Protein synthesis
Cap-dependent translation - the main output mTORC1 exists to control, and the step where a signalling decision becomes physical growth.
Making new proteins. Building proteins from mRNA - the main job mTORC1 exists to control, and the step where a signaling decision (mTOR is on) turns into an actual physical outcome (the cell grows).
Controlled through 4E-BP/eIF4E and S6K1/PDCD4/eIF4A arms; ribosome-profiling shows the response is transcript-selective, not uniform.
TL;DR. Protein synthesis appears in 19 curated studies in Oliver's mTOR Atlas: 1 in people (1 human study); 8 in animal models; 8 at the molecular level (cells, biochemistry, structure); 2 reviews. It has 3 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| Protein synthesis activates Muscle growth mechanism: functional-consequence · this link in full · on the map table | Ongoing protein-building is what physically builds muscle; in mice, the signals that drive it are needed for muscle growth and are enough to cause it. In people, blocking mTOR blunts the rise in muscle protein-building after a single bout of exercise, but how much muscle is gained over months under the drug was not measured. Holds under: Mouse (BOD2001) and cultured myotubes (ROM2001). The human study DRU2009 is cited on the step before this one (LOAD-MTORC1): rapamycin blocked the rise in muscle protein synthesis 1-2 h after one bout of contractions (and also blocked ERK1/2). It did not measure muscle growth, so it is not evidence for this arrow. Requires mechanical load. mTORC1 activation without loading does not reproduce healthy hypertrophy, and constitutive activation alone is not sufficient. plausible in people, not shown directly · settled in the literature | A | BOD2001, ROM2001 conflicting: LAP2026 |
| eIF4E activates Protein synthesis mechanism: functional-consequence · this link in full · on the map table | Freed eIF4E brings the ribosome to the mRNA – the step that actually turns a growth signal into new protein. Holds under: Biochemical and cell-based evidence (mouse cells with ribosome profiling, mouse models with human prostate cancer data in one study) plus a review. How much a given tissue depends on eIF4E-driven translation is not settled by these sources. plausible in people, not shown directly · settled in the literature | M | MAX2009, HSI2012, THO2012 |
| PDCD4 inhibits Protein synthesis mechanism: functional-consequence · this link in full · on the map table | PDCD4 jams a helper enzyme so some mRNAs can't be unwound and read. Holds under: SUZ2008 shows by structure and binding assays that PDCD4 binds the N-terminal domain of eIF4A and displaces eIF4G and RNA, which is the step asserted here. Cell-level evidence that PDCD4 loss changes translation of structured mRNAs is not in this corpus. plausible in people, not shown directly · settled in the literature | M | SUZ2008 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 1 |
| A | Animal model | 8 |
| M | Molecular — cells, biochemistry, structure | 8 |
| R | Review — secondary literature, not a new result | 2 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2009 | H | Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis DRU2009 Rapamycin given before resistance exercise blocked the early (1–2 h) post-exercise rise in human muscle protein synthesis, which was about 40% in the control group. Rapamycin also blocked the rise in ERK1/2 phosphorylation and blunted MNK1, so the authors conclude that mTORC1 drives the response only in part. The study measured acute protein synthesis, not muscle growth. |
| 2026 | A | D-Amino Acid Prodrug DLMEH Activates mTORC1 via Sestrin2 to Restore Muscle Protein Synthesis in Sarcopenia. SHIM2026 DLMEH, a D-leucine ester prodrug, binds Sestrin2 with leucine-like potency (Kd 28.3 uM, equivalent to L-leucine) and activates mTORC1 in a Sestrin2-dependent way. It restored protein synthesis in human myotubes and preserved muscle mass, grip strength and endurance in a rat dexamethasone-induced atrophy model (not an ageing sarcopenia model). |
| 2026 | A | Lsp2 links mTORC1 to TOP mRNA translation and lifespan in Drosophila WAN2026 Identifies Lsp2, a Drosophila fat-body storage protein, as an amino-acid-induced feedback activator of mTORC1 that specifically boosts translation of TOP-motif mRNAs (mostly ribosomal proteins) via 4E-BP — a rapamycin-resistant arm of mTORC1 output. Genetic loss of Lsp2 reduces TOP mRNA translation and robustly extends lifespan without cost to reproduction, revealing a rapamycin-independent route from mTORC1 activity to organismal longevity. |
