Figures & data
Figure 1. Rag GTPase-dependent amino acid signaling pathway upstream of mTORC1. (A) Current model of mTORC1 activation by amino acids in mammals. In the presence of amino acids, the heterodimeric Rag GTPase complex is comprised of GTP-bound RagA/B and GDP-bound RagC/D (active Rag complex). The active Rag complex anchors mTORC1 to the lysosome. During amino acid scarcity, mTORC1 is dispersed throughout the cell at an unknown location. Ragulator functions as a scaffold to anchor the Rag complex to the lysosome, and is a GEF for RagA/B. v-ATPase binds to Ragulator and is required for mTORC1 activity. GATOR1 functions upstream of the Rag complex as a GAP for RagA/B. KICKSTOR is thought to tether GATOR1 to the lysosome. GATOR2 functions upstream of GATOR1 and inhibits GATOR1 through an unknown mechanism. Sestrin1/2 is a cytosolic leucine sensor and CASTOR1/2 is a cytosolic arginine sensor. In the absence of amino acids, Sestrin1/2 and CASTOR1/2 bind to and inhibit GATOR2. The presence of leucine or arginine interrupts the interaction between Sestrin1/2 and GATOR2 or CASTOR1/2 and GATOR2. FLCN-FNIP2 is a GAP for RagC/D. Positive regulators of mTORC1 are indicated in green and negative regulators are indicated in red. (B) Current model of TORC1 activation by amino acids in yeast. In their active form, Gtr1 binds to GTP and Gtr2 binds to GDP. Ego1, Ego2, and Ego3 form the EGO complex that anchors the Gtr complex to the lysosome. Vam6 is a GEF for Gtr1. Lst7-Lst4 acts as a GAP for Gtr2. SEACAT inhibits SEACIT, which is a GAP for Gtr1. Methionine activates TORC1 activity by promoting SAM synthesis, which in turn activates PP2A and inhibits SEACIT. Leucine activates TORC1 through Cdc60. Positive regulators of TORC1 are indicated in green and negative regulators are indicated in red.
Figure 2. Rag GTPase-independent amino acid signaling pathway upstream of mTORC1. (A) Current model of mTORC1 activation by glutamine independently of Rag GTPases. v-ATPase is required for mTORC1 activity. The cycling of GTP-bound and GDP-bound Arf1 facilitates mTORC1 lysosomal localization and activation by glutamine. Positive regulators of mTORC1 are indicated in green. (B) Current model of Gtr1-independent TORC1 activation by glutamine. Pib2, Vsp34, and Vsp15 are required for TORC1 activation. Positive regulators of mTORC1 and TORC1 are indicated in green.
Table 1. Comparison of Amino Acid signaling components in mammals and yeast.