eIF4E
Cap-binding protein that recruits the ribosome to an mRNA. Held hostage by 4E-BP1 until mTORC1 phosphorylates the latter - the rate-limiting step of cap-dependent translation.
The clamp that starts reading mRNA. A protein that grabs onto mRNA and starts the process of building a new protein from it. Normally it's held back by 4E-BP1; mTORC1 releases that hold, which is the key step that turns on protein production.
Rate-limiting for cap-dependent initiation; a proto-oncogene in its own right when overexpressed.
TL;DR. eIF4E appears in 11 curated studies in Oliver's mTOR Atlas: 1 in animal models; 8 at the molecular level (cells, biochemistry, structure); 2 reviews. No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| 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 |
| 4E-BP1 inhibits eIF4E mechanism: competitive-inhibition · this link in full · on the map table | Untagged 4E-BP1 clamps onto eIF4E and blocks it; mTORC1 tags 4E-BP1 to make it let go – releasing a brake, not pressing an accelerator. Holds under: Biochemical and cell-culture evidence (in vitro assays, mammalian and mouse cells, plus one review). It establishes the binding switch itself. It does not measure how much translation changes in a given tissue, in whole animals or in people. plausible in people, not shown directly · settled in the literature | M | MAX2009, THO2012, SCH2003, FIN2002 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 1 |
| M | Molecular — cells, biochemistry, structure | 8 |
| R | Review — secondary literature, not a new result | 2 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 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. |
| 2012 | M | A unifying model for mTORC1-mediated regulation of mRNA translation THO2012 Used ribosome profiling with the complete inhibitor Torin1 to address a long-standing debate: in these cells, mTORC1's translational control runs largely through the 4E-BP family acting on a specific class of mRNAs (TOP motifs). Losing just the 4E-BPs makes translation of TOP mRNAs resistant to mTOR inhibition - naming them the master effectors. |
| 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. |
| 2003 | M | TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function SCH2003 The TOS motif mediates raptor binding and controls multisite 4E-BP1 phosphorylation by mTORC1. |
| 2002 | M | Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E FIN2002 mTOR controls mammalian cell size through its downstream translational targets S6K1 and 4E-BP1/eIF4E. |
| 2002 | M | Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling TEE2002 The authors coexpressed hamartin (TSC1) and tuberin (TSC2) in cultured cells and followed two main outputs of mTOR. Together, the two proteins reduced phosphorylation of 4E-BP1, so more 4E-BP1 stayed bound to the translation factor eIF4E; a TSC2 mutant found in TSC patients was defective at this. Hamartin plus tuberin also lowered S6K1 activity, but did not affect S6K1 mutants that resist rapamycin, which points to mTOR as the step being blocked. In nutrient-deprived cells, hamartin and tuberin prevented amino acids from switching S6K1 back on. The authors concluded that the TSC1-TSC2 complex acts as an inhibitor of mTOR signalling and suggested that TSC tumours may come from too much mTOR activity. Boundary: overexpression in cultured mammalian cells; the link to tumours in TSC patients is a proposal, not tested in patient tissue here. |
| 2002 | M | A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus TAN2002 The authors showed that mTOR, 4E-BP1, 4E-BP2 and eIF4E are present in rat hippocampus and sit in dendrites, close to synapses, where their staining overlapped with the postsynaptic protein PSD-95. Blocking mTOR with rapamycin in hippocampal slices reduced late-phase long-term potentiation (LTP) after high-frequency stimulation, while early-phase LTP was unaffected. Rapamycin also blocked the synaptic potentiation induced by the growth factor BDNF. This was one of the early papers to tie a rapamycin-sensitive pathway to the protein-synthesis-dependent phase of synaptic plasticity and to suggest it controls local translation at synapses. Boundary: rodent brain slices and cultured neurons; mTOR targets were localised but their phosphorylation during LTP was not reported in the abstract; no behaviour or memory test. |
| 1999 | M | Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism GIN1999 4E-BP1 is phosphorylated by an ordered, priming two-step mechanism that controls its release of eIF4E. |
| 1997 | M | Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin BRU1997 mTOR directly phosphorylates 4E-BP1 (PHAS-I), releasing eIF4E and establishing mTOR's role in translational control. |
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