mTORC1-mediated signalling

mTORC1 integrates four major signals – growth factors, energy status, oxygen and amino acids – to regulate many processes that are involved in the promotion of cell growth. Growth factors stimulate mTORC1 through the activation of the canonical insulin and Ras signaling pathways. The energy status of the cell is signaled to mTORC1 through AMP-activated protein kinase (AMPK), a key sensor of intracellular energy status. Energy depletion (low ATP:ADP ratio) activates AMPK which phosphorylates TSC2, increasing its GAP activity towards Rheb which reduces mTORC1 activation. AMPK can reduce mTORC1 activity by directly phosphorylating Raptor. Amino acids positively regulate mTORC1 (reviewed by Guertin & Sabatini 2007). In the presence of amino acids, Rag proteins bind Raptor to promote the relocalization of mTORC1 from the cytoplasm to lysosomal membranes where it is activated by Rheb. Translocation of mTOR to the lysosome requires active Rag GTPases and a complex known as Ragulator, a pentameric protein complex that anchors the Rag GTPases to lysosomes (Sancak et al. 2008, 2010, Bar-Peled et al. 2012). Rag proteins function as heterodimers, consisting of GTP-bound RagA or RagB complexed with GDP-bound RagC or RagD. Amino acids may trigger the GTP loading of RagA/B, thereby promoting binding to raptor and assembly of an activated mTORC1 complex, though a recent study suggested that the activation of mTORC1 is not dependent on Rag GTP charging.

Summary from Reactome (R-HSA-166208), read 2026-09-23.