The tumor suppressor PP2A Abeta regulates the RalA GTPase.
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.
Sablina
Anna A
AA
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Chen
Wen
W
Arroyo
Jason D
JD
Corral
Laura
L
Hector
Melissa
M
Bulmer
Sara E
SE
DeCaprio
James A
JA
Hahn
William C
WC
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*
D009363:Neoplasm Proteins; C432785:PPP2R1B protein, human; D054648:Protein Phosphatase 2; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins