Current Models of Mammalian Target of Rapamycin Complex 1 (mTORC1) Activation by Growth Factors and Amino Acids

Abstract

Mammalian target of rapamycin (mTOR), which is now referred to as mechanistic target of rapamycin, integrates many signals, including those from growth factors, energy status, stress, and amino acids, to regulate cell growth and proliferation, protein synthesis, protein degradation, and other physiological and biochemical processes. The mTOR-Rheb-TSC-TBC complex co-localizes to the lysosome and the phosphorylation of TSC-TBC effects the dissociation of the complex from the lysosome and activates Rheb. GTP-bound Rheb potentiates the catalytic activity of mTORC1. Under conditions with growth factors and amino acids, v-ATPase, Ragulator, Rag GTPase, Rheb, hVps34, PLD1, and PA have important but disparate effects on mTORC1 activation. In this review, we introduce five models of mTORC1 activation by growth factors and amino acids to provide a comprehensive theoretical foundation for future research.

Disruption of the vacuolar-type H+-ATPase complex in liver causes MTORC1-independent accumulation of autophagic vacuoles and lysosomes

“…This supports the view of a crosstalk between the input signals of amino acid concentrations and growth factors. 40,64 Moreover, MTORC1 activity in Atp6ap2 cKO hepatocytes was also responsive to insulin treatment. This might explain the ability of the knockout cells to maintain MTORC1 in an active state even when v-H C -ATPase-mediated amino acid sensing is impaired.…”

Combined copy number and mutation analysis identifies oncogenic pathways associated with transformation of follicular lymphoma

“…We identified mutations in several genes that may activate the mTOR pathway. RRAGC heterodimerizes with RRAGA or RRAGB and, given adequate amino acid levels, can recruit mTORC1 through RAPTOR to the lysosomal membrane, where mTORC1 can be activated by RHEB 40 . Recurrent RRAGC mutations in FL were very recently reported to activate mTORC1 41 .…”

New strategies in sport nutrition to increase exercise performance

“…This complex consists of a number of different proteins, mTOR, GbetaL, raptor, GTP bound Rheb in addition to an apparent required association with lysosomal membranes [94]. Furthermore, mTORC1 has a number of repressors, which must be dissociated from the complex to allow it to become active, such as PRAS40 and DEPTOR [94]. Finally the amino acid sensitive lipid kinase hVPS34 also plays a key role in mTORC1 activation [95] as does the MAPK family member MAP4K3 [96] ( Figure 2).…”