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

Berrout, Jonathan; Kyriakopoulou, Eleni; Moparthi, Lavanya LU ; Hogea, Alexandra S.; Berrout, Liza; Ivan, Cristina-Elena; Lorger, Mihaela; Boyle, John F.; Peers, Chris and Muench, Stephen, et al. (2017) In Nature Communications 8(1).
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... (More)

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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Nature Communications
volume
8
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85031787418
  • wos:000412999700015
ISSN
2041-1723
DOI
10.1038/s41467-017-00983-w
language
English
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yes
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81021cf5-a69b-40d6-94d6-6cfda6ae0972
date added to LUP
2017-10-30 13:20:55
date last changed
2018-01-16 13:24:49
@article{81021cf5-a69b-40d6-94d6-6cfda6ae0972,
  abstract     = {<p>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.</p>},
  articleno    = {983},
  author       = {Berrout, Jonathan and Kyriakopoulou, Eleni and Moparthi, Lavanya and Hogea, Alexandra S. and Berrout, Liza and Ivan, Cristina-Elena and Lorger, Mihaela and Boyle, John F. and Peers, Chris and Muench, Stephen and Gomez, Jacobo Elies and Hu, Xin and Hurst, Carolyn and Hall, Thomas and Umamaheswaran, Sujanitha and Wesley, Laura and Gagea, Mihai and Shires, Michael and Manfield, Iain and Knowles, Margaret A. and Davies, Simon and Suhling, Klaus and Gonzalez, Yurema Teijeiro and Carragher, Neil and Macleod, Kenneth G. and Abbott, N Joan and Calin, George A and Gamper, Nikita and Zygmunt, Peter M. and Timsah, Zahra},
  issn         = {2041-1723},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {TRPA1-FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p},
  url          = {http://dx.doi.org/10.1038/s41467-017-00983-w},
  volume       = {8},
  year         = {2017},
}