Abstract
The A subunit of protein phosphatase 2A (PP2A) consists of 15 nonidentical repeats. The catalytic C subunit binds to C-terminal repeats 11–15 and regulatory B subunits bind to N-terminal repeats 1–10. Recently, four cancer-associated mutants of the Aα subunit have been described: Glu64→Asp in lung carcinoma, Glu64→Gly in breast carcinoma, Arg418→Trp in melanoma, and Δ171–589 in breast carcinoma. Based on our model of PP2A, we predicted that Glu64→Asp and Glu64→Gly might be defective in B subunit binding, whereas Arg418→Trp and Δ171–589 might bind neither B nor C subunits. We generated these mutants by site-directed mutagenesis and assayed their ability to associate with different forms of B subunits (B, B′, B′′) or with the catalytic C subunit. The results demonstrate that all mutants are defective in binding either B or B and C subunits. Specifically, the N-terminal mutants, Glu64→Asp and Glu64→Gly, are defective in B′ but normal in B, B′′, and C subunit binding, whereas the C-terminal mutants Arg418→Trp and Δ171–589 bind none of the B subunits nor the C subunit. The implications of these findings with regard to the potential role of PP2A as a tumor suppressor are discussed.
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Acknowledgements
We thank Marc Mumby for the Bα and B′α1 cDNA plasmids, and Brian Hemmings for the B′′/PR72 cDNA plasmid. We also acknowledge the UCSD Cancer Center sequencing facility. This work was supported by the Tobacco-Related Diseases Research Program, grant 8RT-0037 and Public Health Service grant CA-36111.
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Ruediger, R., Pham, H. & Walter, G. Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the Aα subunit gene. Oncogene 20, 10–15 (2001). https://doi.org/10.1038/sj.onc.1204059
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DOI: https://doi.org/10.1038/sj.onc.1204059
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