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EMBO Rep. 2018 Jun 15. pii: e45670. doi: 10.15252/embr.201745670. [Epub ahead of print]

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

Author information

1
Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London, London, UK.
2
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
3
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore.
4
Division of Basic Science Research, Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
5
Department of Obstetrics and Gynecology, National University Health System, Singapore, Singapore.
6
Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.
7
Department of Biochemistry, National University of Singapore, Singapore, Singapore.
8
Department of Surgery and Cancer, Ovarian Cancer Action Research Centre, Imperial College London, London, UK h.gabra@imperial.ac.uk c.recchi@imperial.ac.uk.
9
Early Clinical Development, IMED Biotech Unit, AstraZeneca, Cambridge, UK.

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

PMID:
29907679
DOI:
10.15252/embr.201745670

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