The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP).
The PPP1R15 Family of eIF2-alpha Phosphatase Targeting Subunits (GADD34 and CReP).
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EIF2-Alpha磷酸酶靶向亚基的PPP1R15家族（GADD34和CREP）。
DOI：
10.3390/ijms242417321
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发表时间：
2023-12-10
影响因子：
5.6
通讯作者：
Weiser, Douglas C.
中科院分区：
文献类型：
--
作者：
Hicks, Danielle;Giresh, Krithika;Wrischnik, Lisa A.;Weiser, Douglas C.
脊椎动物PPP 1 R15家族由蛋白质GADD 34组成（生长停滞和DNA损伤诱导蛋白34，PPP 1 R15 A基因的产物）和CReP（eIF 2 α磷酸化的组成型阻遏物，PPP 1 R15 B基因的产物），两者通过调节亚细胞定位作为蛋白磷酸酶1（PP 1）的靶向/调节亚基发挥作用，调节底物特异性和与靶蛋白组装复合物。这些蛋白的主要细胞功能是在细胞应激期间通过PP 1促进真核起始因子2-α（eIF 2 α）的去磷酸化。本文从eIF 2 α通过整合蛋白反应（ISR）磷酸化的机制入手，对GADD 34和CReP的细胞功能、生物化学和药理学进行综述。我们讨论了GADD 34和CReP作为未折叠蛋白反应（UPR）的反馈抑制剂的作用，并强调了它们作为PERK依赖性分支抑制剂的关键功能，这是特别重要的，因为它可以介导细胞存活或细胞死亡，这取决于应激刺激持续多久，GADD 34和CReP在微调这种细胞决定中发挥关键作用。我们简要讨论了GADD 34和CReP同系物在模型系统中的作用，然后重点介绍我们从基因敲除小鼠和人类患者中了解到的有关其功能的信息，然后简要回顾了GADD 34和CReP涉及的几种疾病，包括癌症，糖尿病，特别是神经退行性疾病。由于GADD 34和CReP在人类健康和疾病方面的潜在重要性，我们将讨论GADD 34和/或CReP的几种药理学抑制剂，这些抑制剂显示出作为治疗方法的前景以及关于其作用机制的争议。本次审查将完成GADD 34和CReP的生化特性的讨论，其调节和其他相互作用的合作伙伴，这些蛋白质可能在其他细胞途径中发挥的作用提供洞察。最后，我们将简要概述未来研究的关键领域。
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.
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影响因子：
7.7
作者：
Andreev DE;O'Connor PB;Fahey C;Kenny EM;Terenin IM;Dmitriev SE;Cormican P;Morris DW;Shatsky IN;Baranov PV
通讯作者：
Baranov PV
影响因子：
4.5
作者：
Loveless TB;Topacio BR;Vashisht AA;Galaang S;Ulrich KM;Young BD;Wohlschlegel JA;Toczyski DP
通讯作者：
Toczyski DP
影响因子：
8
作者：
Amundson, SA;Zhan, Q;Fornace, AJ
通讯作者：
Fornace, AJ
影响因子：
16.8
作者：
Carrara M;Sigurdardottir A;Bertolotti A
通讯作者：
Bertolotti A
肌动蛋白动力学通过调节真核起始因子2α去磷酸化来调节综合应力反应。
影响因子：
7.7
作者：
Chambers JE;Dalton LE;Clarke HJ;Malzer E;Dominicus CS;Patel V;Moorhead G;Ron D;Marciniak SJ
通讯作者：
Marciniak SJ