Circumventing Cellular Control of PP2A by Methylation Promotes Transformation in an Akt-Dependent Manner

• Published in: Neoplasia (New York, N.Y.) Vol. 14; no. 7; pp. 585 - 599
• Main Authors: Jackson, Jennifer B, Pallas, David C
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2012; Elsevier
• Subjects: Antigens, Polyomavirus Transforming - chemistry; Antigens, Polyomavirus Transforming - metabolism; Carboxylic Ester Hydrolases - genetics; Carboxylic Ester Hydrolases - metabolism; Cell Line; Cell Proliferation; Cell Size; Cell Survival; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Enzyme Activation - genetics; Gene Expression Regulation; Humans; Methylation; Oncology; Polyomavirus; Protein Multimerization; Protein O-Methyltransferase - genetics; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Ribosomal Protein S6 Kinases - metabolism; RNA Interference; Signal Transduction; Simian virus 40; LCMT-1; PME-1; polyomavirus middle tumor antigen; small hairpin RNA; protein phosphatase methylesterase 1; dominant interfering Akt mutant (T308A/S473A); shRNA; protein phosphatase 2A; LCMT-1 shRNA; leucine carboxyl methyltransferase 1; polyomavirus small tumor antigen; SVST; PP2A C subunit; Akt-AA; L3; S6 kinase; S6K; PP2A; PyST; VC; vector control; rpS6; ribosomal protein S6; PyMT; PP2Ac; simian virus 40 small tumor antigen
• ISSN: 1476-5586; 1522-8002; 1476-5586; 1522-8002
• DOI: 10.1593/neo.12768

Abstract Heterotrimeric protein phosphatase 2A (PP2A) consists of catalytic C (PP2Ac), structural A, and regulatory B-type subunits, and its dysfunction has been linked to cancer. Reversible methylation of PP2Ac by leucine carboxyl methyltransferase 1 (LCMT-1) and protein phosphatase methylesterase 1 (PME-1) differentially regulates B-type subunit binding and thus PP2A function. Polyomavirus middle (PyMT) and small (PyST) tumor antigens and SV40 small tumor antigen (SVST) are oncoproteins that block PP2A function by replacing certain B-type subunits, resulting in cellular transformation. Whereas the B-type subunits replaced by these oncoproteins seem to exhibit a binding preference for methylated PP2Ac, PyMT does not. We hypothesize that circumventing the normal cellular control of PP2A by PP2Ac methylation is a general strategy for ST- and MT-mediated transformation. Two predictions of this hypothesis are (1) that PyST and SVST also bind PP2A in a methylation-insensitive manner and (2) that down-regulation of PP2Ac methylation will activate progrowth and prosurvival signaling and promote transformation. We found that SVST and PyST, like PyMT, indeed form PP2A heterotrimers independently of PP2Ac methylation. In addition, reducing PP2Ac methylation through LCMT-1 knockdown or PME-1 overexpression enhanced transformation by activating the Akt and p70/p85 S6 kinase (S6K) pathways, pathways also activated by MT and ST oncoproteins. These results support the hypothesis that MT and ST oncoproteins circumvent cellular control of PP2A by methylation to promote transformation. They also implicate LCMT-1 as a negative regulator of Akt and p70/p85 S6K. Therefore, disruption of PP2Ac methylation may contribute to cancer, and modulation of this methylation may serve as an anticancer target.