The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1

Mol Cell. 2013 Nov 21;52(4):495-505. doi: 10.1016/j.molcel.2013.09.016. Epub 2013 Oct 3.

Abstract

The mTORC1 kinase is a master growth regulator that senses numerous environmental cues, including amino acids. The Rag GTPases interact with mTORC1 and signal amino acid sufficiency by promoting the translocation of mTORC1 to the lysosomal surface, its site of activation. The Rags are unusual GTPases in that they function as obligate heterodimers, which consist of RagA or B bound to RagC or D. While the loading of RagA/B with GTP initiates amino acid signaling to mTORC1, the role of RagC/D is unknown. Here, we show that RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP bound for the interaction to occur. We identify FLCN and its binding partners, FNIP1/2, as Rag-interacting proteins with GAP activity for RagC/D, but not RagA/B. Thus, we reveal a role for RagC/D in mTORC1 activation and a molecular function for the FLCN tumor suppressor.

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

  • Amino Acids / metabolism*
  • Carrier Proteins / metabolism
  • GTPase-Activating Proteins / physiology
  • HEK293 Cells
  • Humans
  • Intracellular Membranes / metabolism
  • Lysosomes / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins / metabolism*
  • Multiprotein Complexes / metabolism*
  • Protein Binding
  • Protein Transport
  • Proto-Oncogene Proteins / physiology*
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*
  • Tumor Suppressor Proteins / physiology*

Substances

  • Amino Acids
  • Carrier Proteins
  • FLCN protein, human
  • FNIP1 protein, human
  • FNIP2 protein, human
  • GTPase-Activating Proteins
  • Multiprotein Complexes
  • Proto-Oncogene Proteins
  • RRAGC protein, human
  • RRAGD protein, human
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins