AMPK phosphorylation of raptor mediates a metabolic checkpoint.
AMPK is a highly conserved sensor of cellular energy status that is activated under conditions of low intracellular ATP. AMPK responds to energy stress by suppressing cell growth and biosynthetic processes, in part through its inhibition of the rapamycin-sensitive mTOR (mTORC1) pathway. AMPK phosphorylation of the TSC2 tumor suppressor contributes to suppression of mTORC1; however, TSC2-deficient cells remain responsive to energy stress. Using a proteomic and bioinformatics approach, we sought to identify additional substrates of AMPK that mediate its effects on growth control. We report here that AMPK directly phosphorylates the mTOR binding partner raptor on two well-conserved serine residues, and this phosphorylation induces 14-3-3 binding to raptor. The phosphorylation of raptor by AMPK is required for the inhibition of mTORC1 and cell-cycle arrest induced by energy stress. These findings uncover a conserved effector of AMPK that mediates its role as a metabolic checkpoint coordinating cell growth with energy status.
Gwinn
Dana M
DM
Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Shackelford
David B
DB
Egan
Daniel F
DF
Mihaylova
Maria M
MM
Mery
Annabelle
A
Vasquez
Debbie S
DS
Turk
Benjamin E
BE
Shaw
Reuben J
RJ
D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008815:Mice, Inbred Strains; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D019151:Peptide Library; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D040901:Proteomics; D000076223:Regulatory-Associated Protein of mTOR; D012694:Serine / Q000378:metabolism; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D009097:Multienzyme Complexes; D046912:Multiprotein Complexes; D019151:Peptide Library; D011506:Proteins; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D014157:Transcription Factors; D012694:Serine; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases