title: Greatwall promotes cell transformation by hyperactivating AKT in human malignancies.
abstract: The PP2A phosphatase is often inactivated in cancer and is considered as a tumour suppressor. A new pathway controlling PP2A activity in mitosis has been recently described. This pathway includes the Greatwall (GWL) kinase and its substrates endosulfines. At mitotic entry, GWL is activated and phosphorylates endosulfines that then bind and inhibit PP2A. We analysed whether GWL overexpression could participate in cancer development. We show that GWL overexpression promotes cell transformation and increases invasive capacities of cells through hyperphosphorylation of the oncogenic kinase AKT. Interestingly, AKT hyperphosphorylation induced by GWL is independent of endosulfines. Rather, GWL induces GSK3 kinase dephosphorylation in its inhibitory sites and subsequent SCF-dependent degradation of the PHLPP phosphatase responsible for AKT dephosphorylation. In line with its oncogenic activity, we find that GWL is often overexpressed in human colorectal tumoral tissues. Thus, GWL is a human oncoprotein that promotes the hyperactivation of AKT via the degradation of its phosphatase, PHLPP, in human malignancies.
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Université de Montpellier, Montpellier, France.
authors.forename: Jorge
authors.initials: J
authors.lastname: Vera
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Institut National de la Santé et de la Recherche Medicale, Université Bordeaux Segalen, Bordeux, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Lartigue
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Université de Montpellier, Montpellier, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Vigneron
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Université de Montpellier, Montpellier, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gadea
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Université de Montpellier, Montpellier, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Gire
authors.affiliation: Institut de Recherche en Cancérologie de Montpellier, Université de Montpellier, Montpellier, France.
authors.forename: Maguy
authors.initials: M
authors.lastname: Del Rio
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Institut National de la Santé et de la Recherche Medicale, Université Bordeaux Segalen, Bordeux, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Soubeyran
authors.affiliation: Department of Medical Oncology, Institut Bergonié, Institut National de la Santé et de la Recherche Medicale, Université Bordeaux Segalen, Bordeux, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Chibon
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Université de Montpellier, Montpellier, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lorca
authors.affiliation: Centre de Recherche de Biochimie Macromoléculaire, Université de Montpellier, Montpellier, France.
authors.forename: Anna
authors.initials: A
authors.lastname: Castro
mesh_terms: D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D010455:Peptides; C075663:endosulfine; D044843:SKP Cullin F-Box Protein Ligases; C555237:MASTL protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases
keywords: Akt; Greatwall; PHLPP; PP2A; cell biology; cell invasion; human; oncogene