Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy depletion-induced suppression of mTORC1

Cell growth can be suppressed by stressful environments, but the role of stress pathways in this process is largely unknown. Here we show that a cascade of p38β mitogen activated protein kinase and p38 regulated/activated kinase (PRAK) plays a role in energy starvation-induced suppression of mammalian target of rapamycin (mTOR), that energy starvation activates the p38β-PRAK cascade, and that p38β- or PRAK-deletion diminishes energy depletion-induced suppression of mTORC1 and reduction of cell size. We show that p38β-PRAK operates independent from the known mTORC1 inactivation pathways – phosphorylation of tuberous sclerosis protein 2 (TSC2) and raptor by AMP activated protein kinase (AMPK), and surprisingly, PRAK directly regulates Ras homolog enriched in brain (Rheb), a key component of the mTORC1 pathway by phosphorylation. Phosphorylation of Rheb at serine 130 by PRAK impairs Rheb’s nucleotide-binding ability and inhibits Rheb-mediated mTORC1 activation. The direct regulation of Rheb by PRAK integrates a stress pathway with the mTORC1 pathway in response to energy depletion.