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

• Published in: Nature communications Vol. 11; no. 1; pp. 3586 - 20
• Main Authors: Abu-Thuraia, Afnan, Goyette, Marie-Anne, Boulais, Jonathan, Delliaux, Carine, Apcher, Chloé, Schott, Céline, Chidiac, Rony, Bagci, Halil, Thibault, Marie-Pier, Davidson, Dominique, Ferron, Mathieu, Veillette, André, Daly, Roger J., Gingras, Anne-Claude, Gratton, Jean-Philippe, Côté, Jean-François
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/95; 14/19; 42/41; 59/5; 631/114; 631/337; 631/45; 631/67; 631/80; 64/60; 82/58; 82/80; Adhesion; Axl protein; Breast cancer; Cell adhesion & migration; Cell migration; Humanities and Social Sciences; Kinases; Metastases; Metastasis; multidisciplinary; Paxillin; Phosphorylation; Protein-tyrosine kinase receptors; Proteins; Receptors; Science; Science (multidisciplinary); Signaling; Therapeutic applications; Tumors; Tyrosine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17415-x

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. AXL receptor tyrosine kinase has a role in metastasis but the mechanism is unclear. In this study, the authors show that AXL activation can control focal adhesion dynamics via PEAK1 and that AXL-mediated PEAK1 phosphorylation is required for metastasis of triple negative breast cancer cells in vivo.