乳腺癌细胞迁移的ErbB2受体酪氨酸激酶的效应器。然而，其作用机制尚不清楚。我们在本研究中报告，Memo通过改变MT生长和缩短阶段之间的转换频率来控制ErbB2调节的MT动力学。此外，尽管缺乏Memo的细胞可以组装Rac1依赖性肌动蛋白网络并形成片状伪足，但它们显示出片状伪足标志物（如α-辅肌动蛋白-1）的定位缺陷，并且在迁移细胞前沿下方的短寿命黏附位点数量减少。最后，我们证明Memo是RhoA鸟苷三磷酸酶及其效应器mDia1定位于质膜所必需的，并且Memo-RhoA-mDia1信号传导协调片状伪足肌动蛋白网络的组织、黏附位点形成以及细胞前沿内的MT生长以维持细胞运动。
