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. Knowles, Simon Davies, Klaus Suhling, Yurema Teijeiro Gonzalez, Neil Carragher, Kenneth Macleod, N. Joan Abbott, George A. Calin, Nikita Gamper, Peter M. Zygmunt and Zahra Timsah ()
Additional contact information
Jonathan Berrout: University of Leeds
Eleni Kyriakopoulou: University of Leeds
Lavanya Moparthi: Lund University
Alexandra S. Hogea: University of Leeds
Liza Berrout: The University of Texas at Brownsville
Cristina Ivan: The University of Texas MD Anderson Cancer Center
Mihaela Lorger: St James’s University Hospital
John Boyle: University of Leeds
Chris Peers: University of Leeds
Stephen Muench: University of Leeds
Jacobo Elies Gomez: University of Leeds
Xin Hu: The University of Texas MD Anderson Cancer Center
Carolyn Hurst: University of Leeds
Thomas Hall: University of Leeds
Sujanitha Umamaheswaran: Anna University
Laura Wesley: University of Leeds
Mihai Gagea: The University of Texas MD Anderson Cancer Center, Unit 63
Michael Shires: St James’s University Hospital
Iain Manfield: University of Leeds
Margaret A. Knowles: University of Leeds
Simon Davies: University of Leeds
Klaus Suhling: King’s College London
Yurema Teijeiro Gonzalez: King’s College London
Neil Carragher: University of Edinburgh
Kenneth Macleod: University of Edinburgh
N. Joan Abbott: Franklin-Wilkins Building, King’s College London
George A. Calin: The University of Texas MD Anderson Cancer Center
Nikita Gamper: University of Leeds
Peter M. Zygmunt: Lund University
Zahra Timsah: University of Leeds

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00983-w

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