Synergistic inactivation of AXL: a (cross)road to cure ovarian cancer?
| Autor: | Chiara Zurzolo |
|---|---|
| Přispěvatelé: | Trafic membranaire et Pathogénèse, Institut Pasteur [Paris] (IP), The author is grateful to Simona Paladino and Stephanie Lebreton for the critical discussion of the literature and to all members of the Zurzolo laboratory for their work, enthusiasm and continuous support., ANR-16-CE16-0020,nicostress,Réseaux neuronaux sous-tendant l'intéraction entre stress et nicotine dans le cadre des troubles psychiatriques(2016), ANR-16-CE16-0019,Neurotunn,Role des nanotubes membranaires dans la propagation d'agrégats protéiques impliqués dans les maladie neurodégénératives(2016), Zurzolo, C., Institut Pasteur [Paris] |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Biochemistry Receptor tyrosine kinase law.invention Cell Movement law News & Views Phosphorylation Therapeutic strategy Ovarian Neoplasms biology Kinase Chemistry Receptor-Like Protein Tyrosine Phosphatases Class 5 GPI-Linked Protein 3. Good health Benzocycloheptenes MESH: Ovarian Neoplasms Cholesterol Treatment Outcome MESH: Cell Adhesion Molecules Intercellular Signaling Peptides and Proteins MESH: Phosphoric Monoester Hydrolases Female Protein Binding Human Cell Survival MAP Kinase Signaling System Phosphatase [SDV.CAN]Life Sciences [q-bio]/Cancer Phosphoric Monoester Hydrolase MESH: Receptor-Like Protein Tyrosine Phosphatases Class 5 GPI-Linked Proteins Malignancy Dephosphorylation 03 medical and health sciences Membrane Microdomains Cell Line Tumor Proto-Oncogene Proteins Genetics medicine Animals Humans Neoplasm Invasiveness Gene Silencing Molecular Biology Fallopian Tubes MESH: Humans Tumor Suppressor Proteins Ovarian Neoplasm Receptor Protein-Tyrosine Kinases Epithelial Cells Triazoles medicine.disease Axl Receptor Tyrosine Kinase Enzyme Activation MESH: Proto-Oncogene Proteins 030104 developmental biology Cell Adhesion Molecule Cancer research biology.protein Suppressor MESH: GPI-Linked Proteins Ovarian cancer Cell Adhesion Molecules Chickens MESH: Female |
| Zdroj: | EMBO Reports EMBO Reports, 2018, 19 (8), pp.e46492. ⟨10.15252/embr.201846492⟩ EMBO Reports, EMBO Press, 2018, 19 (8), pp.e46492. ⟨10.15252/embr.201846492⟩ |
| ISSN: | 1469-221X 1469-3178 |
| DOI: | 10.15252/embr.201846492⟩ |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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