The GTPase-Activating Protein RN-tre Controls Focal Adhesion Turnover and Cell Migration
The GTPase-Activating Protein RN-tre Controls Focal Adhesion Turnover and Cell Migration
复制标题
DOI：
10.1016/j.cub.2013.09.060
复制
发表时间：
2013-12-02
期刊：
影响因子：
9.2
通讯作者：
Lanzetti, Letizia
中科院分区：
文献类型：
--
作者：
Palamidessi, Andrea;Frittoli, Emanuela;Lanzetti, Letizia
背景资料：整合素介导的细胞与细胞外基质（ECM）的粘附依赖于粘着斑（FA）的动态形成，粘着斑是由多种胞质和跨膜蛋白组成的生物化学和机械敏感性平台。在迁移过程中，有一个恒定的周转ECM接触，最初形成为新生的粘附在前缘，成熟成FA的肌动球蛋白张力建立，然后在细胞后部解体，从而允许细胞分离。尽管FA组装的机制已经在很大程度上得到了定义，但调节其分解的分子电路仍然难以捉摸。结果如下：在这里，我们表明，RN-tre，GTP酶激活蛋白（GAP）的Rabs，包括Rab 5和Rab 43，是一种新的调节FA动力学和细胞迁移。RN-tre定位于FA和Rab 5阳性囊泡池，主要与经历快速重塑的FA相关。我们发现RN-tre抑制β 1整合素的内吞作用，但不抑制β 3整合素的内吞作用，并延迟FA的转换，最终损害β 1依赖性趋化细胞迁移，但不影响β 3依赖性趋化细胞迁移。所有这些作用都是由其GAP活性介导的，并依赖于Rab 5。结论：我们的研究结果确定RN-tre为Rab 5-GAP，其在趋化细胞迁移过程中时空控制FA重塑。
Background: Integrin-mediated adhesion of cells to the extracellular matrix (ECM) relies on the dynamic formation of focal adhesions (FAs), which are biochemical and mechanosensitive platforms composed of a large variety of cytosolic and transmembrane proteins. During migration, there is a constant turnover of ECM contacts that initially form as nascent adhesions at the leading edge, mature into FAs as actomyosin tension builds up, and are then disassembled at the cell rear, thus allowing for cell detachment. Although the mechanisms of FA assembly have largely been defined, the molecular circuitry that regulates their disassembly still remains elusive. Results: Here, we show that RN-tre, a GTPase-activating protein (GAP) for Rabs including Rab5 and Rab43, is a novel regulator of FA dynamics and cell migration. RN-tre localizes to FAs and to a pool of Rab5-positive vesicles mainly associated with FAs undergoing rapid remodeling. We found that RN-tre inhibits endocytosis of beta 1, but not beta 3, integrins and delays the turnover of FAs, ultimately impairing beta 1-dependent, but not beta 3-dependent, chemotactic cell migration. All of these effects are mediated by its GAP activity and rely on Rab5. Conclusions: Our findings identify RN-tre as the Rab5-GAP that spatiotemporally controls FA remodeling during chennotactic cell migration.