Na⁺-coupled high affinity, lysosomal arginine transporter and sensor, SLC38A9 (561aas; 11 TMSs) (Gu et al. 2017). Also transports many other amino acids with low affinity and specificity (Rebsamen et al. 2015). The rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar ATPase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Wang et al. 2015 showed that lysosomal SLC38A9 interacts with Rag GTPases and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is probably the arginine sensor for the mTORC1 pathway.  Jung et al. 2015 confirmed SLC38A9 to be a Rag-Ragulator complex member, transducing amino acid availability to mTORC1. Lysosomal cholesterol activates TORC1 via an SLC38A9-Niemann-Pick C1 signaling complex (Castellano et al. 2017). The Niemann-Pick C1 (NPC1) protein (TC# 2.A.6.6.1), which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function (Castellano et al. 2017). Ragulator and SLC38A9 are each unique guanine exchange factors (GEFs) that collectively push the Rag GTPases toward the active state (Shen and Sabatini 2018). Ragulator triggers GTP release from RagC, thus resolving the locked inactivated state of the Rag GTPases. Upon arginine binding, SLC38A9 converts RagA from the GDP- to the GTP-loaded state, and therefore activates the Rag GTPase heterodimer. Thus, Ragulator and SLC38A9 act on the Rag GTPases to activate the mTORC1 pathway in response to nutrient sufficiency.