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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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, 2017. "TRPA1–FGFR2 binding event is a regulatory oncogenic driver modulated by miRNA-142-3p," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00983-w
    DOI: 10.1038/s41467-017-00983-w
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    Cited by:

    1. Lavanya Moparthi & Viktor Sinica & Vamsi K. Moparthi & Mohamed Kreir & Thibaut Vignane & Milos R. Filipovic & Viktorie Vlachova & Peter M. Zygmunt, 2022. "The human TRPA1 intrinsic cold and heat sensitivity involves separate channel structures beyond the N-ARD domain," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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