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

The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer
Title:
The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer
Other Titles:
EMBO Reports
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Publication Date:
15 June 2018
Citation:
EMBO Rep (2018)19:e45670
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.
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Funding Info:
We would like to thank Dr. Vladimir Pelicic, Dr. Elaina Maginn and Dr. Christophe Lamaze for critical reading of the manuscript. This project was funded by Ovarian Cancer Action, and infrastructure support was provided by Imperial Experimental Cancer Medicine Centre, Cancer Research UK Imperial Centre, National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC) and Imperial College Healthcare NHS Trust Tissue Bank. J.A. was funded by NUS Graduate School for the Integrated Sciences and Engineering, National University of Singapore. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.
Description:
The full paper is available for download at the publisher's URL: https://doi.org/10.15252/embr.201745670
ISSN:
1469-221X
1469-3178
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