The tumor suppressor PP2A Aβ regulates the RaIA GTPase

The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme family that regulates numerous signaling pathways. Biallelic mutations of the structural PP2A A beta subunit occur in several types of human tumors; however, the functional consequences of these cancer-associated PP2A A beta mutations in cell transformation remain undefined. Here we show that suppression of PP2A A beta expression permits immortalized human cells to achieve a tumorigenic state. Cancer-associated A beta mutants fail to reverse tumorigenic phenotype induced by PP2A A beta suppression, indicating that these mutants function as null alleles. Wild-type PP2A A beta but not cancer-derived A beta mutants form a complex with the small GTPase RalA. PP2A A beta-containing complexes dephosphorylate RalA at Ser183 and Ser194, inactivating RalA and abolishing its transforming function. These observations identify PP2A A beta as a tumor suppressor gene that transforms immortalized human cells by regulating the function of RalA.