MTORC1
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein kinase complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
mTOR Complex 1 is composed of the mTOR protein complex, regulatory-associated protein of mTOR, mammalian lethal with SEC13 protein 8, PRAS40 and DEPTOR. This complex embodies the classic functions of mTOR, namely as a nutrient/energy/redox sensor and controller of protein synthesis. The activity of this complex is regulated by rapamycin, insulin, growth factors, phosphatidic acid, certain amino acids and their derivatives, mechanical stimuli, and oxidative stress. Recently it has been also demonstrated that cellular bicarbonate metabolism can be regulated by mTORC1 signaling.
The role of mTORC1 is to activate translation of proteins. 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.
Activation at the lysosome
TSC complex
Almost all of the variables required for protein synthesis affect mTORC1 activation by interacting with the TSC1/TSC2 protein complex. TSC2 is a GTPase activating protein. Its GAP activity interacts with a G protein called Rheb by hydrolyzing the GTP of the active Rheb-GTP complex, converting it to the inactive Rheb-GDP complex. The active Rheb-GTP activates mTORC1 through unelucidated pathways. Thus, many of the pathways that influence mTORC1 activation do so through the activation or inactivation of the TSC1/TSC2 heterodimer. This control is usually performed through phosphorylation of the complex. This phosphorylation can cause the dimer to dissociate and lose its GAP activity, or the phosphorylation can cause the heterodimer to have increased GAP activity, depending on which amino acid residue becomes phosphorylated. Thus, the signals that influence mTORC1 activity do so through activation or inactivation of the TSC1/TSC2 complex, upstream of mTORC1.Ragulator-Rag complex
mTORC1 interacts at the Ragulator-Rag complex on the surface of the lysosome in response to amino acid levels in the cell. 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. Active Rag heterodimers interact with raptor, localizing mTORC1 to the surface of late endosomes and lysosomes where the Rheb-GTP is located. 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.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. GATOR1 inhibits Rags and GATOR2 activates Rags by inhibiting DEPDC5.Upstream signaling
Receptor tyrosine kinases
Akt/PKB pathway
Insulin-like growth factors can activate mTORC1 through the receptor tyrosine kinase -Akt/PKB signaling pathway. Ultimately, Akt phosphorylates TSC2 on serine residue 939, serine residue 981, and threonine residue 1462. These phosphorylated sites will recruit the cytosolic anchoring protein 14-3-3 to TSC2, disrupting the TSC1/TSC2 dimer. When TSC2 is not associated with TSC1, TSC2 loses its GAP activity and can no longer hydrolyze Rheb-GTP. This results in continued activation of mTORC1, allowing for protein synthesis via insulin signaling.Akt will also phosphorylate PRAS40, causing it to fall off of the Raptor protein located on mTORC1. Since PRAS40 prevents Raptor from recruiting mTORC1's substrates 4E-BP1 and S6K1, its removal will allow the two substrates to be recruited to mTORC1 and thereby activated in this way.
Furthermore, since insulin is a factor that is secreted by pancreatic beta cells upon glucose elevation in the blood, its signaling ensures that there is energy for protein synthesis to take place. In a negative feedback loop on mTORC1 signaling, S6K1 is able to phosphorylate the insulin receptor and inhibit its sensitivity to insulin. This has great significance in diabetes mellitus, which is due to insulin resistance.
MAPK/ERK pathway
s, such as insulin like growth factor 1, can activate the MAPK/ERK pathway, which can inhibit the TSC1/TSC2 complex, activating mTORC1. In this pathway, the G protein Ras is tethered to the plasma membrane via a farnesyl group and is in its inactive GDP state. Upon growth factor binding to the adjacent receptor tyrosine kinase, the adaptor protein GRB2 binds with its SH2 domains. This recruits the GEF called Sos, which activates the Ras G protein. Ras activates Raf, which activates Mek, which activates Erk. Erk can go on to activate RSK. Erk will phosphorylate the serine residue 644 on TSC2, while RSK will phosphorylate serine residue 1798 on TSC2. These phosphorylations will cause the heterodimer to fall apart, and prevent it from deactivating Rheb, which keeps mTORC1 active.RSK has also been shown to phosphorylate raptor, which helps it overcome the inhibitory effects of PRAS40.
JNK pathway
c-Jun N-terminal kinase signaling is part of the mitogen-activated protein kinase 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. 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.Wnt pathway
The Wnt pathway is responsible for cellular growth and proliferation during organismal development; thus, it could be reasoned that activation of this pathway also activates mTORC1. Activation of the Wnt pathway inhibits glycogen synthase kinase 3 beta. When the Wnt pathway is not active, GSK3B is able to phosphorylate TSC2 on Ser1341 and Ser1337 in conjunction with AMPK phosphorylation of Ser1345. It has been reported that the AMPK is required to first phosphorylate Ser1345 before GSK3B can phosphorylate its target serine residues. This phosphorylation of TSC2 would activate this complex, if GSK3B were active. Since the Wnt pathway inhibits GSK3 signaling, the active Wnt pathway is also involved in the mTORC1 pathway. Thus, mTORC1 can activate protein synthesis for the developing organism.Cytokines
like tumor necrosis factor alpha can induce mTOR activity through IKK beta, also known as IKK2. IKK beta can phosphorylate TSC1 at serine residue 487 and TSC1 at serine residue 511. This causes the heterodimer TSC complex to fall apart, keeping Rheb in its active GTP-bound state.Energy and oxygen
Energy status
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.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.
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.
LKB1, also known as STK11, is a known tumor suppressor that can activate AMPK. More studies on this aspect of mTORC1 may help shed light on its strong link to cancer.
Hypoxic stress
When oxygen levels in the cell are low, it will limit its energy expenditure through the inhibition of protein synthesis. Under hypoxic conditions, hypoxia inducible factor one alpha will stabilize and activate transcription of REDD1, also known as DDIT4. After translation, this REDD1 protein will bind to TSC2, which prevents 14-3-3 from inhibiting the TSC complex. Thus, TSC retains its GAP activity towards Rheb, causing Rheb to remain bound to GDP and mTORC1 to be inactive.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.