Amino acid nutrient sensors upstream of mTORC1

The amino acid nutrient sensors upstream of mTORC1 are a specialized group of proteins and complexes that detect the availability of specific amino acids and relay this information to the Mechanistic Target of Rapamycin Complex 1 (mTORC1) (Wolfson et al., 2016; Chantranupong et al., 2016). This sensing system includes cytosolic sensors like Sestrin2 (for leucine), CASTOR1 (for arginine), and SAMTOR (for S-adenosylmethionine), as well as the lysosomal membrane sensor SLC38A9 (for arginine) (Rebsamen et al., 2015; Gu et al., 2017). These sensors typically function by modulating the activity of the GATOR1 and GATOR2 complexes, which in turn regulate the nucleotide-loading state of the Rag GTPases (Bar-Peled et al., 2013). When amino acids are present, the sensors promote the formation of active Rag heterodimers that recruit mTORC1 to the lysosomal surface for activation by Rheb (Sancak et al., 2008). This pathway is a fundamental regulator of cellular anabolic processes, including protein synthesis and cell growth, while suppressing catabolic processes like autophagy. Dysregulation of these sensors is implicated in various pathologies, particularly cancer, where hyperactivation supports tumor growth, and metabolic or neurodegenerative diseases (Saxton and Sabatini, 2017). Therapeutic targeting of these sensors, such as with the Sestrin2 modulator NV-5138, offers a way to selectively tune mTORC1 activity for treating conditions like treatment-resistant depression or metabolic disorders (Kato et al., 2019).

Other names

mTORC1 nutrient sensing pathwayAmino acid sensing branch of mTORC1Sestrin-CASTOR-SLC38A9 axisRag-dependent nutrient sensing pathwaySestrin2CASTOR1SLC38A9SAMTORSAR1BGATOR1GATOR2Rag GTPases

Modulation of mTORC1 activity by mimicking or blocking nutrient signals, activation of Rag GTPases, inhibition of GATOR1 GAP activity, and disruption of sensor-GATOR2 interactions.