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 & 

 Jean-François Côté 

Nature Communications volume 11, Article number: 3586 (2020) 

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.