2. Academic Validation
  3. CNK2 promotes cancer cell motility by mediating ARF6 activation downstream of AXL signalling

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

  • Nat Commun. 2023 Jun 15;14(1):3560. doi: 10.1038/s41467-023-39281-z.
Guillaume Serwe # 1 2,  David Kachaner # 1,  Jessica Gagnon # 1 2,  Cédric Plutoni 1,  Driss Lajoie 1,  Eloïse Duramé 1 2,  Malha Sahmi 1,  Damien Garrido 1,  Martin Lefrançois 1,  Geneviève Arseneault 1,  Marc K Saba-El-Leil 1,  Sylvain Meloche 1 2 3,  Gregory Emery 1 2 4,  Marc Therrien 5 6 7
Affiliations

Affiliations

  • 1 Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada.
  • 2 Molecular Biology Program, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
  • 3 Department of Pharmacology and Physiology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
  • 4 Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
  • 5 Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada. marc.therrien@umontreal.ca.
  • 6 Molecular Biology Program, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada. marc.therrien@umontreal.ca.
  • 7 Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montréal, QC, Canada. marc.therrien@umontreal.ca.
  • # Contributed equally.
PMID: 37322019 DOI: 10.1038/s41467-023-39281-z
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.

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