| 2026 | A | Feeding-Induced Muscle mTORC1 Signaling Regulates Postprandial Protein Synthesis and Endurance but Not Muscle Size LAP2026 Using a mouse model expressing an AKT-nonphosphorylatable TSC2 mutant specifically in skeletal muscle, the Manning lab genetically separated feeding-induced from contraction-induced mTORC1 activation. AKT-mediated TSC2 phosphorylation is required for feeding (but not contraction) to activate muscle mTORC1 and drive postprandial protein synthesis — yet mice lacking this feeding-induced signal have normal muscle mass and myofiber size, and instead show improved maximal endurance capacity with a modest rise in mitochondrial content. The finding dissociates mTORC1's role in postprandial anabolism from its role in maintaining steady-state muscle mass, and is a directly relevant data point for whether the pattern/source of mTORC1 activation (feeding vs. mechanical) — not just its average level — shapes downstream outcomes. |
| 2015 | A | The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation LIP2015 S6K1, a main output of mTORC1, phosphorylates the clock protein BMAL1 rhythmically, and that phosphorylation lets BMAL1 join the translation machinery and drive protein synthesis. Protein synthesis rates oscillated over the day in a BMAL1-dependent way. A direct molecular bridge between mTORC1 output and the 24-hour clock. |
| 2013 | A | Autism-related deficits via dysregulated eIF4E-dependent translational control GKO2013 Mice lacking 4E-BP2, the main brain brake on eIF4E downstream of mTORC1, showed autism-like behaviours: reduced social approach in the three-chamber test, more self-grooming and marble burying, and more ultrasonic calls as pups. Polysome profiling of hippocampus showed that, of 24 autism-linked mRNAs tested, only the neuroligin 1-4 mRNAs shifted to heavier polysomes in the knockout, with no change in their mRNA levels or in global protein synthesis; eIF4E-overexpressing mice showed the same neuroligin shift. Knockout neurons had larger excitatory than inhibitory synaptic charge transfer, raising the excitation/inhibition ratio. Five days of brain infusion of 4EGI-1, which blocks eIF4E binding to eIF4G, brought cap-bound eIF4E/eIF4G and neuroligin levels back to normal and reversed the social deficit, and knocking down neuroligin 1 (but not neuroligin 2) partly restored social behaviour. Boundary: mouse genetic models (male mice for behaviour); mTOR itself was not manipulated; the link to human autism is by analogy. |
| 2007 | A | Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans HAN2007 The authors systematically tested whether lowering protein synthesis extends lifespan in the worm C. elegans. Reducing ribosomal proteins, the S6 kinase homologue rsks-1 or translation-initiation factors increased lifespan, and these perturbations, like TOR inhibition, increased resistance to heat stress. Different kinds of translation inhibition split into two groups: one that needed the FOXO transcription factor DAF-16 for the lifespan and stress effects and one that did not. The results linked TOR, but not sir-2.1, to the lifespan extension caused by dietary restriction in worms, and suggested that neither TOR inhibition nor dietary restriction works simply by reducing total protein synthesis. Boundary: Nematode only, with gene knockdown by RNAi or mutation; drafted from the abstract only, so effect sizes and which TOR experiments were new in this paper are not given here. |
| 2005 | A | Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis RUV2005 The authors made knock-in mice in which all five phosphorylatable serines of ribosomal protein S6 were replaced by alanine, so rpS6 could not be phosphorylated. Contrary to the then widely accepted model, translational control of 5'TOP mRNAs was unaffected. Fibroblasts from these mice made protein faster and divided faster, yet were smaller than wild-type cells, and rapamycin did not shrink them further, which points to rpS6 phosphorylation as a downstream effector of mTOR in cell-size control. Adult mutant mice also had smaller pancreatic beta-cells, less pancreatic insulin, low blood insulin and impaired glucose tolerance. Boundary: Mouse knock-in and mouse cells. Separates rpS6 phosphorylation from 5'TOP control in these systems; not tested in people. Drafted from the abstract only. |
| 2001 | A | Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo BOD2001 Akt/mTOR signalling is necessary and sufficient to drive skeletal-muscle hypertrophy and counteract atrophy in vivo. |
