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. 2020 Aug 25;11(9):989. doi: 10.3390/genes11090989

Figure 3.

Figure 3

Amino acid sensing by mTORC1. (A) The Rag-dependent signaling pathway. Ala, Arg, His, Leu, Met, Ser, Thr, and Val can filter through upstream sensors in order to activate the Rag GTPases. Under sufficient amino acid conditions, the Rag GTPase heterodimer (GTP-RagA or RagB and GDP-RagC or RagD) interacts with mTORC1 at the lysosome, where Rheb resides. The Ragulator (consisting of p18, p14, MP1, C7orf59 and HBXIP) then anchors the Rag proteins to the lysosome and acts as a GEF for RagA and RagB. The FLCN-FNIP complex is a GAP for RagC and RagD. The v-ATPase, which is required for amino acid signaling to mTORC1, then binds to the Ragulator. KICSTOR (consisting of KPTN, ITFG2, C12orf66, and SZT2) anchors GATOR1 (consisting of DEPDC5, NPRL2 and NPRL3), the GAP for RagA and RagB, to the lysosome. GATOR2 (consisting of SEC13, SEH1L, WDR24, WDR59, and MIOS) inhibits GATOR1, through an unknown mechanism. Sestrin2 and CASTOR1 bind to GATOR2, preventing the inhibition of GATOR1 by GATOR2. Leu and Arg bind to sensors Sestrin2 and CASTOR1, respectively, which blocks Sestrin2-GATOR2 and CASTOR1-GATOR2 from interacting. (B) The Rag-independent signaling pathway. Only Gln and Asn activate mTORC1. The only known components that are required are the v-ATPase, Rheb, and the small GTPase Arf1. The cycling of Arf1 between a GTP- and a GDP-bound state promotes mTORC1 activation and lysosomal localization through an unknown mechanism. Adenosine diphosphate ribosylation factor 1 (Arf1); cellular Arg sensor for mTORC1 subunit 1 (CASTOR1); DEP domain containing 5 (DEPDC5); folliculin (FLCN); folliculin interacting protein (FNIP); GTPase-activating protein activity toward Rags (GATOR1); guanine nucleotide exchange factor (GEF); GTPase activating protein (GAP); hepatitis B virus X-interacting protein (HBXIP); integrin α FG-GAP repeat containing 2 (ITFG2); Kaptin (KPTN); meiosis regulator for oocyte development (MIOS); MEK partner 1 (MP1); mTOR complex 1 (mTORC1); NPR2 like, GATOR1 complex subunit (NPRL2); NPR3 like, GATOR1 complex subunit (NPRL3); vacuolar H+-ATPase (v-ATPase); Ras homolog enriched in brain (Rheb); SEH1-like nucleoporin (SEH1L); solute carrier family 38 member 9 (SLC38A9); seizure threshold 2 (SZT2); tuberous sclerosis complex (TSC); WD repeat-containing protein 24 (WDR24); WD repeat-containing protein 59 (WDR59).