Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3

Gain-of-function alterations to the sonic hedgehog (SHH) signaling cascade have been found in a wide range of tumors. Three SHH effectors, GLI1, GLI2, and GLI3, regulate transcription of diverse genes involved in cell growth and cell proliferation. Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, alpha 4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. Conversely, inhibition of PP2A results in increased expression of cyclin D1. In summary, our findings reveal the existence of a hitherto unrecognized molecular cross-talk between the oncogenic SHH pathway and the tumor suppressor PP2A and suggest a novel mechanism underlying the anticancerogenic effects of rapamycin.