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The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP)
Danielle Hicks1,2, Krithika Giresh2, Lisa A Wrischnik2
1Department of Science, Mathematics and Engineering, Modesto Junior College, Modesto, CA 95350, USA.
International Journal of Molecular Sciences
|December 23, 2023
Summary
GADD34 and CReP regulate protein phosphatase 1 (PP1) to control the integrated stress response (ISR). These proteins are key in cell fate decisions during stress and are implicated in diseases like cancer and neurodegeneration.
Area of Science:
- Molecular Biology
- Cellular Stress Response
- Protein Phosphatase Regulation
Background:
- The PPP1R15 family, including GADD34 and CReP, are regulatory subunits of protein phosphatase 1 (PP1).
- They are crucial for dephosphorylating eukaryotic initiation factor 2-alpha (eIF2α) during cellular stress.
- This dephosphorylation is a key component of the integrated stress response (ISR).
Purpose of the Study:
- To provide a comprehensive review of GADD34 and CReP functions, biochemistry, and pharmacology.
- To elucidate their roles as feedback inhibitors of the unfolded protein response (UPR), particularly the PERK-dependent branch.
- To explore their implications in human diseases and potential therapeutic strategies.
Main Methods:
- Literature review of cellular functions, biochemistry, and pharmacology of GADD34 and CReP.
- Analysis of data from knockout mice and human patients.
- Discussion of existing and potential pharmacological inhibitors.
Main Results:
- GADD34 and CReP fine-tune cell survival or death decisions mediated by the PERK pathway.
- They are implicated in cancer, diabetes, and neurodegenerative diseases.
- Pharmacological inhibitors targeting GADD34 and/or CReP show therapeutic promise.
Conclusions:
- GADD34 and CReP are critical regulators of cellular stress responses and cell fate.
- Dysregulation of these proteins is linked to various human diseases.
- Targeting GADD34 and CReP offers potential therapeutic avenues, though mechanisms require further clarification.
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