title: ATM-mediated phosphorylation activates the tumor-suppressive function of B56γ-PP2A.
abstract: Protein phosphatase 2A (PP2A) is a family of heterotrimeric protein phosphatases that has a multitude of functions inside the cell, acting through various substrate targets in cell-signaling pathways. Recent evidence suggests that a subset of PP2A holoenzymes function as tumor suppressors and one particular family of B subunits, B56, are implicated in this function. However, the regulatory mechanisms that govern activation of B56-PP2A tumor-suppressive function have not been elucidated. In the present study, we demonstrate that ataxia-telangiectasia mutated (ATM) directly phosphorylates and specifically regulates B56γ3, B56γ2 and B56δ, after DNA damage. We further show that phosphorylation of B56γ3 at Ser510 leads to an increase in B56γ3-PP2A complexes, and direction of PP2A phosphatase activity toward the substrate p53, activating its tumor-suppressive functions. In addition, we found that under cell growth conditions B56γ3 is kept at low levels through the actions of the E3 ubiquitin ligase MDM2, and, importantly, phosphorylation of B56γ3 by ATM leads to upregulation of the protein by blocking MDM2-mediated B56γ3 ubiquitination. Finally, we show that Ser510 phosphorylation significantly enhances the ability of B56γ3 to inhibit cell proliferation and anchorage-independent growth. These results provide mechanistic insight into the regulation of PP2A tumor-suppressive function, and suggest a model for parallel regulation of p53 and B56γ3.
authors: Department of Biochemistry, University of California, Riverside, USA.
authors: G P
authors: GP
authors: Shouse
authors: Y
authors: Y
authors: Nobumori
authors: M J
authors: MJ
authors: Panowicz
authors: X
authors: X
authors: Liu
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D013912:Threonine; D012694:Serine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C503981:PPP2R5C protein, human; D054648:Protein Phosphatase 2