Regulation of mTORC1 by the Rag GTPases

Abstract

The Rag GTPases are an evolutionarily conserved family that play a crucial role in amino acid sensing by the mammalian target of rapamycin complex 1 (mTORC1). mTORC1 is often referred to as the master regulator of cell growth. mTORC1 hyperactivation is observed in multiple diseases such as cancer, obesity, metabolic disorders, and neurodegeneration. The Rag GTPases sense amino acid levels and form heterodimers, where RagA or RagB binds to RagC or RagD, to recruit mTORC1 to the lysosome where it becomes activated. Here, we review amino acid signaling to mTORC1 through the Rag GTPases.

Keywords: Rag GTPases; amino acid sensing; mTORC1; signaling.

Figure 1.. mTORC1 regulation by Rag GTPases.

Amino acids and growth factors converge at the lysosome to activate mTORC1. Components implicated in amino acid sensing by mTORC1 via the Rag GTPases are Ragulator, v-ATPase, SLC38A9, KICSTOR, FLCN–FNIP, GATOR complexes (GATOR1 and GATOR2), Leu sensor Sestrin2, Arg sensor CASTOR1, and S-adenosylmethionine (SAM) sensor SAMTOR. TSC and Rheb regulate mTORC1 downstream of growth factors. (A) In absence of amino acids, GATOR1 exhibits GAP activity for RagA/B. Inactive Rag GTPases recruit TSC and FLCN–FNIP to the lysosomal surface where TSC's GAP activity prevents activation of Rheb. Sestrin2 and CASTOR1 interacts with GATOR2 and prevents GATOR2 from inhibiting GATOR1. (B) In presence of amino acids, folliculin and its associated proteins (FLCN–FNIP) acts as a GAP for RagC/D and GATOR2 inhibits GATOR1 GAP activity for RagA/B. The v-ATPase and SLC38A9 (arginine sensor) are required for mTORC1 activation at the lysosome. The active Rag GTPase heterodimer interacts with mTORC1 and recruits it to the lysosome subsequently promoting its activation by Rheb.

Figure 2.. Different Rag GTPases heterodimers and mTORC1 substrates.

The Rag paralogues form distinct heterodimer complexes to phosphorylate certain mTORC1 substrates.