TRPA1-FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p.
TRPA1-FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p.
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DOI：
10.1038/s41467-017-00983-w
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发表时间：
2017-10-16
影响因子：
16.6
通讯作者：
Timsah Z
中科院分区：
文献类型：
--
作者：
Berrout J;Kyriakopoulou E;Moparthi L;Hogea AS;Berrout L;Ivan C;Lorger M;Boyle J;Peers C;Muench S;Gomez JE;Hu X;Hurst C;Hall T;Umamaheswaran S;Wesley L;Gagea M;Shires M;Manfield I;Knowles MA;Davies S;Suhling K;Gonzalez YT;Carragher N;Macleod K;Abbott NJ;Calin GA;Gamper N;Zygmunt PM;Timsah Z
最近的证据表明，离子通道TRPA 1与肺腺癌（LUAD）有关，其作用和作用机制仍不清楚。我们先前已经确定，膜受体FGFR 2通过其C-末端富含脯氨酸的基序介导的异常蛋白质-蛋白质相互作用来驱动LUAD进展。在这里，我们报告的N-末端锚蛋白重复TRPA 1直接结合到C-末端脯氨酸丰富的FGFR 2基序诱导受体的组成性激活，从而促进LUAD的进展和转移。此外，我们表明，在转移到大脑后，TRPA 1被耗尽，这是由TRPA 1靶向外泌体microRNA（miRNA-142- 3 p）从脑星形胶质细胞转移到癌细胞所触发的效应。这种下调反过来又抑制了TRPA 1介导的FGFR 2活化，阻碍了转移过程。我们的研究揭示了一个直接结合事件，并表征了TRPA 1锚蛋白重复序列在调节FGFR 2驱动的致癌过程中的作用;这是一种被miRNA-142- 3 p阻碍的机制。据报道，TRPA 1与肺癌腺癌（LUAD）有关，但其机制尚不清楚。在这里，作者提出TRPA 1/FGFR 2相互作用在LUAD中起作用，并表明星形胶质细胞通过外泌体递送的miRNA-142- 3 p介导TRPA 1的下调来对抗脑转移。
Recent evidence suggests that the ion channel TRPA1 is implicated in lung adenocarcinoma (LUAD), where its role and mechanism of action remain unknown. We have previously established that the membrane receptor FGFR2 drives LUAD progression through aberrant protein–protein interactions mediated via its C-terminal proline-rich motif. Here we report that the N-terminal ankyrin repeats of TRPA1 directly bind to the C-terminal proline-rich motif of FGFR2 inducing the constitutive activation of the receptor, thereby prompting LUAD progression and metastasis. Furthermore, we show that upon metastasis to the brain, TRPA1 gets depleted, an effect triggered by the transfer of TRPA1-targeting exosomal microRNA (miRNA-142-3p) from brain astrocytes to cancer cells. This downregulation, in turn, inhibits TRPA1-mediated activation of FGFR2, hindering the metastatic process. Our study reveals a direct binding event and characterizes the role of TRPA1 ankyrin repeats in regulating FGFR2-driven oncogenic process; a mechanism that is hindered by miRNA-142-3p. TRPA1 has been reported to contribute lung cancer adenocarcinoma (LUAD), but the mechanisms are unclear. Here the authors propose that TRPA1/FGFR2 interaction is functional in LUAD and show that astrocytes oppose brain metastasis by mediating the downregulation of TRPA1 through exosome-delivered miRNA-142-3p.
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