Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1.
Nat Cell Biol
; 13(3): 263-72, 2011 Mar.
Article
in En
| MEDLINE
| ID: mdl-21336308
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 p38ß 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 p38ß-PRAK cascade. Depletion of p38ß or PRAK diminishes the suppression of mTOR complex 1 (mTORC1) and reduction of cell size induced by energy starvation. We show that p38ß-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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neuropeptides
/
Proteins
/
Gene Expression Regulation, Enzymologic
/
Protein Serine-Threonine Kinases
/
Monomeric GTP-Binding Proteins
/
Intracellular Signaling Peptides and Proteins
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Cell Biol
Year:
2011
Document type:
Article
Affiliation country:
China