Disruption of protein phosphatase 2A subunit interaction in human cancers with mutations in the Aα subunit gene

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 A alpha subunit have been described: Glu64-->Asp in lung carcinoma, Glu64 --> Gly in breast carcinoma, Arg418 --> Trp in melanoma, and Delta 171-589 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 Delta 171 - 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 Delta 171-589 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.