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

• Published in: EMBO reports Vol. 19; no. 8
• Main Authors: Antony, Jane, Zanini, Elisa, Kelly, Zoe, Tan, Tuan Zea, Karali, Evdoxia, Alomary, Mohammad, Jung, Youngrock, Nixon, Katherine, Cunnea, Paula, Fotopoulou, Christina, Paterson, Andrew, Roy‐Nawathe, Sushmita, Mills, Gordon B, Huang, Ruby Yun‐Ju, Thiery, Jean Paul, Gabra, Hani, Recchi, Chiara
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2018; Springer Nature B.V; John Wiley and Sons Inc
• Subjects: Animals; AXL; Axl protein; Benzocycloheptenes - pharmacology; Cancer; Cell Adhesion Molecules - metabolism; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cell Survival - drug effects; Chickens; Cholesterol; Cholesterol - metabolism; Coordination compounds; Deactivation; EMBO03; EMBO37; Enzyme Activation - drug effects; Epidermal growth factor receptors; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Fallopian Tubes - pathology; Female; Gene Silencing - drug effects; GPI-Linked Proteins - metabolism; Humans; Inactivation; Intercellular Signaling Peptides and Proteins - metabolism; Ligands; Lipids; MAP Kinase Signaling System - drug effects; Medical prognosis; Membrane Microdomains - metabolism; Motility; Neoplasm Invasiveness; OPCML; Ovarian cancer; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Phosphatase; Phosphorylation - drug effects; Protein Binding - drug effects; Proto-Oncogene Proteins - metabolism; PTPRG; Receptor Protein-Tyrosine Kinases - metabolism; Receptor-Like Protein Tyrosine Phosphatases, Class 5 - metabolism; Signaling; Suppressors; Treatment Outcome; Triazoles - pharmacology; Tumor Suppressor Proteins - metabolism; Tumors; AXL; ovarian cancer; OPCML; PTPRG
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.201745670

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. Synopsis The GPI‐anchored tumour suppressor OPCML interacts with the oncogenic RTK AXL inducing its redistribution into cholesterol‐rich membrane domains. There, AXL is de‐phosphorylated by the resident phosphatase PTPRG, inhibiting AXL‐dependent signalling, motility and invasion. Binding of Gas6 to the oncogenic RTK AXL promotes its interaction with the tumour suppressor OPCML. The Gas6/AXL/OPCML complex accumulates in cholesterol‐rich lipid domains, where the phosphatase PTPRG de‐phosphorylates AXL. The coordinated action of OPCML and PTPRG blocks AXL signalling and inhibits Gas6‐stimulated motility and invasion in ovarian cancer cells. Graphical Abstract The GPI‐anchored tumour suppressor OPCML interacts with the oncogenic RTK AXL inducing its redistribution into cholesterol‐rich membrane domains. There, AXL is de‐phosphorylated by the resident phosphatase PTPRG, inhibiting AXL‐dependent signalling, motility and invasion.