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

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, Sylvain Meloche, Gregory Emery and Marc Therrien ()
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Guillaume Serwe: Université de Montréal
David Kachaner: Université de Montréal
Jessica Gagnon: Université de Montréal
Cédric Plutoni: Université de Montréal
Driss Lajoie: Université de Montréal
Eloïse Duramé: 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
Gregory Emery: Université de Montréal
Marc Therrien: Université de Montréal

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39281-z

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