TY - JOUR
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
N1 - Publisher Copyright:
© 2017 The Author(s).
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
C2 - 29038531
AN - SCOPUS:85031787418
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 947
ER -