The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer

EMBO Rep. 2018 Aug;19(8):e45670. doi: 10.15252/embr.201745670. Epub 2018 Jun 15.

Abstract

In ovarian cancer, the prometastatic RTK AXL promotes motility, invasion and poor prognosis. Here, we show that reduced survival caused by AXL overexpression can be mitigated by the expression of the GPI-anchored tumour suppressor OPCML Further, we demonstrate that AXL directly interacts with OPCML, preferentially so when AXL is activated by its ligand Gas6. As a consequence, AXL accumulates in cholesterol-rich lipid domains, where OPCML resides. Here, phospho-AXL is brought in proximity to the lipid domain-restricted phosphatase PTPRG, which de-phosphorylates the RTK/ligand complex. This prevents AXL-mediated transactivation of other RTKs (cMET and EGFR), thereby inhibiting sustained phospho-ERK signalling, induction of the EMT transcription factor Slug, cell migration and invasion. From a translational perspective, we show that OPCML enhances the effect of the phase II AXL inhibitor R428 in vitro and in vivo We therefore identify a novel mechanism by which two spatially restricted tumour suppressors, OPCML and PTPRG, coordinate to repress AXL-dependent oncogenic signalling.

Keywords: AXL; OPCML; PTPRG; ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axl Receptor Tyrosine Kinase
  • Benzocycloheptenes / pharmacology
  • Cell Adhesion Molecules / metabolism*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Chickens
  • Cholesterol / metabolism
  • Enzyme Activation / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Fallopian Tubes / pathology
  • Female
  • GPI-Linked Proteins / metabolism
  • Gene Silencing / drug effects
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Signaling System / drug effects
  • Membrane Microdomains / metabolism
  • Neoplasm Invasiveness
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5 / metabolism*
  • Treatment Outcome
  • Triazoles / pharmacology
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Benzocycloheptenes
  • Cell Adhesion Molecules
  • GPI-Linked Proteins
  • Intercellular Signaling Peptides and Proteins
  • OPCML protein, human
  • Proto-Oncogene Proteins
  • Triazoles
  • Tumor Suppressor Proteins
  • growth arrest-specific protein 6
  • bemcentinib
  • Cholesterol
  • Receptor Protein-Tyrosine Kinases
  • Receptor-Like Protein Tyrosine Phosphatases, Class 5
  • Axl Receptor Tyrosine Kinase