PPP6C

更新于：2025-05-07

基本信息

别名

PP6、PP6C、PPP6

+ [4]

简介

Catalytic subunit of protein phosphatase 6 (PP6) (PubMed:17079228, PubMed:29053956, PubMed:32474700). PP6 is a component of a signaling pathway regulating cell cycle progression in response to IL2 receptor stimulation (PubMed:10227379). N-terminal domain restricts G1 to S phase progression in cancer cells, in part through control of cyclin D1 (PubMed:17568194). During mitosis, regulates spindle positioning (PubMed:27335426). Down-regulates MAP3K7 kinase activation of the IL1 signaling pathway by dephosphorylation of MAP3K7 (PubMed:17079228). Participates also in the innate immune defense against viruses by desphosphorylating RIGI, an essential step that triggers RIGI-mediated signaling activation (PubMed:29053956). Also regulates innate immunity by acting as a negative regulator of the cGAS-STING pathway: mediates dephosphorylation and inactivation of CGAS and STING1 (PubMed:32474700, PubMed:32753499). CGAS dephosphorylation at 'Ser-435' impairs its ability to bind GTP, thereby inactivating it (PubMed:32474700).

关联

项与 PPP6C 相关的药物

CN118063558

专利挖掘

靶点

PPP6C

作用机制-

在研机构

深圳市人民医院 [+1]

原研机构

深圳市人民医院 [+1]

在研适应症

呼吸系统疾病

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PPP6C 相关的临床结果

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100 项与 PPP6C 相关的转化医学

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0 项与 PPP6C 相关的专利（医药）

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239

项与 PPP6C 相关的文献（医药）

2025-05-01·Phytomedicine

10-Hydroxydec-2-enoic acid reduces vascular smooth muscle cell inflammation via interacting with Toll-like receptor 4

Article

作者: Wang, Yongqing ; Chen, Zhiqiang ; Jia, Feng ; Wang, Yanyan ; Zeng, Lei ; Jin, Jingxian ; Tang, Huaijian ; Zhang, Li ; Fan, Pei

BACKGROUND10-Hydroxydec-2-enoic acid (10-HDA), a unique and marker compound in royal jelly, has a wide range of bio-activities. However, its role in regulating inflammation of vascular smooth muscle cell (VSMC), which is essential to a set of vascular diseases, is still unknown.PURPOSEOur study aimed to investigate whether 10-HDA exerts effect on VSMC inflammation via interacting with toll-like receptor 4 (TLR4), a pivotal inflammatory initiator.METHODSA package of proteins, which might participate in TLR4-mediated signaling, influenced by 10-HDA were analyzed in mouse VSMCs with Angiotensin Ⅱ(Ang Ⅱ) or lipopolysaccharide (LPS) stimulation. Accordingly, pro- or anti-inflammatory cytokines, reactive oxygen species (ROS), and anti-oxidants that are closely relevant to inflammatory process were determined. The possible mode for 10-HDA interacting with TLR4 was also characterized. Moreover, involvement of a key miRNA in 10-HDA regulating VSMC inflammation was identified.RESULTSIn the presence of Ang Ⅱ, 10-HDA inhibited the TLR4 expression in a dose-dependent manner. In such occasion, 10-HDA hindered the up-regulation of specificity protein 1 (SP1) and serine/threonine-protein phosphatase 6 catalytic subunit (PPP6C), the phosphorylation of extracellular signal-regulated kinase 1/2, TGF-β-activated kinase 1, and nuclear factor-κB p56, as well as the enhancement of myeloid differentiation primary response gene 88. Apart from SP1 and PPP6C, the level change of these proteins by 10-HDA was similar with LPS stimulation. The effect might be resulted from 10-HDA blocking TLR4 through multiple atomic interactions. 10-HDA mitigated the increase of pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-2 (IL-2), and IL-6, as well as increased the anti-inflammatory cytokine IL-10, in the Ang Ⅱ- or LPS-induced VSMCs. Correspondingly, the level of ROS was attenuated and the anti-oxidants such as glutathione and superoxide dismutase were fortified. The data indicated the anti-inflammatory potential of 10-HDA in VSMCs, which was associated with 10-HDA's capability of relieving oxidative stress. Additionally, the expression of miR-17-5p was saved by 10-HDA from Ang Ⅱ- or LPS-treated VSMCs, which might be relevant to SP1 and PPP6C targeting.CONCLUSIONThe present work of 10-HDA, for the first time, revealed its ability to alleviate VSMC inflammation by targeting TLR4 and therefore modulate the downstream inflammatory participants. Our data will cast light on the utilization of 10-HDA in VSMC inflammation-related vascular disorders.

