The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP)
The vertebrate PPP1R15 family consists of the proteins GADD34 (growth arrest and DNA damage-inducible protein 34, the product of the PPP1R15A gene) and CReP (constitutive repressor of eIF2α phosphorylation, the product of the PPP1R15B gene), both of which function as targeting/regulatory subunits fo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/24/17321 |
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| author | Danielle Hicks Krithika Giresh Lisa A. Wrischnik Douglas C. Weiser |
| author_facet | Danielle Hicks Krithika Giresh Lisa A. Wrischnik Douglas C. Weiser |
| author_sort | Danielle Hicks |
| collection | DOAJ |
| description | The vertebrate PPP1R15 family consists of the proteins GADD34 (growth arrest and DNA damage-inducible protein 34, the product of the PPP1R15A gene) and CReP (constitutive repressor of eIF2α phosphorylation, the product of the PPP1R15B gene), both of which function as targeting/regulatory subunits for protein phosphatase 1 (PP1) by regulating subcellular localization, modulating substrate specificity and assembling complexes with target proteins. The primary cellular function of these proteins is to facilitate the dephosphorylation of eukaryotic initiation factor 2-alpha (eIF2α) by PP1 during cell stress. In this review, we will provide a comprehensive overview of the cellular function, biochemistry and pharmacology of GADD34 and CReP, starting with a brief introduction of eIF2α phosphorylation via the integrated protein response (ISR). We discuss the roles GADD34 and CReP play as feedback inhibitors of the unfolded protein response (UPR) and highlight the critical function they serve as inhibitors of the PERK-dependent branch, which is particularly important since it can mediate cell survival or cell death, depending on how long the stressful stimuli lasts, and GADD34 and CReP play key roles in fine-tuning this cellular decision. We briefly discuss the roles of GADD34 and CReP homologs in model systems and then focus on what we have learned about their function from knockout mice and human patients, followed by a brief review of several diseases in which GADD34 and CReP have been implicated, including cancer, diabetes and especially neurodegenerative disease. Because of the potential importance of GADD34 and CReP in aspects of human health and disease, we will discuss several pharmacological inhibitors of GADD34 and/or CReP that show promise as treatments and the controversies as to their mechanism of action. This review will finish with a discussion of the biochemical properties of GADD34 and CReP, their regulation and the additional interacting partners that may provide insight into the roles these proteins may play in other cellular pathways. We will conclude with a brief outline of critical areas for future study. |
| first_indexed | 2024-03-08T20:41:36Z |
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| id | doaj.art-2f5138aab1874ffb835002a6b73a2cca |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T20:41:36Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-2f5138aab1874ffb835002a6b73a2cca2023-12-22T14:14:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-12-0124241732110.3390/ijms242417321The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP)Danielle Hicks0Krithika Giresh1Lisa A. Wrischnik2Douglas C. Weiser3Department of Science, Mathematics and Engineering, Modesto Junior College, Modesto, CA 95350, USADepartment of Biological Sciences, University of the Pacific, Stockton, CA 95211, USADepartment of Biological Sciences, University of the Pacific, Stockton, CA 95211, USADepartment of Biological Sciences, University of the Pacific, Stockton, CA 95211, USAThe vertebrate PPP1R15 family consists of the proteins GADD34 (growth arrest and DNA damage-inducible protein 34, the product of the PPP1R15A gene) and CReP (constitutive repressor of eIF2α phosphorylation, the product of the PPP1R15B gene), both of which function as targeting/regulatory subunits for protein phosphatase 1 (PP1) by regulating subcellular localization, modulating substrate specificity and assembling complexes with target proteins. The primary cellular function of these proteins is to facilitate the dephosphorylation of eukaryotic initiation factor 2-alpha (eIF2α) by PP1 during cell stress. In this review, we will provide a comprehensive overview of the cellular function, biochemistry and pharmacology of GADD34 and CReP, starting with a brief introduction of eIF2α phosphorylation via the integrated protein response (ISR). We discuss the roles GADD34 and CReP play as feedback inhibitors of the unfolded protein response (UPR) and highlight the critical function they serve as inhibitors of the PERK-dependent branch, which is particularly important since it can mediate cell survival or cell death, depending on how long the stressful stimuli lasts, and GADD34 and CReP play key roles in fine-tuning this cellular decision. We briefly discuss the roles of GADD34 and CReP homologs in model systems and then focus on what we have learned about their function from knockout mice and human patients, followed by a brief review of several diseases in which GADD34 and CReP have been implicated, including cancer, diabetes and especially neurodegenerative disease. Because of the potential importance of GADD34 and CReP in aspects of human health and disease, we will discuss several pharmacological inhibitors of GADD34 and/or CReP that show promise as treatments and the controversies as to their mechanism of action. This review will finish with a discussion of the biochemical properties of GADD34 and CReP, their regulation and the additional interacting partners that may provide insight into the roles these proteins may play in other cellular pathways. We will conclude with a brief outline of critical areas for future study.https://www.mdpi.com/1422-0067/24/24/17321GADD34CRePPPP1R15PPP1R15APPP1R15BPP1 |
| spellingShingle | Danielle Hicks Krithika Giresh Lisa A. Wrischnik Douglas C. Weiser The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP) International Journal of Molecular Sciences GADD34 CReP PPP1R15 PPP1R15A PPP1R15B PP1 |
| title | The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP) |
| title_full | The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP) |
| title_fullStr | The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP) |
| title_full_unstemmed | The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP) |
| title_short | The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP) |
| title_sort | ppp1r15 family of eif2 alpha phosphatase targeting subunits gadd34 and crep |
| topic | GADD34 CReP PPP1R15 PPP1R15A PPP1R15B PP1 |
| url | https://www.mdpi.com/1422-0067/24/24/17321 |
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