The Tumor Suppressor PP2A Aβ 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.

PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail)

“…These biochemical data can be explained in light of recent structural findings: Glu64 forms a hydrogen bond with the Ca C terminus, thereby stabilizing the A-PR61/B 0 g1 interface [36,37] (see Box 1, Figure Ib), Arg418 maps to the A-C interface and forms a hydrogen bond with Glu67 of Ca [34,36]. In addition, partial knockdown of the Aa subunit results in selective loss of PP2A holoenzymes containing the PR61/B 0 g subunit [29,30], rendering cells tumorigenic via increased Ser62 phosphorylation and stabilization of c-Myc [5,29,30]. The overexpression of Aa harboring cancerderived mutations cannot rescue this phenotype [29].…”

“…Similar to Aa, Ab subunits harboring cancer-derived mutations display diminished capacity to bind to the C-or specific B-type subunits [30,39] and fail to rescue the transformed phenotype of cells caused by reduced Ab levels [30]. Aa expression also fails to revert the Abdependent phenotype, indicating that Aa and Ab prevent cell transformation via distinct mechanisms.…”

“…Aa expression also fails to revert the Abdependent phenotype, indicating that Aa and Ab prevent cell transformation via distinct mechanisms. For Ab, this involves complex formation with and dephosphorylation of the small GTPase RalA [30]. Cancer-associated mutations have also been identified in PPP2R5C, which encodes PR61/B 0 g. In melanoma, an N-terminally truncated form of PR61/B 0 g1 is associated with increased metastasis and genetic instability [3] owing to impaired phosphatase activity towards paxillin and Hdm2 (human homolog of double minute 2), two proteins involved in oncogenic signaling pathways [3,36].…”

High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids

“…Loss of BTG4 is a common event in chronic lymphocytic leukaemia, and epigenetic silencing of BTG4 by CpG island methylation occurs in colorectal cancer (Auer et al 2005, Toyota et al 2008. PPP2R1B regulates RaIA GTPase and inhibits cell growth (Sablina et al 2007). Inactivation of PPP2R1B by downregulation, or mutation, has been demonstrated in B-cell chronic lymphocytic leukaemia, lung cancer and colon cancer (Wang et al 1998).…”

Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation

“…However, we and others have determined that Ral growth regulatory activities are regulated by phosphorylation. Hahn and colleagues showed that serine-threonine protein phosphatase 2A dephosphorylation of RalA at S183 and S194 abolished RalA transforming activity (8). Two other studies determined that S194 could be phosphorylated by Aurora A and that this phosphorylation was essential for RalA transforming activity (9) and RalA-dependent PDAC anchorage-independent and tumorigenic growth (10).…”