The eIF2alpha phosphorylation pathway as a novel component of PI3K signaling with implications in tumor treatment
Bibliographic record
Abstract
Inhibition of protein synthesis by phosphorylation of eIF2alpha on serine 51 is mediated by a family of kinases activated by various forms of stress. The biological outcome of eIF2alpha phosphorylation can either be cytoprotective or pro-apoptotic. Translation is also regulated at the initiation step by modulation of eIF4E downstream of the PI3K/Akt/mTOR signaling pathway. Our research reveals that the PI3K/Akt/mTOR pathway can also regulate translation initiation by modulation of eIF2alpha kinase activity and eIF2alpha phosphorylation. Our findings provide evidence that the tumor suppressor PTEN activates the PKR- eIF2alpha phosphorylation pathway independently of its phosphatase activity but requires an intact PDZ-binding motif. Activation of the PKR- eIF2alpha phosphorylation pathway is essential for the anti-proliferative and pro-apoptotic functions of PTEN. Our work is in line with the pro-apoptotic functions of PKR and shows its requirement for the tumor suppressive functions of PTEN. The second important effector downstream of PI3K signaling, Akt, regulates a wide variety of biological processes. Our research shows that the eIF2alpha kinase PERK is a novel substrate of Akt. Indeed, Akt phosphorylates PERK on threonine 799 which inhibits its catalytic activity and ability to induce eIF2alpha phosphorylation. We further demonstrate that PERK activation and eIF2alpha phosphorylation counteract the biological functions of Akt in response to stress conditions including ER stress and oxidative stress. Our findings show that the cytoprotective PERK- eIF2alpha phosphorylation pathway is activated following treatment with pharmacological inhibitors of PI3K and Akt. We demonstrate that inactivation of the PERK-eIF2alpha phosphorylation pathway increases the susceptibility of tumor cells to death by pharmacological inhibitors of the PI3K/Akt pathway.The last arm of PI3K signaling is the mTORC1 pathway which is mainly involved in translational control. Our research reveals that mTORC1 interacts with PERK leading to its activation and induction of eIF2alpha phosphorylation independently of the kinase activity of mTOR. We further demonstrate that pharmacological inhibition of mTORC1 by rapamycin specifically induces PERK activation and eIF2alpha phosphorylation without initiating an ER stress response. Moreover, our findings reveal that the interaction between mTORC1 and PERK is increased following rapamycin treatment suggesting that a preferential localization of mTORC1 to the ER might be responsible for its ability to regulate PERK activity. Our research reveals a novel link between mTOR signaling and translational control through the eIF2alpha phosphorylation pathway.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".