title: ROS-mediated EB1 phosphorylation through Akt/GSK3β pathway: implication in cancer cell response to microtubule-targeting agents.
abstract: Microtubule-targeting agents (MTAs) are largely administered in adults and children cancers. Better deciphering their mechanism of action is of prime importance to develop more convenient therapy strategies. Here, we addressed the question of how reactive oxygen species (ROS) generation by mitochondria can be necessary for MTA efficacy. We showed for the first time that EB1 associates with microtubules in a phosphorylation-dependent manner, under control of ROS. By using phospho-defective mutants, we further characterized the Serine 155 residue as critical for EB1 accumulation at microtubule plus-ends, and both cancer cell migration and proliferation. Phosphorylation of EB1 on the Threonine 166 residue triggered opposite effects, and was identified as a requisite molecular switch in MTA activities. We then showed that GSK3β activation was responsible for MTA-triggered EB1 phosphorylation, resulting from ROS-mediated inhibition of upstream Akt. We thus disclosed here a novel pathway by which generation of mitochondrial ROS modulates microtubule dynamics through phosphorylation of EB1, improving our fundamental knowledge about this oncogenic protein, and pointing out the need to re-examine the current dogma of microtubule targeting by MTAs. The present work also provides a strong mechanistic rational to the promising therapeutic strategies that currently combine MTAs with anti-Akt targeted therapies.
authors.affiliation: Aix Marseille Université, Inserm, CRO2 UMR_S 911, Marseille, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Le Grand
authors.forename: Amandine
authors.initials: A
authors.lastname: Rovini
authors.forename: Veronique
authors.initials: V
authors.lastname: Bourgarel-Rey
authors.forename: Stephane
authors.initials: S
authors.lastname: Honore
authors.forename: Sonia
authors.initials: S
authors.lastname: Bastonero
authors.forename: Diane
authors.initials: D
authors.lastname: Braguer
authors.forename: Manon
authors.initials: M
authors.lastname: Carre
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D019084:Fluorescent Antibody Technique, Indirect; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C500985:MAPRE1 protein, human; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; D050257:Tubulin Modulators; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3