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

Nat Commun. 2020 Jul 17;11(1):3586. doi: 10.1038/s41467-020-17415-x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Cell Line, Tumor
  • Cell Movement*
  • Focal Adhesions / genetics
  • Focal Adhesions / metabolism*
  • Humans
  • Neoplasm Invasiveness
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / physiopathology
  • Paxillin / genetics
  • Paxillin / metabolism
  • Phosphorylation
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • NEDD9 protein, human
  • PXN protein, human
  • Paxillin
  • Proto-Oncogene Proteins
  • PEAK1 protein, human
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • axl receptor tyrosine kinase