Figure 1. mTORC1 activation by nutrient sensing and growth factor signaling. (IMAGE)
Caption
mTORC1 activation requires the coordinated input of amino acid sufficiency and growth factor signaling, operating as an “AND” gate. To ensure both conditions are met, mTORC1 must first translocate to the lysosomal surface by anchoring onto the Rag GTPases, a step gated by amino acid availability. Cytosolic amino acids are detected by direct sensors, including CASTOR1 (arginine), Sestrin2, SAR1B, and LARS (leucine), that converge on the GATOR1-GATOR2 axis, which modulates the Rag-Ragulator complex. In addition, amino acid availability can be sensed by the FLCN/FNIP complex, which regulates Rag complex configuration since it is a GAP for Rag C/D. Metabolic derivatives of amino acids can also regulate mTORC1 via distinct, Rag-dependent or Rag-independent mechanisms. Lysosomal amino acids are communicated via the lysosomal transmembrane protein SLC38A9 to the Ragulator-Rag machinery. Once recruited to the lysosome, mTORC1 can be activated by GTP-bound Rheb, whose loading state is governed by the TSC complex, the principal brake on mTORC1 that integrates growth factor signaling and stress-responsive inputs including energy status (AMPK), DNA damage (p53), and hypoxia (REDD1). Thus, full kinase activation occurs only when both arms are simultaneously engaged. Positive regulators are indicated in red and negative regulators in blue. mTORC1: mechanistic target of rapamycin complex 1; SAM: S-adenosylmethionine; SAMTOR: SAM sensor upstream of mTORC1; CASTOR1: cellular arginine sensor for mTORC1 subunit 1; SAR1B: secretion-associated Ras-related GTPase 1B; LARS: leucyl-tRNA synthetase 1, cytosolic; GATOR1/2: GAP activity toward Rags complex 1/2; KICSTOR: KPTN–ITFG2–C12orf66–SZT2 complex; FLCN: folliculin; α-KG: α-ketoglutarate; v-ATPase: vacuolar-type H+-ATPase; Rag: Ras-related GTP-binding protein; Ragulator: Ragulator complex (or late endosomal/lysosomal adaptor and MAPK and mTOR activator, LAMTOR); SLC38A9: solute carrier family 38 member 9; Rheb: Ras homolog enriched in brain; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; TSC: tuberous sclerosis complex; AMPK: AMP-activated protein kinase; p53: tumor protein p53; REDD1: regulated in development and DNA damage responses 1.
Credit
© David C. Rubinsztein*, et al. 2026. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
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