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regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway

Definition

Target type: biologicalprocess

Any process that modulates the frequency, rate or extent of an endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway. [GOC:BHF, GOC:mtg_apoptosis, GOC:rl, GOC:TermGenie, PMID:20160352]

The endoplasmic reticulum (ER) is a critical organelle responsible for protein folding, modification, and trafficking. ER stress occurs when the accumulation of unfolded or misfolded proteins in the ER lumen overwhelms its protein folding capacity. This triggers a complex signaling pathway known as the unfolded protein response (UPR), aimed at restoring ER homeostasis. However, prolonged or severe ER stress can activate the intrinsic apoptotic signaling pathway, leading to programmed cell death.

The regulation of ER stress-induced intrinsic apoptotic signaling pathway involves a intricate interplay of molecular mechanisms, including:

1. **UPR Activation:** Three transmembrane sensors in the ER membrane, PERK, ATF6, and IRE1α, are activated by unfolded proteins. They initiate distinct branches of the UPR.

- **PERK** (Protein kinase RNA-like endoplasmic reticulum kinase): Phosphorylates the eukaryotic initiation factor 2α (eIF2α), leading to a temporary global translation inhibition, reducing the burden of protein synthesis.
- **ATF6** (Activating transcription factor 6): Translocates to the Golgi apparatus where it is cleaved, releasing the active transcription factor ATF6-N, which upregulates genes involved in ER chaperone protein production and ER expansion.
- **IRE1α** (Inositol-requiring enzyme 1α): Activates the splicing of XBP1 mRNA, generating a transcription factor that induces the expression of ER chaperones and genes involved in ER-associated degradation (ERAD).

2. **Apoptosis Induction:** When ER stress persists despite UPR activation, the pro-apoptotic signaling pathway is initiated.

- **IRE1α**: Activates the transcription factor CHOP (C/EBP homologous protein), which promotes the expression of pro-apoptotic genes like GADD34 and TRB3, contributing to apoptosis. IRE1α also activates JNK (c-Jun N-terminal kinase), a kinase involved in apoptotic signaling.
- **PERK:** Activates the transcription factor ATF4, which promotes the expression of the pro-apoptotic gene CHOP, leading to the activation of caspase-12.
- **Caspase-12:** An ER-resident caspase, is activated by ER stress and initiates the apoptotic cascade. It activates caspase-9, which in turn activates the executioner caspases (caspase-3, -6, and -7).
- **Mitochondrial Dysregulation:** ER stress can lead to mitochondrial dysfunction, including the release of cytochrome c from the mitochondria into the cytosol. This activates the apoptosome, a protein complex composed of Apaf-1, caspase-9, and cytochrome c, which triggers the caspase cascade.

3. **Apoptotic Execution:** Activated caspases dismantle the cell by cleaving crucial cellular proteins, leading to DNA fragmentation, nuclear condensation, and ultimately cell death.

4. **Feedback Loop:** The activation of apoptotic signaling pathways can further amplify ER stress, creating a positive feedback loop that reinforces the apoptotic process.

The intricate balance between UPR activation and apoptotic signaling determines cell fate under ER stress conditions. While the UPR aims to restore ER homeostasis, prolonged or severe stress overwhelms its capacity and triggers the apoptotic pathway, leading to cell death. Understanding the mechanisms of ER stress-induced apoptosis is crucial for developing strategies to combat various diseases associated with ER stress, such as cancer, neurodegenerative disorders, and metabolic diseases.'
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Proteins (1)

ProteinDefinitionTaxonomy
Eukaryotic translation initiation factor 2-alpha kinase 3A eukaryotic translation initiation factor 2-alpha kinase 3 that is encoded in the genome of human. [PRO:CNx, UniProtKB:Q9NZJ5]Homo sapiens (human)

Compounds (6)

CompoundDefinitionClassesRoles
entrectinibentrectinib : 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 p937NMS P937: a polo-like kinase 1 inhibitor; structure in first source
nms-p118NMS-P118: a PARP-1 inhibitor; structure in first source
gsk2656157biaryl;
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-amine7-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-e973NMS-E973: structure in first source