AXL confers cell migration and invasion by hijacking a PEAK1-regulated focal adhesion protein network

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, André Veillette, Roger J. Daly, Anne-Claude Gingras, Jean-Philippe Gratton and Jean-François Côté ()
Additional contact information
Afnan Abu-Thuraia: Montreal Clinical Research Institute (IRCM)
Marie-Anne Goyette: Montreal Clinical Research Institute (IRCM)
Jonathan Boulais: Montreal Clinical Research Institute (IRCM)
Carine Delliaux: Montreal Clinical Research Institute (IRCM)
Chloé Apcher: Montreal Clinical Research Institute (IRCM)
Céline Schott: Montreal Clinical Research Institute (IRCM)
Rony Chidiac: Université de Montréal
Halil Bagci: Montreal Clinical Research Institute (IRCM)
Marie-Pier Thibault: Montreal Clinical Research Institute (IRCM)
Dominique Davidson: Montreal Clinical Research Institute (IRCM)
Mathieu Ferron: Montreal Clinical Research Institute (IRCM)
André Veillette: Montreal Clinical Research Institute (IRCM)
Roger J. Daly: Monash University
Anne-Claude Gingras: Sinai Health System
Jean-Philippe Gratton: Université de Montréal
Jean-François Côté: Montreal Clinical Research Institute (IRCM)

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: Abstract Aberrant expression of receptor tyrosine kinase AXL is linked to metastasis. AXL can be activated by its ligand GAS6 or by other kinases, but the signaling pathways conferring its metastatic activity are unknown. Here, we define the AXL-regulated phosphoproteome in breast cancer cells. We reveal that AXL stimulates the phosphorylation of a network of focal adhesion (FA) proteins, culminating in faster FA disassembly. Mechanistically, AXL phosphorylates NEDD9, leading to its binding to CRKII which in turn associates with and orchestrates the phosphorylation of the pseudo-kinase PEAK1. We find that PEAK1 is in complex with the tyrosine kinase CSK to mediate the phosphorylation of PAXILLIN. Uncoupling of PEAK1 from AXL signaling decreases metastasis in vivo, but not tumor growth. Our results uncover a contribution of AXL signaling to FA dynamics, reveal a long sought-after mechanism underlying AXL metastatic activity, and identify PEAK1 as a therapeutic target in AXL positive tumors.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17415-x

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DOI: 10.1038/s41467-020-17415-x

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