title: The tumor suppressor PP2A Abeta regulates the RalA GTPase.
abstract: The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme family that regulates numerous signaling pathways. Biallelic mutations of the structural PP2A Abeta subunit occur in several types of human tumors; however, the functional consequences of these cancer-associated PP2A Abeta mutations in cell transformation remain undefined. Here we show that suppression of PP2A Abeta expression permits immortalized human cells to achieve a tumorigenic state. Cancer-associated Abeta mutants fail to reverse tumorigenic phenotype induced by PP2A Abeta suppression, indicating that these mutants function as null alleles. Wild-type PP2A Abeta but not cancer-derived Abeta mutants form a complex with the small GTPase RalA. PP2A Abeta-containing complexes dephosphorylate RalA at Ser183 and Ser194, inactivating RalA and abolishing its transforming function. These observations identify PP2A Abeta as a tumor suppressor gene that transforms immortalized human cells by regulating the function of RalA.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Anna A
authors.initials: AA
authors.lastname: Sablina
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.forename: Jason D
authors.initials: JD
authors.lastname: Arroyo
authors.forename: Laura
authors.initials: L
authors.lastname: Corral
authors.forename: Melissa
authors.initials: M
authors.lastname: Hector
authors.forename: Sara E
authors.initials: SE
authors.lastname: Bulmer
authors.forename: James A
authors.initials: JA
authors.lastname: DeCaprio
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D000483:Alleles; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D020725:ral GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; C432785:PPP2R1B protein, human; D054648:Protein Phosphatase 2; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins