title: Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1.
abstract: 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 (MAPK) and p38-regulated/activated kinase (PRAK) plays a role in energy-starvation-induced suppression of mammalian target of rapamycin (mTOR), and that energy starvation activates the p38β-PRAK cascade. Depletion of p38β or PRAK diminishes the suppression of mTOR complex 1 (mTORC1) and reduction of cell size induced by energy starvation. We show that p38β-PRAK operates independently of the known mTORC1 inactivation pathways--phosphorylation of tuberous sclerosis protein 2 (TSC2) and Raptor by AMP-activated protein kinase (AMPK)--and surprisingly, that PRAK directly regulates Ras homologue enriched in brain (Rheb), a key component of the mTORC1 pathway, by phosphorylation. Phosphorylation of Rheb at Ser 130 by PRAK impairs the nucleotide-binding ability of Rheb 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.
authors.affiliation: The Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zheng
authors.forename: Yan-Hai
authors.initials: YH
authors.lastname: Wang
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Wu
authors.forename: Su-Qin
authors.initials: SQ
authors.lastname: Wu
authors.forename: Bao-Ju
authors.initials: BJ
authors.lastname: Lu
authors.forename: Meng-Qiu
authors.initials: MQ
authors.lastname: Dong
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: Peiqing
authors.initials: P
authors.lastname: Sun
authors.forename: Sheng-Cai
authors.initials: SC
authors.lastname: Lin
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
authors.forename: Jiahuai
authors.initials: J
authors.lastname: Han
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D049109:Cell Proliferation; D005347:Fibroblasts / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007525:Isoelectric Focusing / Q000379:methods; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D034622:RNA Interference; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; C111049:MAP-kinase-activated kinase 5; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D020559:Monomeric GTP-Binding Proteins