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CNK2 promotes cancer cell motility by mediating ARF6 activation downstream of AXL signalling

Author

Listed:
  • Guillaume Serwe

    (Université de Montréal
    Université de Montréal)

  • David Kachaner

    (Université de Montréal)

  • Jessica Gagnon

    (Université de Montréal
    Université de Montréal)

  • Cédric Plutoni

    (Université de Montréal)

  • Driss Lajoie

    (Université de Montréal)

  • Eloïse Duramé

    (Université de Montréal
    Université de Montréal)

  • Malha Sahmi

    (Université de Montréal)

  • Damien Garrido

    (Université de Montréal)

  • Martin Lefrançois

    (Université de Montréal)

  • Geneviève Arseneault

    (Université de Montréal)

  • Marc K. Saba-El-Leil

    (Université de Montréal)

  • Sylvain Meloche

    (Université de Montréal
    Université de Montréal
    Université de Montréal)

  • Gregory Emery

    (Université de Montréal
    Université de Montréal
    Université de Montréal)

  • Marc Therrien

    (Université de Montréal
    Université de Montréal
    Université de Montréal)

Abstract

Cell motility is a critical feature of invasive tumour cells that is governed by complex signal transduction events. Particularly, the underlying mechanisms that bridge extracellular stimuli to the molecular machinery driving motility remain partially understood. Here, we show that the scaffold protein CNK2 promotes cancer cell migration by coupling the pro-metastatic receptor tyrosine kinase AXL to downstream activation of ARF6 GTPase. Mechanistically, AXL signalling induces PI3K-dependent recruitment of CNK2 to the plasma membrane. In turn, CNK2 stimulates ARF6 by associating with cytohesin ARF GEFs and with a novel adaptor protein called SAMD12. ARF6-GTP then controls motile forces by coordinating the respective activation and inhibition of RAC1 and RHOA GTPases. Significantly, genetic ablation of CNK2 or SAMD12 reduces metastasis in a mouse xenograft model. Together, this work identifies CNK2 and its partner SAMD12 as key components of a novel pro-motility pathway in cancer cells, which could be targeted in metastasis.

Suggested Citation

  • Guillaume Serwe & David Kachaner & Jessica Gagnon & Cédric Plutoni & Driss Lajoie & Eloïse Duramé & Malha Sahmi & Damien Garrido & Martin Lefrançois & Geneviève Arseneault & Marc K. Saba-El-Leil & Syl, 2023. "CNK2 promotes cancer cell motility by mediating ARF6 activation downstream of AXL signalling," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39281-z
    DOI: 10.1038/s41467-023-39281-z
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    References listed on IDEAS

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    1. Afnan Abu-Thuraia & Marie-Anne Goyette & Jonathan Boulais & Carine Delliaux & Chloé Apcher & Céline Schott & Rony Chidiac & Halil Bagci & Marie-Pier Thibault & Dominique Davidson & Mathieu Ferron & An, 2020. "AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network," Nature Communications, Nature, vol. 11(1), pages 1-20, December.
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    3. Sandrine Etienne-Manneville & Alan Hall, 2002. "Rho GTPases in cell biology," Nature, Nature, vol. 420(6916), pages 629-635, December.
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