Target type: biologicalprocess
Any process that modulates the rate, frequency, or extent of eIF2 alpha phosphorylation as a cellular response to endoplasmic reticulum stress. [GOC:dph, GOC:tb]
The endoplasmic reticulum (ER) is a cellular organelle responsible for protein folding and modification. When the ER is stressed, for example, due to an accumulation of unfolded proteins, a complex signaling pathway is activated, leading to the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α). This phosphorylation has a crucial role in regulating protein synthesis and ultimately restoring ER homeostasis.
The regulation of eIF2α phosphorylation during ER stress is mediated by a cascade of events involving several key players:
1. **ER Stress Sensors:** The ER membrane harbors transmembrane proteins called ER stress sensors, including PERK (PKR-like ER kinase), ATF6 (activating transcription factor 6), and IRE1α (inositol-requiring enzyme 1α). These sensors are activated upon accumulation of unfolded proteins in the ER lumen.
2. **PERK Activation:** Upon sensing ER stress, PERK undergoes oligomerization and autophosphorylation. This activated PERK then phosphorylates eIF2α on its serine 51 residue.
3. **eIF2α Phosphorylation:** Phosphorylation of eIF2α by PERK inhibits the initiation of protein translation, thereby reducing the load of unfolded proteins in the ER. This is because eIF2α is a critical component of the translation initiation complex, and its phosphorylation prevents the formation of the ternary complex containing eIF2α, GTP, and the initiator methionine tRNA (Met-tRNAi).
4. **ATF4 Induction:** The phosphorylation of eIF2α also leads to the increased translation of specific mRNAs, including the transcription factor ATF4. ATF4 is a key player in the unfolded protein response (UPR) and activates the expression of genes involved in protein folding, ERAD (ER-associated protein degradation), and autophagy.
5. **ATF6 Activation:** ER stress also activates ATF6, a transcription factor residing in the ER membrane. ATF6 is cleaved by proteases in response to ER stress, releasing the cytosolic fragment that translocates to the nucleus. ATF6 then activates the expression of genes involved in protein folding, ERAD, and lipid biosynthesis.
6. **IRE1α Activation:** Another ER stress sensor, IRE1α, oligomerizes and activates its endoribonuclease activity upon ER stress. IRE1α cleaves the mRNA of XBP1, a transcription factor involved in the UPR. This splicing event leads to the translation of a functional XBP1 protein that further activates the expression of genes involved in protein folding, ERAD, and autophagy.
7. **Negative Feedback Mechanisms:** The UPR is a complex and tightly regulated process. Several negative feedback mechanisms are in place to prevent excessive or prolonged activation of the pathway. These mechanisms include the dephosphorylation of eIF2α by protein phosphatase 1 (PP1) and the degradation of ATF4 by proteasomes.
In summary, the regulation of eIF2α phosphorylation during ER stress is a crucial mechanism for maintaining ER homeostasis. The phosphorylation of eIF2α reduces protein translation, promotes the expression of UPR genes, and ultimately restores the balance of protein folding and degradation in the ER. This intricate process is essential for cell survival and function.'
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Protein | Definition | Taxonomy |
---|---|---|
Eukaryotic translation initiation factor 2-alpha kinase 3 | A eukaryotic translation initiation factor 2-alpha kinase 3 that is encoded in the genome of human. [PRO:CNx, UniProtKB:Q9NZJ5] | Homo sapiens (human) |
Compound | Definition | Classes | Roles |
---|---|---|---|
entrectinib | entrectinib : A member of the class of indazoles that is 1H-indazole substituted by [4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzoyl]amino and 3,5-difluorobenzyl groups at positions 3 and 5, respectively. It is a potent inhibitor of TRKA, TRKB, TRKC, ROS1, and ALK (IC50 values of 0.1 to 1.7 nM), and used for the treatment of NTRK, ROS1 and ALK gene fusion-positive solid tumours. entrectinib: inhibits TRK, ROS1, and ALK receptor tyrosine kinases; structure in first source | benzamides; difluorobenzene; indazoles; N-methylpiperazine; oxanes; secondary amino compound; secondary carboxamide | antibacterial agent; antineoplastic agent; apoptosis inducer; EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor |
nms p937 | NMS P937: a polo-like kinase 1 inhibitor; structure in first source | ||
nms-p118 | NMS-P118: a PARP-1 inhibitor; structure in first source | ||
gsk2656157 | biaryl; indoles; methylpyridines; organofluorine compound; pyrrolopyrimidine; tertiary carboxamide | antineoplastic agent; EC 3.1.3.48 (protein-tyrosine-phosphatase) inhibitor; PERK inhibitor | |
7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1h-indol-5-yl)-7h-pyrrolo(2,3-d)pyrimidin-4-amine | 7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine: inhibits protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK); structure in first source | ||
nms-e973 | NMS-E973: structure in first source |