2025-03-06·Current Medicinal Chemistry

Functional Role of Protein Phosphatase-6 (PPP6c): Regulation of Expression and Modulation of Activity

Article

作者: Tatiana, Ruksha ; Mariya, Aksenenko

Abstract:This review produces information about the role of protein phosphatase-6 (PPP6C) in various biological processes such as cell proliferation, cell cycle regulation, apoptosis, autophagy, cell migration and differentiation, and DNA damage repair. The issues of the participation of PPP6C in the formation of tumor progression and the role of PPP6C in the epigenetic regulation of the tumor process are covered. The article presents in detail the classification of mutations depending on the biological effects they have. It has been shown that various types of mutations in the PPP6C gene can change the composition of the heterotrimeric complex, favoring some regulatory subunits over others, which promotes selective dephosphorylation of substrates to maintain cell viability and change their biological behavior. In particular, their proliferative activity is disrupted, leading to mitosis arrest at various cell cycle stages. An increase in the activity of Aurora A or a decrease in the activity of DNA-dependent protein kinase is considered the main molecular mechanism of tumor development associated with the inactivation of the pp6c protein. The article also discusses the topic of pharmacological modulation of PPP6C activity. PP6 is a protein involved in many biological processes. In this regard, it is especially important to clarify the role of each PP6 holoenzyme and the molecular mechanisms that regulate the formation of the PP6 complex. Changes in the activity of this phosphatase can disrupt cell functioning.

2025-03-01·Phytomedicine

Exploring the therapeutic potential of Abelmoschi Corolla in psoriasis: Mechanisms of action and inflammatory pathway disruption

Article

作者: Qu, Baoquan ; Zhao, Ning ; Zhu, Haoyue ; Li, Ping ; Zhao, Jingxia ; Li, Ruonan ; Ma, Huike ; Li, Guanglu

BACKGROUNDPsoriasis is a prevalent chronic inflammatory skin condition for which existing treatments often fall short of fully addressing patient needs. Abelmoschi Corolla (AC), a traditional Chinese medicine, and its ethanol extract, huangkui capsule, are well established for the treatment of chronic kidney diseases. The therapeutic mechanisms of AC include anti-inflammatory effects and immune modulation, which align with psoriasis treatment strategies. Nevertheless, the potential of AC as a therapeutic agent for psoriasis remains unexplored.PURPOSEThis study aimed to evaluate the efficacy of AC in treating psoriasis and, if effective, to elucidate the underlying mechanisms by which AC exerts its therapeutic effects.METHODSTo assess the therapeutic potential of AC, an imiquimod-induced psoriasis-like mouse model was utilized. Bioinformatics and machine learning approaches were employed to predict the targets and mechanisms of AC in psoriasis. Further validation was performed using targeted metabolite quantification, immunohistochemistry, polymerase chain reaction, and western blotting.RESULTSAC treatment significantly improved psoriasis-like skin lesions, as indicated by enhancements in appearance, PASI scores, a reduction in epidermal hyperproliferation, and decreased immune cell infiltration. Bioinformatics and machine learning analyses identified arginase 1 (ARG1) as a key target of AC in psoriasis. Experimental validation demonstrated that AC reduced ARG1 expression, arginine metabolism, and polyamine production by upregulating PP6 expression and inhibiting C/EBP-β activation in psoriatic keratinocytes, resulting in the suppression of dendritic cell infiltration and a reduction in the expression of inflammatory cytokines, including IL-23, IL-6, IL-1β, IL-17A, and TNF-α.CONCLUSIONSAC disrupted the inflammatory pathways associated with psoriasis and alleviated imiquimod-induced psoriasis-like skin inflammation by inhibiting ARG1 overexpression and arginine metabolism in psoriatic keratinocytes. These findings suggest that AC has significant potential as a therapeutic agent for psoriasis and warrants further research and development.

