p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity.
p190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity.
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DOI：
10.1083/jcb.201710058
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发表时间：
2018-09-03
期刊：
影响因子：
--
通讯作者：
Hansen SH
中科院分区：
文献类型：
--
作者：
Frank SR;Köllmann CP;Luong P;Galli GG;Zou L;Bernards A;Getz G;Calogero RA;Frödin M;Hansen SH
ARHGAP35编码RhoGAP p190A是人类癌症中最常见的突变基因之一，这表明p190A可能具有肿瘤抑制功能。Frank等人证明p190A及其平行体p190B通过抑制yap介导的基因转录介导上皮细胞增殖的接触抑制。ARHGAP35编码p190A RhoGAP是一种癌症相关基因，其突变谱提示具有肿瘤抑制功能。在这项研究中，我们证明了ARHGAP35的杂合性缺失发生在人类肿瘤中。我们试图在上皮细胞中鉴定p190A RhoGAP （p190A）及其类似的p190B的肿瘤抑制能力。我们发现p190A和p190B在促进细胞增殖的接触抑制（CIP）中发挥重要作用，这一功能依赖于RhoGAP活性。无偏mRNA测序分析证实p190A和p190B调节与Hippo通路相关的基因表达。因此，我们确定p190A和p190B通过激活LATS激酶和抑制Rho-ROCK途径，抑制yap - tead调节的基因转录，从而诱导CIP。最后，我们证明在Matrigel中培养的上皮细胞中，单个p190平行序列的缺失足以引起YAP的核易位和CIP的紊乱。总的来说，我们的数据揭示了与ARHGAP35的肿瘤抑制功能一致的新机制。
ARHGAP35 encoding the RhoGAP p190A is one of the most frequently mutated genes in human cancer, which suggests that p190A may have a tumor-suppressive function. Frank et al. demonstrate that p190A and its paralog p190B mediate contact inhibition of epithelial cell proliferation by repressing YAP-mediated gene transcription. ARHGAP35 encoding p190A RhoGAP is a cancer-associated gene with a mutation spectrum suggestive of a tumor-suppressor function. In this study, we demonstrate that loss of heterozygosity for ARHGAP35 occurs in human tumors. We sought to identify tumor-suppressor capacities for p190A RhoGAP (p190A) and its paralog p190B in epithelial cells. We reveal an essential role for p190A and p190B to promote contact inhibition of cell proliferation (CIP), a function that relies on RhoGAP activity. Unbiased mRNA sequencing analyses establish that p190A and p190B modulate expression of genes associated with the Hippo pathway. Accordingly, we determine that p190A and p190B induce CIP by repressing YAP–TEAD-regulated gene transcription through activation of LATS kinases and inhibition of the Rho–ROCK pathway. Finally, we demonstrate that loss of a single p190 paralog is sufficient to elicit nuclear translocation of YAP and perturb CIP in epithelial cells cultured in Matrigel. Collectively, our data reveal a novel mechanism consistent with a tumor-suppressor function for ARHGAP35.
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发表时间：
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期刊：
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影响因子：
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