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

Afnan Abu-Thuraia1,2, Marie-Anne Goyette1,2, Jonathan Boulais1

  • 1Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada.

Nature Communications
|July 19, 2020
PubMed

Insights

Aberrant AXL receptor tyrosine kinase signaling drives breast cancer metastasis by promoting focal adhesion disassembly. Targeting PEAK1 kinase may inhibit AXL-driven cancer spread.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Aberrant expression of receptor tyrosine kinase AXL is implicated in cancer metastasis.
  • The specific signaling pathways through which AXL promotes metastasis remain largely undefined.

Purpose of the Study:

  • To elucidate the AXL-regulated phosphoproteome in breast cancer cells.
  • To identify the molecular mechanisms linking AXL signaling to cancer metastasis.

Main Methods:

  • Phosphoproteomic analysis of breast cancer cells.
  • Co-immunoprecipitation assays to identify protein complexes.
  • In vivo metastasis assays.

Main Results:

  • AXL activation phosphorylates focal adhesion proteins, accelerating focal adhesion disassembly.
  • AXL signaling phosphorylates NEDD9, which binds CRKII, leading to PEAK1 phosphorylation.
  • PEAK1, in complex with CSK, phosphorylates PAXILLIN, promoting metastasis.
  • Disrupting the PEAK1-AXL interaction reduces metastasis but not tumor growth.

Conclusions:

  • AXL signaling contributes to focal adhesion dynamics and cancer cell metastasis.
  • A novel signaling axis involving AXL, NEDD9, CRKII, PEAK1, CSK, and PAXILLIN mediates AXL's metastatic activity.
  • PEAK1 represents a potential therapeutic target for AXL-positive tumors.

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