Cancer-associated PP2A Aα subunits induce functional haploinsufficiency and tumorigenicity

The introduction of SV40 small t antigen or the suppression of PP2A B56 gamma subunit expression contributes to the experimental transformation of human cells. To investigate the role of cancer-associated PP2A A alpha subunit mutants in transformation, we introduced several PP2A A alpha mutants into immortalized but nontumorigenic human cells. These PP2A A alpha mutants exhibited defects in binding to other PP2A subunits and impaired phosphatase activity. Although overexpression of these mutants failed to render immortalized cells tumorigenic, partial suppression of endogenous PP2A A alpha expression activated the AKT pathway and permitted cells to form tumors in immunodeficient mice. These findings suggest that cancer-associated A alpha mutations contribute to cancer development by inducing functional haploinsufficiency, disturbing PP2A holoenzyme composition, and altering the enzymatic activity of PP2A.