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.

mTORC1 interacts at the Ragulator-Rag complex on the surface of the lysosome in response to amino acid levels in the cell.

[13] Active Rag heterodimers interact with raptor, localizing mTORC1 to the surface of late endosomes and lysosomes where the Rheb-GTP is located.

[20] 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.

[19] In this pathway, the G protein Ras is tethered to the plasma membrane via a farnesyl group and is in its inactive GDP state.

Thus, JNK activation plays a role in protein synthesis via subsequent downstream effectors of mTORC1 such as S6 kinase and eIFs.

[28] Cytokines like tumor necrosis factor alpha (TNF-alpha) can induce mTOR activity through IKK beta, also known as IKK2.

This causes the heterodimer TSC complex to fall apart, keeping Rheb in its active GTP-bound state.

In order for translation to take place, abundant sources of energy, particularly in the form of ATP, need to be present.

[33] When oxygen levels in the cell are low, it will limit its energy expenditure through the inhibition of protein synthesis.

[34][35] 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] mTORC1 activates transcription and translation through its interactions with p70-S6 Kinase 1 (S6K1) and 4E-BP1, the eukaryotic initiation factor 4E (eIF4E) binding protein 1, primarily via phosphorylation and dephosphorylation of its downstream targets.

[39] The helicase is required to remove hairpin loops that arise in the 5' untranslated regions of mRNA, which prevent premature translation of proteins.

[46] Active S6K can bind to the SKAR scaffold protein that can get recruited to exon junction complexes (EJC).

[48][49] S6K also can phosphorylate programmed cell death 4 (PDCD4), which marks it for degradation by ubiquitin ligase Beta-TrCP (BTRC).

[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.

[55] Autophagy is the major degradation pathway in eukaryotic cells and is essential for the removal of damaged organelles via macroautophagy or proteins and smaller cellular debris via microautophagy from the cytoplasm.

[56] Thus, autophagy is a way for the cell to recycle old and damaged materials by breaking them down into their smaller components, allowing for the resynthesis of newer and healthier cellular structures.

[57] Upon activation, mTORC1 will phosphorylate autophagy-related protein 13 (Atg 13), preventing it from entering the ULK1 kinase complex, which consists of Atg1, Atg17, and Atg101.

[66] 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.

[77] Paradoxically, even though rapamycin is a federally approved immunosuppressant, its inhibition of mTORC1 results in better quantity and quality of functional memory T cells.

[79] mTORC1 inhibition with rapamycin has also been linked to a dramatic increase of B cells in old mice, enhancing their immune systems.

[75] This paradox of rapamycin inhibiting the immune system response has been linked to several reasons, including its interaction with regulatory T cells.

[79] Resistance exercise, the amino acid L-leucine, and beta-hydroxy beta-methylbutyric acid (HMB) are known to induce signaling cascades in skeletal muscle cells that result in mTOR phosphorylation, the activation of mTORC1, and subsequently the initiation of myofibrillar protein synthesis (i.e., the production of proteins such as myosin, titin, and actin), thereby facilitating muscle hypertrophy.

The NMDA receptor antagonist ketamine has been found to activate the mTORC1 pathway in the medial prefrontal cortex (mPFC) of the brain as an essential downstream mechanism in the mediation of its rapid-acting antidepressant effects.

[80] NV-5138 is a ligand and modulator of sestrin2, a leucine amino acid sensor and upstream regulatory pathway of mTORC1, and is under development for the treatment of depression.

[80] The drug has been found to directly and selectively activate the mTORC1 pathway, including in the mPFC, and to produce rapid-acting antidepressant effects similar to those of ketamine.

[80] There have been several dietary compounds that have been suggested to inhibit mTORC1 signaling including EGCG, resveratrol, curcumin, caffeine, and alcohol.

[90] mTORC1 inhibition by everolimus has been shown to normalize tumor blood vessels, to increase tumor-infiltrating lymphocytes, and to improve adoptive cell transfer therapy.

Rapamycin and its analogues also have procoagulant side effects caused by off-target binding of the activated immunophilin FKBP12, which are not produced by structurally unrelated inhibitors of mTORC such as gedatolisib, WYE-687 and XL-388.