项与 PPP6C 相关的新闻（医药）

2023-04-10

·生物谷

蛋糕烧烤自由实现了？Nature子刊：抵御高脂饮食不利影响的方法找到了，或将不再是健康的威胁！

近日，一条“研究称高脂饮食自由或将实现”的微博话题引起网友们的广泛关注。不少网友表示自己已经准备好实现饮食自由了。图片来源：新浪微博由于摄入大量脂肪会增加代谢紊乱的风险，高脂饮食一直被列在营养师的黑名单中。而加州大学欧文分校（UCI）的生物学家在如何避免高脂肪饮食造成的有害影响方面取得了重要发现。他们的研究发表在 Nature Communications 上。AMPK 是维持体内代谢平衡的关键蛋白复合物UCI的研究集中在 AMPK 蛋白质复合物上，它可以感知身体的营养并采取行动保持平衡。例如，如果 AMPK 检测到葡萄糖含量低，它可以促进脂质分解以产生能量。因此，AMPK 的激活已成为治疗与代谢紊乱相关疾病（如糖尿病、肥胖、脂肪肝、癌症和衰老）的热门靶点。AMPK 的活性受可逆磷酸化的严格调控，而大量脂肪的摄入会阻碍 AMPK 的活性，导致新陈代谢失衡。然而，直到现在，有关脂肪如何在细胞中抑制AMPK活性的研究十分有限，尤其是在活体模型中。SAPS3参与AMPK的去磷酸化调控为探究调控AMPK去磷酸化的蛋白质，研究人员利用 Flag 标记的 AMPKα 进行了蛋白质质谱分析，发现磷酸酶PP6的调节亚基SAPS3 和 PP6 的催化亚基可以与AMPK形成复合物。PP6 的催化亚基是真核生物中最保守的蛋白质之一，没有特异性。PP6磷酸酶的特异性调控取决于其调节SAPS3。那么，含SAPS3的PP6复合物是否能响应葡萄糖匮乏的营养条件将AMPK 去磷酸化呢？蛋白共表达和免疫共沉淀实验表明SAPS3/PP6复合物可在葡萄糖匮乏的条件下与磷酸化的AMPK结合，PP6催化亚基与AMPK的结合需要SAPS3的参与。研究人员进一步在细胞和小鼠中敲除SAPS3来探索其在AMPK信号通路中的作用。他们发现敲除SAPS3后，即便恢复葡萄糖水平，细胞也无法调控AMPK的去磷酸化。他们还发现在小鼠中进行肝脏特异性 SAPS3敲除足以阻止高脂饮食诱发的肝脂肪变性、肥胖和胰岛素抗性的发生。图注：SAPS3参与AMPK的去磷酸化调控图片来源：参考文献【1】SAPS3的缺失能缓解高脂饮食带来的不利影响为系统地检查 SAPS3 缺失对肝脏代谢的影响，研究人员分别将对照小鼠（FF，正常表达SAPS3）和肝脏特异性敲除SAPS3小鼠（LKO）喂食对照（CD，均衡饮食）和高脂肪饮食（HFD），之后收集肝脏样本进行代谢分析。实验结果表明喂食高脂饮食后，小鼠SAPS3的缺失可以加强脂肪酸的氧化，降低脂肪酸的合成，从而缓解高脂饮食给小鼠代谢平衡带来的干扰。图注：小鼠中SAPS3 的肝脏特异性缺失足以改善高脂肪饮食带来的全身反应图片来源：参考文献【1】研究人员继续对小鼠的肝脏组织进行了RNA测序（RNA-Seq）来探究在高脂饮食下SAPS3是否从基因转录水平影响小鼠的代谢。RNA 表达谱数据表明，SAPS3 的缺失对均衡饮食影响有限，而对高脂饮食下的基因表达有显著影响。比如脂肪生成和长链脂肪酸合成因 SAPS3 的缺失而受损。令人欣喜的是，SAPS3的敲除降低了心血管疾病发病机制相关基因的转录水平。图注：高脂饮食和SAPS3敲除对肝脏组织基因转录水平的影响图片来源：参考文献【1】AMPK 参与SAPS3的缺失对代谢的调控过程AMPK在SAPS3 缺失影响肝脏代谢的过程中是否起到了重要作用呢？为了回答这个问题，研究人员在小鼠胚胎成纤维细胞（MEF）中敲除AMPK的组分后，利用13C同位素示踪法研究葡萄糖和脂肪酸的代谢产物。实验结果发现SAPS3的缺失可增强糖酵解中间产物的生成，而AMPK 的敲除则阻断了这一过程。图注：AMPK参与SAPS3对代谢的调控图片来源：参考文献【1】此外，在体内实验中，他们在喂食LKO小鼠16周后使用AMPK非特异性抑制剂Compound C对小鼠进行处理，发现AMPK被抑制后SAPS3的缺失无法缓解高脂饮食对代谢带来的不利影响。SAPS3抑制剂有望治疗代谢紊乱相关疾病“去除 SAPS3 抑制成分可以释放这些小鼠体内的 AMPK 激活，使它们在摄入大量脂肪的情况下仍能保持正常的能量平衡，”该研究的通讯作者、UCI分子生物学与生物化学教授 Mei Kong 说，“我们对他们保持正常体重、避免肥胖和患糖尿病的能力感到惊讶。”【2】这一发现或将启发科学家们采用一种新疗法来治疗与代谢相关的疾病。“如果我们阻断这种抑制活动，我们就可以帮助人们重新激活他们的 AMPK，”Kong 实验室的项目科学家、文章第一作者 Ying Yang 表示，“它可以帮助克服肥胖、糖尿病、脂肪肝等疾病。”研究人员正致力于开发可以抑制 SAPS3 并恢复代谢平衡的分子化合物。他们计划下一步研究 SAPS3 在癌症、衰老等其他代谢系统紊乱的情况下的作用。参考文献：【1】Yang, Y., Reid, M.A., Hanse, E.A. et al. SAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice. Nat Commun 14, 1368 (2023). https://doi.org/10.1038/s41467-023-36809-1 【2】EurekAlert! (n.d.). Study shows how to prevent a high-fat diet from throwing metabolism out of whack. [online] Available at: https://www.eurekalert.org/news-releases/985231 [Accessed 8 Apr. 2023].撰文 | Qianyue编辑 | cici会议推荐点精彩推荐：1、首次！德国Alessandra Moretti教授研究13年后，这颗“迷你心脏”类器官终于拥有了完整的“外衣”！2、类器官最新进展！STEM CELL REP：实验室首次成功建立患者特异性 T 细胞发育的胸腺类器官3、闻闻味道就能瘦？iScience：伴侣独特的气味不但助眠抗衰，还能减重、延长寿命8%！4、重大发现！两篇Cell：揭示中性粒细胞在肿瘤免疫疗法中的重要作用，或为免疫疗法成败的关键！5、延缓痴呆新发现！《欧洲心脏杂志》：首次确定大脑中因高血压而受损的特定区域，降血压或成为延缓痴呆症的有效手段！

