Characterization of tumor‐derived B56γ mutations and their effect on the tumor suppressor function of B56γ‐PP2A (802.21)

Protein phosphatase 2A (PP2A) is a family of serine/threonine phosphatases with diverse cellular functions. Previous study reported that B56γ subunit directs PP2A toward tumor suppressive function by dephosphorylating and activating tumor suppressor p53. B56γ‐PP2A also inhibits cell transformation by an unknown p53‐independent mechanism. In this study, we investigate the inactivation mechanism of B56γ tumor suppressive function through characterization of B56γ mutations identified in human cancer. The first class mutations disrupt interaction between B56γ and AC core, and thus B56γ fails to regulate its substrates and completely lose tumor suppressive function. Further, we show that C39R mutation within HEAT repeat1 disrupts B56γ binding with AC core, providing structural insight that intact HEAT repeat1 is required for B56γ‐PP2A holoenzyme assembly. The second class mutations prevent specific substrates from binding B56γ and cause partial reduction of tumor suppressive function of B56γ. We find that A383G and F395C mutations disrupt B56γ from interacting p53. Mutants are unable to dephosphorylate p53 and thus lack p53‐dependent tumor suppressive function, implying that bridging interaction between B56γ and p53 is required for p53 activation by B56γ‐PP2A. In addition, we identified S220N mutation that specifically disrupts p53‐independent function of B56γ, suggesting that it may disrupt the binding of unknown substrates. Although it remains to be investigated how frequently these mutations occur, our results underline the importance of B56γ tumor suppressive function in human cancer. Grant Funding Source : Supported by NIH