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

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Title: The tumour suppressor OPCML promotes AXL inactivation by the phosphatase PTPRG in ovarian cancer
Authors: Antony, J
Zanini, E
Kelly, Z
Tan, TZ
Karali, E
Alomary, M
Jung, Y
Nixon, K
Cunnea, P
Fotopoulou, C
Paterson, A
Roy-Nawathe, S
Mills, GB
Huang, RY-J
Thiery, JP
Gabra, H
Recchi, C
Item Type: Journal Article
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.
Issue Date: 1-Aug-2018
Date of Acceptance: 23-May-2018
URI: http://hdl.handle.net/10044/1/60882
DOI: https://dx.doi.org/10.15252/embr.201745670
ISSN: 1469-221X
Publisher: EMBO Press
Journal / Book Title: EMBO Reports
Volume: 19
Issue: 8
Copyright Statement: © 2018 The Authors. Published by EMBO Press.
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
AXL
OPCML
ovarian cancer
PTPRG
RECEPTOR TYROSINE KINASES
EPITHELIAL-MESENCHYMAL TRANSITION
THERAPEUTIC TARGET
MEMBRANE
RESISTANCE
INVASION
NETWORKS
FAMILY
GROWTH
GAMMA
AXL
OPCML
PTPRG
ovarian cancer
Animals
Benzocycloheptenes
Cell Adhesion Molecules
Cell Line, Tumor
Cell Movement
Cell Survival
Chickens
Cholesterol
Enzyme Activation
Epithelial Cells
Fallopian Tubes
Female
GPI-Linked Proteins
Gene Silencing
Humans
Intercellular Signaling Peptides and Proteins
MAP Kinase Signaling System
Membrane Microdomains
Neoplasm Invasiveness
Ovarian Neoplasms
Phosphorylation
Protein Binding
Proto-Oncogene Proteins
Receptor Protein-Tyrosine Kinases
Receptor-Like Protein Tyrosine Phosphatases, Class 5
Treatment Outcome
Triazoles
Tumor Suppressor Proteins
Fallopian Tubes
Cell Line, Tumor
Membrane Microdomains
Epithelial Cells
Animals
Chickens
Humans
Ovarian Neoplasms
Neoplasm Invasiveness
Triazoles
Benzocycloheptenes
Cholesterol
Receptor Protein-Tyrosine Kinases
Intercellular Signaling Peptides and Proteins
Cell Adhesion Molecules
Proto-Oncogene Proteins
Tumor Suppressor Proteins
Treatment Outcome
Cell Movement
Cell Survival
MAP Kinase Signaling System
Gene Silencing
Enzyme Activation
Protein Binding
Phosphorylation
Female
Receptor-Like Protein Tyrosine Phosphatases, Class 5
GPI-Linked Proteins
AXL
OPCML
PTPRG
ovarian cancer
0601 Biochemistry and Cell Biology
Developmental Biology
Publication Status: Published
Conference Place: England
Article Number: e45670
Online Publication Date: 2018-06-15
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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