p190A inactivating mutations cause aberrant RhoA activation and promote malignant transformation via the Hippo-YAP pathway in endometrial cancer
p190A inactivating mutations cause aberrant RhoA activation and promote malignant transformation via the Hippo-YAP pathway in endometrial cancer
复制标题
p190A 失活突变导致 RhoA 异常激活，并通过 Hippo-YAP 通路促进子宫内膜癌恶性转化
DOI：
10.1038/s41392-020-0170-6
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发表时间：
2020-05-27
影响因子：
39.3
通讯作者：
Wan, Xiaoping
中科院分区：
文献类型：
--
作者：
Wen, Xiaoli;Wan, Jing;Wan, Xiaoping
GTP酶的Rho家族受到GTP酶激活蛋白（GAP）的大家族的严格调节，所述GAP刺激Rho GTP酶的相对弱的内在GTP水解活性。p190 A是一种有效的广泛表达的GAP，作用于RhoA GTP酶。p190 A在子宫内膜癌中经常发生突变，但p190 A突变对子宫内膜肿瘤发生的作用尚不清楚。在这里，我们确定p190 A是Hippo-YAP信号通路的上游调节因子，该信号通路是细胞增殖、凋亡和细胞命运的关键调节因子。p190 A基因敲除可促进子宫内膜癌细胞的增殖、迁移和上皮-间质转化（EMT），而这部分依赖于雅普的激活。野生型p190 A，而不是子宫内膜癌相关突变体，抑制核定位，转录活性，和恶性转化功能的雅普。此外，雅普的核定位在p190 A突变的子宫内膜癌中增强。这些发现揭示了Hippo-YAP通路驱动的子宫内膜肿瘤发生的新分子机制，并阐明了靶向Hippo-YAP通路治疗p190 A突变子宫内膜癌的潜力。
The Rho family of GTPases is strictly regulated by a large family of GTPase-activating proteins (GAPs) that stimulate the relatively weak intrinsic GTP-hydrolyzing activity of Rho GTPases. p190A is a potent and widely expressed GAP that acts on RhoA GTPases. p190A is frequently mutated in endometrial cancer, but the contribution of p190A mutations to endometrial tumorigenesis remains unclear. Here we identified that p190A is an upstream regulator of the Hippo-YAP signaling pathway, which is a critical regulator of cell proliferation, apoptosis, and cell fate. p190A knockout in endometrial cancer cells promoted cell proliferation, migration, and epithelial–mesenchymal transition (EMT), which were partially dependent on YAP activation. Wild-type p190A, but not endometrial cancer-associated mutants, suppressed the nuclear localization, transcriptional activity, and malignant transformation function of YAP. Moreover, the nuclear localization of YAP was enhanced in p190A-mutated endometrial cancer. These findings reveal novel molecular mechanisms underlying Hippo-YAP pathway-driven endometrial tumorigenesis and elucidate the potential for therapy targeting the Hippo-YAP pathway in p190A-mutated endometrial cancer.