mTORC1

mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.^[1][2]

mTOR Complex 1 (mTORC1) is composed of the

The role of mTORC1 is to activate translation of proteins.[8] In order for cells to grow and proliferate by manufacturing more proteins, the cells must ensure that they have the resources available for protein production. Thus, for protein production, and therefore mTORC1 activation, cells must have adequate energy resources, nutrient availability, oxygen abundance, and proper growth factors in order for mRNA translation to begin.^[4]

Activation at the lysosome

The TSC complex

Almost all of the variables required for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 protein complex.

mTORC1 interacts at the Ragulator-Rag complex on the surface of the lysosome in response to amino acid levels in the cell.^[11][12] Even if a cell has the proper energy for protein synthesis, if it does not have the amino acid building blocks for proteins, no protein synthesis will occur. Studies have shown that depriving amino acid levels inhibits mTORC1 signaling to the point where both energy abundance and amino acids are necessary for mTORC1 to function. When amino acids are introduced to a deprived cell, the presence of amino acids causes Rag GTPase heterodimers to switch to their active conformation.^[13] Active Rag heterodimers interact with raptor, localizing mTORC1 to the surface of late endosomes and lysosomes where the Rheb-GTP is located.^[14] This allows mTORC1 to physically interact with Rheb. Thus the amino acid pathway as well as the growth factor/energy pathway converge on endosomes and lysosomes. Thus the Ragulator-Rag complex recruits mTORC1 to lysosomes to interact with Rheb.^[15][16]

Regulation of the Ragulator-Rag complex

Rag activity is regulated by at least two highly conserved complexes: the "GATOR1" complex containing DEPDC5, NPRL2 and NPRL3 and the ""GATOR2" complex containing Mios, WDR24, WDR59, Seh1L, Sec13.^[17] GATOR1 inhibits Rags (it is a GTPase-activating protein for Rag subunits A/B) and GATOR2 activates Rags by inhibiting DEPDC5.

Upstream signaling

Receptor tyrosine kinases

Akt/PKB pathway

Insulin-like growth factors can activate mTORC1 through the

RSK has also been shown to phosphorylate raptor, which helps it overcome the inhibitory effects of PRAS40.^[24]

JNK pathway

c-Jun N-terminal kinase (JNK) signaling is part of the mitogen-activated protein kinase (MAPK) signaling pathway essential in stress signaling pathways relating to gene expression, neuronal development, and cell survival. Recent studies have shown there is a direct molecular interaction where JNK phosphorylates Raptor at Ser-696, Thr-706, and Ser-863.^[25][26] Therefore, mTORC1 activity is JNK-dependent. Thus, JNK activation plays a role in protein synthesis via subsequent downstream effectors of mTORC1 such as S6 kinase and eIFs.^[27]

Wnt pathway

The

In order for translation to take place, abundant sources of energy, particularly in the form of ATP, need to be present. If these levels of ATP are not present, due to its hydrolysis into other forms like AMP, and the ratio of AMP to ATP molecules gets too high, AMPK will become activated. AMPK will go on to inhibit energy consuming pathways such as protein synthesis.^[30]

AMPK can phosphorylate TSC2 on serine residue 1387, which activates the GAP activity of this complex, causing Rheb-GTP to be hydrolyzed into Rheb-GDP. This inactivates mTORC1 and blocks protein synthesis through this pathway.^[31]

AMPK can also phosphorylate Raptor on two serine residues. This phosphorylated Raptor recruits 14-3-3 to bind to it and prevents Raptor from being part of the mTORC1 complex. Since mTORC1 cannot recruit its substrates without Raptor, no protein synthesis via mTORC1 occurs.^[32]

LKB1, also known as

Due to the lack of synthesis of ATP in the mitochondria under hypoxic stress or hypoxia, AMPK will also become active and thus inhibit mTORC1 through its processes.[36]

Downstream signaling

mTORC1 activates transcription and translation through its interactions with

Previous studies suggest that S6K signaling is mediated by mTOR in a rapamycin-dependent manner wherein S6K is displaced from the eIF3 complex upon binding of mTOR with eIF3.[42] Hypophosphorylated S6K is located on the eIF3 scaffold complex. Active mTORC1 gets recruited to the scaffold, and once there, will phosphorylate S6K to make it active.^[18]

mTORC1

S6K1 can also participate in a positive feedback loop with mTORC1 by phosphorylating mTOR's negative regulatory domain at two sites thr-2446 and ser-2448; phosphorylation at these sites appears to stimulate mTOR activity.[48]^[49]

S6K also can phosphorylate programmed cell death 4 (PDCD4), which marks it for degradation by ubiquitin ligase Beta-TrCP (BTRC). PDCD4 is a tumor suppressor that binds to eIF4A and prevents it from being incorporated into the initiation complex.

Role in disease and aging

mTOR was found to be related to aging in 2001 when the ortholog of S6K, SCH9, was deleted in S. cerevisiae, doubling its lifespan.^[50] This greatly increased the interest in upstream signaling and mTORC1. Studies in inhibiting mTORC1 were thus performed on the model organisms of C. elegans, fruitflies, and mice. Inhibition of mTORC1 showed significantly increased lifespans in all model species.^[51][52] Disrupting the gut microbiota of infant mice was found to lead to reduced longevity with signaling of mTORC1 implicated as a potential mechanism.^[53]

Based on upstream signaling of mTORC1, a clear relationship between food consumption and mTORC1 activity has been observed.

mTORC1's ability to inhibit autophagy while at the same time stimulate protein synthesis and cell growth can result in accumulations of damaged proteins and organelles, contributing to damage at the cellular level.[60] Because autophagy appears to decline with age, activation of autophagy may help promote longevity in humans.^[61] Problems in proper autophagy processes have been linked to diabetes, cardiovascular disease, neurodegenerative diseases, and cancer.^[62]

Lysosomal damage

mTORC1 is positioned on

Deletion of the TOR1 gene in yeast increases cellular respiration in the mitochondria by enhancing the translation of mitochondrial DNA that encodes for the complexes involved in the electron transport chain.^[67] When this electron transport chain is not as efficient, the unreduced oxygen molecules in the mitochondrial cortex may accumulate and begin to produce reactive oxygen species.^[68] It is important to note that both cancer cells as well as those cells with greater levels of mTORC1 both rely more on glycolysis in the cytosol for ATP production rather than through oxidative phosphorylation in the inner membrane of the mitochondria.^[69]

Inhibition of mTORC1 has also been shown to increase transcription of the

Though AMPK induced eNOS has been shown to regulate mTORC1 in endothelium. Unlike the other cell type in endothelium eNOS induced mTORC1 and this pathway is required for mitochondrial biogenesis.[71]

Stem cells

Conservation of

There have been over 1,300 clinical trials conducted with mTOR inhibitors since 1970.[110]

References