# SEA and GATOR 10 Years Later
## 5 Function of the SEA and GATOR in Nutrient Sensing and Responding  
### Overview of Amino Acid Axis of Signaling to mTOR1  
One of the principal roles of SEA and GATOR as upstream regulators of mTOR1 is responding to amino acid availability [11; 12] (Figure 3), although the role of both GATOR subcomplexes in glucose sensing has also been reported recently [56]. Effective functioning of the mTOR1 pathway with respect to cellular amino acid levels requires coordinated action of RAG guanosine triphosphatases (RAG-GTPases or RAGs) and their effectors, such as GTPase-activating proteins (GAPs), which stimulate GTP hydrolysis and guanine-nucleotide-exchange factors (GEFs). The major site of mTOR1 activation is the vacuole/lysosomal surface, where mTOR1 is recruited and induced in an RAG-GTPase dependent manner when amino acids are abundant [57; 58]. There are the following four RAG GTPases: RAGA and functionally redundant RAGB; RAGC and functionally redundant RAGD (Figure 3A). They exist as obligate heterodimers, e.g., RAGA (or RAGB) with RAGC (or RAGD). RAGs interact with a pentameric RAGULATOR complex, anchored to the lysosome [57; 58; 59; 60; 61]. RAGULATOR also interacts with v-ATPase, a protein pump at the lysosomal membrane. The guanine nucleotide loading is important for RAGs function. In the presence of amino acids, RAGs are active when RAGA/B is loaded with GTP, and RAGC/D is bound to GDP. Reversely, when amino acids are low, RAGs are inactive, and RAGA/B is loaded with GDP and RAGC/D is bound to GTP. Various GAPs and GEFs promote the conversion of RAGs from active to inactive form. This is where the SEACIT and GATOR1 complexes exert their major functions (see below). A RAG-independent induction of mTOR1 by amino acids both at the vacuole/lysosome and Golgi has also been described in yeast and humans [62; 63; 64; 65], but will not be thoroughly discussed in this review since neither SEA nor GATOR seem to be involved in this mode of mTOR1 activation. Moreover, a recent study revealed that RAG-independent activation of mTOR1 by amino acids derived from protein degradation in lysosomes required HOPS complex and was negatively regulated by activation of the GATOR-RAGs pathway [37]. Thus, evolutionary related HOPS and GATOR2 [3] have similar but divergent roles in activating mTOR1 in response to different amino acid inputs. When amino acids are scarce, some amino acid sensors (see below) interact with and inhibit the GATOR2 complex, thus preventing inhibition of the GATOR1 by GATOR2 (Figure 3A). A mammalian-specific KICSTOR complex tethers GATOR1 to the lysosomal surface [66; 67] where GATOR1 acts as a GAP for RAGA [12], thereby transforming RAGA to its inactive, GDP bound form, which further leads to mTOR1 suppression (Figure 3A). In the presence of amino acids, RAGULATOR and v-ATPase undergo a conformational change that results in RAGULATOR exerting GEF activity towards RAGA or RAGB [60]. RAGULATOR can also trigger GTP release from RAGC [68]. In parallel, upon arginine binding arginine sensor SLC38A9, which resides at the lysosome, stimulates GDP release from RAGA [68]. A complex between folliculin (FLCN) and folliculin-interacting protein (FNIP) 1 and/or 2 is a GAP for RAGC/D [69]. In addition, leucyl-tRNA synthetase (LeuRS or LARS1 or LRS) also has GAP activity towards RAGD [70]. Active RAGULATOR-RAG  
Figure 3: Amino acid signaling. (**A**) mTOR1 signaling in _Homo sapiens_. (**B**) TORC1 signaling in _Saccharomyces cerevisiae_. Yeast and mammalian orthologiques are designated with the same color. Arrows and bars represent activation and inhibition, respectively. See text for more details. stimulates recruitment of mTOR1 to the lysosomal membrane where it is fully activated by small GTPase, RHEB, loaded with GTP [71]. RHEB is under the control of another signaling node--the TSC complex, composed of TSC1, TSC2 and TBC1D7, where TSC2 acts as a GAP to inhibit RHEB. TSC is a nexus of multiple physiological stimuli (e.g., energy status, growth factors, DNA damage) that signal to mTOR1 through PIJK-AKT network [72].