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; Zahra Timsah

doi:10.1038/s41467-017-00983-w

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^*

^*Corresponding author for this work

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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 language	English
Article number	983
Pages (from-to)	1-15
Journal	Nature Communications
Volume	8
Issue number	1
Early online date	16 Oct 2017
DOIs	https://doi.org/10.1038/s41467-017-00983-w
Publication status	Published - 1 Dec 2017

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TRPA1–FGFR2 binding event_BERROUT_Publishedonline16October2017_GOLD VoR (CC BY)Final published version, 3.49 MBLicence: CC BY

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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), 1-15. Article 983. https://doi.org/10.1038/s41467-017-00983-w

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title = "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.",

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

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doi = "10.1038/s41467-017-00983-w",

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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 2017, 'TRPA1-FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p', Nature Communications, vol. 8, no. 1, 983, pp. 1-15. https://doi.org/10.1038/s41467-017-00983-w

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T1 - TRPA1-FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p

AU - Berrout, Jonathan

AU - Kyriakopoulou, Eleni

AU - Moparthi, Lavanya

AU - Hogea, Alexandra S.

AU - Berrout, Liza

AU - Ivan, Cristina

AU - Lorger, Mihaela

AU - Boyle, John

AU - Peers, Chris

AU - Muench, Stephen

AU - Gomez, Jacobo Elies

AU - Hu, Xin

AU - Hurst, Carolyn

AU - Hall, Thomas

AU - Umamaheswaran, Sujanitha

AU - Wesley, Laura

AU - Gagea, Mihai

AU - Shires, Michael

AU - Manfield, Iain

AU - Knowles, Margaret A.

AU - Davies, Simon

AU - Suhling, Klaus

AU - Gonzalez, Yurema Teijeiro

AU - Carragher, Neil

AU - Macleod, Kenneth

AU - Abbott, N. Joan

AU - Calin, George A.

AU - Gamper, Nikita

AU - Zygmunt, Peter M.

AU - Timsah, Zahra

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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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U2 - 10.1038/s41467-017-00983-w

DO - 10.1038/s41467-017-00983-w

M3 - Article

AN - SCOPUS:85031787418

SN - 2041-1723

VL - 8

SP - 1

EP - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 983

ER -

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

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