B56γ Tumor-Associated Mutations Provide New Mechanisms for B56γ-PP2A Tumor Suppressor Activity

Abstract

A subset of the hetero-trimeric PP2A serine/threonine phosphatases that contain B56, and in particular B56γ, can function as tumor suppressors. In response to DNA damage, the B56γ subunit complexes with the PP2A AC core (B56γ–PP2A) and binds p53. This event promotes PP2A-mediated dephosphorylation of p53 at Thr55, which induces expression of p21, and the subsequent inhibition of cell proliferation and transformation. In addition to dephosphorylation of p53, B56γ–PP2A also inhibits cell proliferation and transformation by a second, as yet unknown, p53-independent mechanism. Here, we characterized a panel of B56γ mutations found in human cancer samples and cancer cell lines and showed that the mutations lost B56γ tumor-suppressive activity by two distinct mechanisms; one is by disrupting interaction with the PP2A AC core and the other with B56γ–PP2A substrates (p53 and unknown proteins). For the first mechanism, due to the absence of the C catalytic subunit in the complex, the mutants would be unable to mediate dephosphorylation of any substrate and thus failed to promote both p53-dependent and p53–independent tumor-suppressive function of B56γ-PP2A. For the second mechanism, the mutants lacked specific substrate interactions and thus partially lost tumor-suppressive function, i.e. either p53-dependent or p53-independent contingent upon which substrate binding was affected. Overall the data provide new insight into the mechanisms for inactivation of tumor-suppressive function of B56γ and further indicate the importance of B56γ-PP2A in tumorigenesis.

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