Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1

Cell. 2012 Sep 14;150(6):1196-208. doi: 10.1016/j.cell.2012.07.032.

Abstract

The mTOR Complex 1 (mTORC1) pathway regulates cell growth in response to numerous cues, including amino acids, which promote mTORC1 translocation to the lysosomal surface, its site of activation. The heterodimeric RagA/B-RagC/D GTPases, the Ragulator complex that tethers the Rags to the lysosome, and the v-ATPase form a signaling system that is necessary for amino acid sensing by mTORC1. Amino acids stimulate the binding of guanosine triphosphate to RagA and RagB but the factors that regulate Rag nucleotide loading are unknown. Here, we identify HBXIP and C7orf59 as two additional Ragulator components that are required for mTORC1 activation by amino acids. The expanded Ragulator has nucleotide exchange activity toward RagA and RagB and interacts with the Rag heterodimers in an amino acid- and v-ATPase-dependent fashion. Thus, we provide mechanistic insight into how mTORC1 senses amino acids by identifying Ragulator as a guanine nucleotide exchange factor (GEF) for the Rag GTPases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Amino Acids / metabolism*
  • Animals
  • Drosophila / metabolism*
  • GTP Phosphohydrolases / metabolism
  • Guanine Nucleotide Exchange Factors / chemistry
  • Guanine Nucleotide Exchange Factors / metabolism*
  • HEK293 Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Proteins / metabolism*
  • Signal Transduction*
  • TOR Serine-Threonine Kinases

Substances

  • Adaptor Proteins, Signal Transducing
  • Amino Acids
  • Guanine Nucleotide Exchange Factors
  • LAMTOR4 protein, human
  • LAMTOR5 protein, human
  • Multiprotein Complexes
  • Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • GTP Phosphohydrolases