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

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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.

Original languageEnglish
Article number3586
Number of pages20
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 17 Jul 2020

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