TRPA1- FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p

Abstract

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.

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Item Type:	Article
Authors/Creators:	Berrout, J Kyriakopoula, E Moparthi, L Hogea, AS Berrout, L Ivan, C Lorger, M Boyle, J https://orcid.org/0000-0001-5786-6559 Peers, C Muench, S https://orcid.org/0000-0001-6869-4414 Elies Gomez, J Hu, X Hurst, C https://orcid.org/0000-0001-7719-1325 Hall, T Umamaheswaran, S Wesley, L Gagea, M Shires, M https://orcid.org/0000-0003-0904-6200 Manfield, I Knowles, MA https://orcid.org/0000-0002-9363-8657 Davies, S Suhling, K Teijeiro Gonzalez, Y Carragher, N Macleod, K Abbott, NJ Calin, GA Gamper, N https://orcid.org/0000-0001-5806-0207 Zygmunt, PM Timsah, Z
Copyright, Publisher and Additional Information:	(c) 2017, the Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
Keywords:	TRPA1; lung adenocarcinome; FGFR2; microRNA; brain; growth factor signalling; non-small-cell lung cancer
Dates:	Accepted: 8 August 2017 Published (online): 16 October 2017 Published: 16 October 2017
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Biological Chemistry (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Mechanistic Biology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	24 Oct 2017 16:36
Last Modified:	08 Sep 2020 14:42
Status:	Published
Publisher:	Nature Publishing Group
Identification Number:	10.1038/s41467-017-00983-w
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:122968

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TRPA1- FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p

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