Nuclear PRAS40 couples the Akt/mTORC1 signaling axis to the RPL11-HDM2-p53 nucleolar stress response pathway

The Ribosomal Protein (RP)-HDM2-p53 pathway has been shown to play key roles in oncogene-induced apoptosis and senescence, but the mechanism regulating this pathway remains elusive. The Proline-Rich Akt Substrate of 40 kDA (PRAS40) has recently been identified as a binding partner and inhibitor of the mechanistic Target of Rapamycin Complex 1 (mTORC1). Although other inhibitors of mTORC1 are known tumor suppressors, PRAS40 promotes cell survival and tumorigenesis. Here we demonstrate that Akt- and mTORC1-mediated phosphorylation of PRAS40 at T246 and S221, respectively, promotes nuclear-specific association of PRAS40 with Ribosomal Protein L11 (RPL11). Importantly, silencing of PRAS40 induces upregulation of p53 in a manner dependent upon RPL11. This effect is rescued by wild type PRAS40, but not by the RPL11 binding-null PRAS40 T246A mutant. We find that PRAS40 negatively regulates the RPL11-HDM2-p53 nucleolar stress response pathway and suppresses induction of p53-mediated cellular senescence. This work identifies nuclear PRAS40 as a dual-input signaling checkpoint that links cell growth and proliferation to inhibition of cellular senescence. These findings may help to explain the pro-tumorigenic effect of PRAS40 and identify the PRAS40-RPL11 complex as a promising target for p53-restorative anti-cancer drug discovery.