title: Identification of PP2A complexes and pathways involved in cell transformation.
abstract: The simian virus 40 small t (SV40ST) oncoprotein interacts with protein phosphatase 2A (PP2A), an abundantly expressed family of serine-threonine phosphatases. This interaction is essential for the transformation of human cells by SV40, and several PP2A subunits have been implicated as tumor suppressor genes. However, the pathways controlled by specific PP2A complexes involved in cell transformation remain incompletely understood. Using a comprehensive loss-of-function approach, we identified 4 PP2A regulatory subunits [B56α, B56γ, PR72/PR130, and PTPA (protein phosphatase 2A activator)], which when suppressed replaced the expression of SV40ST in human cell transformation. We found that manipulation of complexes containing PP2A B56α, B56γ, and PR72/PR130 activates the pathways regulated by c-Myc, Wnt, and PI3K (phosphoinositide 3-kinase)/Akt in a manner that depends on their specific phosphatase activity. In contrast, suppression of PTPA disrupts the assembly of PP2A heterotrimeric complexes, which leads to the activation of these same oncogenic pathways. These observations delineate the PP2A family members and pathways perturbed by SV40ST during human cell transformation.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. Anna.Sablina@cme.vib-kuleuven.be
authors.forename: Anna A
authors.initials: AA
authors.lastname: Sablina
authors.forename: Melissa
authors.initials: M
authors.lastname: Hector
authors.forename: Nathalie
authors.initials: N
authors.lastname: Colpaert
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits; D011506:Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C489427:MYC protein, human; D021122:Protein Subunits; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; C087440:PTPA protein, human