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

Jonathan Berrout, Eleni Kyriakopoulou, Lavanya Moparthi, Alexandra S. Hogea, Liza Berrout, Cristina Ivan, Mihaela Lorger, John Boyle, Chris Peers, Stephen Muench, Jacobo Elies Gomez, Xin Hu, Carolyn Hurst, Thomas Hall, Sujanitha Umamaheswaran, Laura Wesley, Mihai Gagea, Michael Shires, Iain Manfield, Margaret A. KnowlesSimon Davies, Klaus Suhling, Yurema Teijeiro Gonzalez, Neil Carragher, Kenneth Macleod, N. Joan Abbott, George A. Calin, Nikita Gamper, Peter M. Zygmunt, Zahra Timsah

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Article number983
JournalNature communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Berrout, J., Kyriakopoulou, E., Moparthi, L., Hogea, A. S., Berrout, L., Ivan, C., Lorger, M., Boyle, J., Peers, C., Muench, S., Gomez, J. E., Hu, X., Hurst, C., Hall, T., Umamaheswaran, S., Wesley, L., Gagea, M., Shires, M., Manfield, I., ... Timsah, Z. (2017). TRPA1-FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p. Nature communications, 8(1), [983]. https://doi.org/10.1038/s41467-017-00983-w