Cancer-associated mutations in the protrusion-targeting region of p190RhoGAP impact tumor cell migration.
Cancer-associated mutations in the protrusion-targeting region of p190RhoGAP impact tumor cell migration.
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DOI：
10.1083/jcb.201601063
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发表时间：
2016-09-26
期刊：
影响因子：
--
通讯作者：
Moreau V
中科院分区：
文献类型：
--
作者：
Binamé F;Bidaud-Meynard A;Magnan L;Piquet L;Montibus B;Chabadel A;Saltel F;Lagrée V;Moreau V
p190RhoGAP (p190A) 是 RhoA 的负调节因子，定位于膜突起，其 GAP 活性是定向迁移所必需的。在这里，Binamé 等人。鉴定了 p190A 中的突出定位序列，并表明该区域中与癌症相关的突变影响 p190A 定位和功能以及肿瘤细胞迁移。细胞前沿需要 RhoGTP 酶（例如 RhoA）的时空调节来实现细胞迁移。 p190RhoGAP (p190A) 是 RhoA 的主要负调节因子，定位于膜突起，其中其 GTP 酶激活蛋白 (GAP) 活性是定向迁移所必需的。在这项研究中，我们研究了 p190A 靶向肌动蛋白突起的分子过程。通过分析肝细胞癌细胞中 p190A 截短版本的亚细胞定位，我们鉴定了一个新的功能性 p190A 结构域：p190A 靶向前缘所必需且充分的突出定位序列 (PLS)。有趣的是，p190A RhoGAP 活性的负调节也需要 PLS。此外，我们还发现 F-肌动蛋白结合蛋白 cortactin 与 PLS 结合，并且是 p190A 靶向突起所必需的。最后，我们证明 PLS 中与癌症相关的突变会影响 p190A 的定位和功能，以及肿瘤细胞的迁移。总而言之，我们的数据揭示了 p190A 在迁移肿瘤细胞中的一种新调节机制。
p190RhoGAP (p190A) is a negative regulator of RhoA and localizes to membrane protrusions, where its GAP activity is required for directional migration. Here, Binamé et al. identify the protrusion-localization sequence in p190A and show that cancer-associated mutations in this region affect p190A localization and function as well as tumor cell migration. Spatiotemporal regulation of RhoGTPases such as RhoA is required at the cell leading edge to achieve cell migration. p190RhoGAP (p190A) is the main negative regulator of RhoA and localizes to membrane protrusions, where its GTPase-activating protein (GAP) activity is required for directional migration. In this study, we investigated the molecular processes responsible for p190A targeting to actin protrusions. By analyzing the subcellular localization of truncated versions of p190A in hepatocellular carcinoma cells, we identified a novel functional p190A domain: the protrusion localization sequence (PLS) necessary and sufficient for p190A targeting to leading edges. Interestingly, the PLS is also required for the negative regulation of p190A RhoGAP activity. Further, we show that the F-actin binding protein cortactin binds the PLS and is required for p190A targeting to protrusions. Lastly, we demonstrate that cancer-associated mutations in PLS affect p190A localization and function, as well as tumor cell migration. Altogether, our data unveil a new mechanism of regulation of p190A in migrating tumor cells.
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