Table 1 Rag GTPase signaling network components in S. cerevisiae and mammalian cells
From: Conserved regulators of Rag GTPases orchestrate amino acid-dependent TORC1 signaling
S. cerevisiae | Mammalian cells | Description |
|---|---|---|
Gtr1 | RagA, RagB | Rag GTPases, heterodimerize with Gtr2 or RagC/D, respectively, bind to and promote the activity of TORC1 when loaded with GTP [5, 15, 17] |
Gtr2 | RagC, RagD | Rag GTPases, heterodimerize with Gtr1 or RagA/B, respectively, bind to and promote the activity of TORC1 when loaded with GDP [5, 15, 17] |
EGO-TC (Ego1-3) | Ragulator (LAMTOR1-5) | Complexes that provide a platform for the Rag GTPases on the vacuolar/lysosomal membrane [15, 30, 36]; Ragulator also has GEF activity toward RagA/B [36] |
v-ATPase | v-ATPase | Stimulates the GEF activity of the Ragulator [39]; binds and mediates pH signals to Gtr1 [44] |
Vam6 (Vps39) | hVps39/hVps39-2? | Binds to and promotes the exchange of GDP for GTP in S. cerevisiae Gtr1 [15]; acts upstream of and binds Gtr1 in an amino acid-dependent manner in vivo in S. pombe [49]; hVps39 is neither a RagA/B GEF nor an interacting protein [36] |
Cdc60 (Leucyl-tRNA synthetase) | LARS (Leucyl-tRNA synthetase) | Conserved positive regulator of Rag GTPases, communicates balanced levels of branched-chain amino acids in yeast or leucine levels in mammals [57, 58]; binds Gtr1 and promotes its activation or antagonizes its inactivation in yeast [57]; binds to and stimulates [58] or not [27], GTPase activity of RagD |
Lst4-Lst7 | FNIP1/2-FLCN | Conserved positive regulatory complex of the Rag GTPases and TORC1 signaling, exerts GAP activity toward Gtr2 or RagC/D [27, 60] |
SEACIT (Iml1/Sea1, Npr2 Npr3) | GATOR1 (DEPDC5, NPRL2, NPRL3) | Conserved negative regulatory complex of the Rag GTPases and TORC1 signaling, exerts GAP activity toward Gtr1 or RagA/B [68–70] |
SEACAT (Seh1, Sec13, Sea2, Sea3, Sea4) | GATOR2 (Seh1L, Sec13, Wdr24, Wdr59, Mios) | Conserved positive regulatory complex of Rag GTPases and TORC1 signaling, likely to function upstream of SEACIT/GATOR1 [68–70] |
E3 ligases(s)? | RNF152 | RING family E3 ligase, ubiquitinates RagA to promote its interaction with GATOR1, inactivates TORC1 signaling in the absence of amino acids [73] |
Skp2? | Skp2 | F-box component of the Skp1/Cullin/F-box (SCF) E3 ligase complex, ubiquitinates RagA to promote its interaction with GATOR1, inactivates TORC1 signaling after prolonged exposure to amino acids [74] |
? | Sestrin1-3 | Negative regulators of Rag GTPases, interact with GATOR2 and inhibit TORC1 activity upstream of GATOR1 and the Rag GTPases [77–79]; may also act as GDIs for RagA/B [76]; Sestrin2 directly binds leucine [82, 83] |
Vacuolar amino acid permeases? | SLC38A9 | Low affinity arginine/glutamine transporter on the lysosomal membrane, interacts with Rag-Ragulator in an amino acid-dependent manner and stimulates amino acid activation of TORC1 [85–87] |
Vacuolar amino acid permeases? | SLC36A1/PAT1 | Regulates H+-dependent amino acid efflux from the lysosome, associates with the Rag GTPases, required for recruitment of TORC1 to the lysosome in the presence of amino acids [89] |
Ste20 family kinase(s)? | MAP4K3 | Regulated by amino acids, functions upstream of Rag GTPases to positively regulate TORC1 in response to amino acids [94–96] |
? | p62 | Adaptor protein that interacts with and stabilizes the active form of Rag GTPase heterodimers, possible alternative platform for the Rag GTPases on the lysosome [97] |
? | SH3BP4 | Prevents GTP binding to RagB, downregulates TORC1 activity [98] |
? | c17orf59 | Prevents Rag GTPases from binding Ragulator [99] |
? /Gdh1-3 | GLS/GDH | Glutaminase (GLS) and glutamate dehydrogenase (GDH) drive glutaminolysis to favor RagB GTP-loading [100]; S. cerevisiae expresses no GLS ortholog |
