title: Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth.
abstract: Somatic missense mutations in the Ser/Thr protein phosphatase 2A (PP2A) Aα scaffold subunit gene PPP2R1A are among the few genomic alterations that occur frequently in serous endometrial carcinoma (EC) and carcinosarcoma, two clinically aggressive subtypes of uterine cancer with few therapeutic options. Previous studies reported that cancer-associated Aα mutants exhibit defects in binding to other PP2A subunits and contribute to cancer development by a mechanism of haploinsufficiency. Here we report on the functional significance of the most recurrent PPP2R1A mutations in human EC, which cluster in Aα HEAT repeats 5 and 7. Beyond predicted loss-of-function effects on the formation of a subset of PP2A holoenzymes, we discovered that Aα mutants behave in a dominant-negative manner due to gain-of-function interactions with the PP2A inhibitor TIPRL1. Dominant-negative Aα mutants retain binding to specific subunits of the B56/B' family and form substrate trapping complexes with impaired phosphatase activity via increased recruitment of TIPRL1. Accordingly, overexpression of the Aα mutants in EC cells harboring wild-type PPP2R1A increased anchorage-independent growth and tumor formation, and triggered hyperphosphorylation of oncogenic PP2A-B56/B' substrates in the GSK3β, Akt, and mTOR/p70S6K signaling pathways. TIPRL1 silencing restored GSK3β phosphorylation and rescued the EC cell growth advantage. Our results reveal how PPP2R1A mutations affect PP2A function and oncogenic signaling, illuminating the genetic basis for serous EC development and its potential control by rationally targeted therapies. Cancer Res; 76(19); 5719-31. ©2016 AACR.
authors.affiliation: Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Dorien
authors.initials: D
authors.lastname: Haesen
authors.affiliation: VIB Center for the Biology of Disease, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Layka
authors.initials: L
authors.lastname: Abbasi Asbagh
authors.affiliation: Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Rita
authors.initials: R
authors.lastname: Derua
authors.affiliation: Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Antoine
authors.initials: A
authors.lastname: Hubert
authors.affiliation: Laboratory of Gynaecological Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schrauwen
authors.affiliation: Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Yana
authors.initials: Y
authors.lastname: Hoorne
authors.affiliation: Laboratory of Gynaecological Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
authors.affiliation: Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Waelkens
authors.affiliation: VIB Center for the Biology of Disease, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Anna
authors.initials: A
authors.lastname: Sablina
authors.affiliation: Laboratory of Protein Phosphorylation and Proteomics, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. veerle.janssens@kuleuven.be.
authors.forename: Veerle
authors.initials: V
authors.lastname: Janssens
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018284:Cystadenocarcinoma, Serous / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D051379:Mice; D020125:Mutation, Missense; D054648:Protein Phosphatase 2 / Q000235:genetics*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C517191:PPP2R1A protein, human; C577326:TIPRL protein, human; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D054648:Protein Phosphatase 2