# SEA and GATOR 10 Years Later
## 5 Function of the SEA and GATOR in Nutrient Sensing and Responding
### GATOR2 Interactions with Leucine Sensors SESTRINs and SAR1B and Argin Sensor CASTOR1  
Cytosolic leucine can be sensed by the proteins from the SESTRIN family (SESTRINs 1-3) [82; 83; 84], by small GTPase SAR1B [85] and by leucyl-tRNA synthetase [70; 86; 87]. Argin is sensed by CASTOR1 protein homodimer in the cytoplasm [88; 89] and by SLC38A9 together with TM45 SF protein at the lysosomal membrane [90; 91; 92].  
GATORs can interact directly with several amino acid sensors (Figure 3A). During leucine or arginine starvation, SESTRIN2 [82], SAR1B [85] or CASTOR1, respectively [88; 89] interact with and inhibit the GATOR2 complex. WDR24 and SEH1L are essential for interaction with SESTRIN2, but it is not known which component of GATOR2 interacts with SESTRIN2 directly [93; 94]. SAR1B directly binds MIPS, but not other GATOR2 subunits [85]. WDR24, SEH1L and MIOS were sufficient for interaction with CASTOR1 [89]; the CASTOR1 N-terminal domain is involved into direct interaction with MIOS [95]. Binding sites for SESTRIN2 and CASTOR1 are located at different parts of GATOR2 [89]. These interactions prevent inhibition of the GATOR1 by GATOR2 [96] and as a consequence, lead to mTORC1 inhibition. Neither SESTRIN2 nor CASTOR1 interact with GATOR1 [89; 93; 97].  
In the presence of amino acids, interaction of leucine to the defined binding pocket in monomeric SESTRIN2 [83] or arginine with its binding pocket at the homodimeric CASTOR1 [88; 95; 98] results in dissociations of these sensors from GATOR2 and relieves mTOR1 inhibition. It is important to note, however, that SESTRIN2-GATOR2 interactions were initially observed in the cell-lines cultured in leucine-rich conditions [93; 97], even if amino acid starvation enhanced this interaction. In vitro addition of leucine reduces the SESTRIN1-GATOR2 or SESTRIN2-GATOR2 interactions, but it does not affect SESTRIN3-GATOR2 interaction [82,84]. Interestingly, SESTRIN2 and SAR1B detect different parts of leucine; SAR1B recognizes the amino group and side chain of leucine [85], while SESTRIN2 interacts with leucine's amino and carboxyl groups [83].  
Interactions of SESTRINs to GATOR2 depends on a cell type and physiological conditions. Thus, in the skeletal muscle of rats, SESTRIN1 is the most abundant isoform, and SESTRIN2 expression is much lower relative to either SESTRIN1 or SESTRIN3. Accordingly, oral administration of leucine to fasted rats induced SESTRIN1-GATOR2 disassembly, but did not affect the interaction of other SESTRIN isoforms with GATOR2 [84]. This suggests that in the rat skeletal muscle, it is probably SESTRIN1 that has a primary role as a leucine sensor and leucine-induced activation of mTOR1 in skeletal muscle happens via SESTRIN1 release from GATOR2. SESTRINs-GATOR2 interactions can also be age dependent. Thus, in the skeletal muscle of young pigs, SESTRIN2 is more abundant than SESTRIN1 but the GATOR2 amounts are the same. Accordingly, during amino acid starvation the abundance of the SESTRIN2-GATOR2 complex reduced more in younger pigs [99].  
Recently, GATOR2 was reported to be required for SESTRIN2-induced AKT activation and AKT translocation to plasma membrane [94]. In addition, GATOR2 physically bridges SESTRIN2 with mTOR2 where WDR59's interaction with mTORC2's component RICTOR is essential for the communication between GATOR2 and mTORC2, and WDR24 is crucial for GATOR2-SESTRIN2 interaction. In HeLa cells, GATOR2 promotes AKT activation and facilitates AKT-dependent inhibitory phosphorylation of TSC2 [75]. Thus, although an exact molecular function of GATOR2 has not yet been defined, it is clear that GATOR2 might have a large repertoire of various activities. Solving the structure of GATOR2 alone and in complex with its interactors will provide essential information about how these multiple functions can be exerted.