Fig. 4

Schematic representation of amino acid, energy and Wnt signaling to mTORC1. Rag GTPases were identified as mediators of amino acid signaling to mTORC1. When an adequate supply of amino acids is present, an active Rag complex consists of GTP-bound Rag A or Rag B and GDP-bound Rag C or Rag D. The Rag complex is able to recruit and anchor mTORC1 to the lysosomal surface which facilitates mTORC1 activation by Rheb. Ragulator functions as a GEF for Rag A/B and also as a scaffold to help anchor the Rag complex to the lysosome. v-ATPase interacts with Ragulator and is required for mTORC1 activity. The GATOR1 complex functions upstream of the Rag complex as a GAP for Rag A/B GTPase and inhibits mTORC1 activity. The GATOR2 complex interacts with and inhibits GATOR1. Sestrin1/2 and CASTOR1/2 are cytosolic leucine and arginine sensor, respectively. The presence of leucine and arginine disrupts the association of Sestrin1/2 and CASTOR1/2 with GATOR2, resulting in the elimination of their inhibition towards GATOR2. SLC38A9 is an important lysosomal arginine sensor and amino acid transporter that directly interacts with Ragulator. FLCN and its binding partner FNIP2 were identified as Rag-interacting proteins with GAP activity for Rag C/D, but not for Rag A/B. Reduction in oxygen or energy levels are sensed by AMPK which can be activated by upstream kinase LKB1 under the conditions of the increased intracellular AMP/ATP and ADP/ATP ratios. The activated AMPK phosphorylates TSC2 and enhances its GAP activity towards Rheb-GTP, finally resulting in the inhibition of mTORC1 activity. Hypoxic stress also stabilizes the transcription factor HIF1α which drives the expression of REDD1. The latter is a negative regulator of mTORC1 activity. Additionally, the activated Wnt signaling pathway stimulates mTORC1 activity via GSK3β repression. Black arrows and red T-bars represent stimulatory and inhibitory signals, respectively