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

Jane Antony, Elisa Zanini, Zoe Kelly, Tuan Zea Tan, Evdoxia Karali, Mohammad Alomary, Youngrock Jung, Katherine Nixon, Paula Cunnea, Christina Fotopoulou, Andrew Paterson, Sushmita Roy-Nawathe, Gordon Mills, Ruby Yun Ju Huang, Jean Paul Thiery, Hani Gabra, Chiara Recchi

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Article numbere45670
JournalEMBO Reports
Volume19
Issue number8
DOIs
StatePublished - Aug 1 2018
Externally publishedYes

Keywords

  • AXL
  • OPCML
  • ovarian cancer
  • PTPRG

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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    Antony, J., Zanini, E., Kelly, Z., Tan, T. Z., Karali, E., Alomary, M., Jung, Y., Nixon, K., Cunnea, P., Fotopoulou, C., Paterson, A., Roy-Nawathe, S., Mills, G., Huang, R. Y. J., Thiery, J. P., Gabra, H., & Recchi, C. (2018). The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer. EMBO Reports, 19(8), [e45670]. https://doi.org/10.15252/embr.201745670