| 2026 | M | mTOR inactivation governs adaptive survival to ribosome biogenesis deficiency FAN2026 mTORC1 inhibition does not restore ribosome biogenesis but redistributes limited ribosomes away from highly-translated 5'TOP mRNAs toward survival-essential transcripts, defining a 'translational fitness' mechanism that lets cancer cells survive ribosome biogenesis deficiency. |
| 2026 | M | IDH3 regulates citrate homeostasis to control metabolic fitness and venetoclax resistance of AML stem cells DEM2026 IDH3A loss in AML leukemic stem cells reduces TCA cycle flux and raises intracellular citrate, activating AMPK and suppressing mTORC1 (lowering translation), which sensitizes cells to BCL2 inhibition by venetoclax - nominating the IDH3A-citrate-AMPK-mTORC1 axis as a target to overcome venetoclax/azacitidine resistance. |
| 2026 | M | Firefox, a protein encoded by circular PVT1, is essential for MYC-driven oncogenesis. TIW2026 A micropeptide (Firefox/FFX) encoded by the circular RNA circPVT1 stimulates AKT-mTORC1 signaling and cap-dependent translation to sustain MYC protein abundance and transcriptional output. FFX depletion reduces MYC levels and impairs tumor growth in MYC-amplified xenograft models, identifying an mTORC1-linked vulnerability in MYC-driven cancers. |
| 2026 | M | 5-Fluorouracil-based chemotherapy disrupts autophagy flux and protein synthesis in cultured myotubes: a role for mTORC1 signaling HAL2026 FOLFOX and oxaliplatin disrupted mTORC1/AMPK regulation of autophagy flux and protein synthesis in cultured myotubes; the effect was not easily reversible on drug withdrawal. Rapamycin (but not metformin) restored autophagy flux and AMPK phosphorylation, though without restoring protein synthesis. |
| 2023 | M | Continuous sensing of nutrients and growth factors by the mTORC1-TFEB axis SPA2023 Live imaging of single MCF10A cells shows mTORC1-TFEB signalling adjusts continuously to amino acids and insulin, given alone, one after another or together; at physiological amino acid levels TFEB, AMPK and AKT activity fluctuate in step, and these graded changes track protein synthesis rate through a distributed set of mTORC1 effectors. |
| 2021 | M | mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis VIL2021 SAMTOR (GU2017) showed the cell can sense S-adenosylmethionine and report it to mTORC1. This study runs the arrow the other way: mTORC1 controls how much SAM the cell makes. Downstream of mTORC1, c-MYC binds intron 1 of MAT2A and raises expression of the enzyme that produces SAM, the cell's main methyl donor; mTORC1 separately increases the protein level of WTAP, the regulatory subunit of the m6A RNA methyltransferase complex. Together these raise m6A methylation of mRNA, which primes the translation machinery for growth. Blocking MAT2A lowers SAM, m6A, protein synthesis rate and tumor growth. |
| 2012 | M | The translational landscape of mTOR signalling steers cancer initiation and metastasis HSI2012 Showed WHY mTOR-driven translation matters for cancer: in prostate cancer, oncogenic mTOR selectively translates a specific set of pro-invasion mRNAs that drive metastasis. An ATP-competitive mTOR inhibitor (INK128) reversed that signature - an early preclinical rationale from mouse models and cell lines, not a clinical result. |
| 2009 | R | Molecular mechanisms of mTOR-mediated translational control MAX2009 Review of the molecular mechanisms of mTOR-mediated translational control. |
| 2009 | R | Translational control of long-lasting synaptic plasticity and memory COS2009 This review gathers evidence that long-lasting synaptic plasticity and long-term memory depend on new protein synthesis, and that the step where mRNA translation starts is a main control point. It covers two arms: the mTORC1 arm (4E-BP2, eIF4E, S6K) that controls cap-dependent translation, and the eIF2alpha arm (GCN2, PKR, ATF4) that controls general translation and specific mRNAs. It also discusses how faulty translational control is linked to disorders such as fragile X syndrome and tuberous sclerosis. It is a summary of work by many labs and gives the field a shared framework rather than new data. Boundary: narrative review; the cited evidence is mainly from rodent slices, rodent behaviour and invertebrate models, not from people. |
| 2006 | M | S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth DOR2006 S6K1 triggers betaTRCP-mediated degradation of the tumour suppressor PDCD4 to promote translation. |
Related entities
Was this page useful?
Thank you. Your answer was counted anonymously.