2021-06-30

·精准药物

【JMC】尤启冬-王磊等：小分子靶向丝苏氨酸蛋白磷酸酶（PPPases）的研究进展

中国药科大学尤启冬教授/王磊副教授等在最新一期的JMC杂志以 Strategies for Targeting Serine/Threonine Protein Phosphatases with Small Molecules in Cancer 为题发表论文，综述了丝苏氨酸蛋白磷酸酶抑制剂的研究现状及策略。蛋白激酶和蛋白磷酸酶分别作为磷酸化和去磷酸化功能的两大类蛋白，在细胞中维系着蛋白磷酸化调控的平衡。蛋白质的磷酸化一般发生在丝氨酸、苏氨酸和酪氨酸上，蛋白激酶通常以 ATP 为底物将磷酸基团转移到这些氨基酸残基上使其磷酸化，蛋白磷酸酶则会将蛋白氨基酸残基上的磷酸水解。二者协调共同调节蛋白的功能、稳定性及信号转导，并发挥生理病理功能。目前发现 107 个蛋白磷酸酶亚家族，可以分为如下 4 类：蛋白酪氨酸磷酸酶（protein tyrosinephosphatases，PTPs）、金属离子依赖性蛋白磷酸酶（metal-dependent protein phosphatases，PPMs）、磷蛋白磷酸酶（phosphoprotein phosphatases，PPPs）以及卤酸脱卤型磷酸酶（phosphatases of the haloaciddehalogenases，HAD 磷酸酶），其中 PPMs 和 PPPs属于蛋白丝 / 苏氨酸磷酸酶。本文主要综述丝氨酸/苏氨酸磷酸酶调节剂的研究进展。到2020年，市场上推出了60多种不同的蛋白激酶抑制剂 (www.brimr.org/PKI/PKIs.htm) ，使激酶成为最具吸引力的药物靶点之一，但磷酸酶调节剂的合理设计面临着巨大的挑战。激酶抑制剂大多是针对ATP结合位点设计的，磷酸酶调节剂的最初努力集中在催化活性位点。然而，由于磷酸酶上活性位点的高度保守性和负电荷是保证紧密结合所必需的，磷酸酶调节剂很难达到理想的选择性和生物利用度。因此，长期以来，磷酸酶被认为是小分子的“不可成药靶点。以诺华公司的开发的TNO155为代表的SHP2抑制剂及其他成功案例，为合理设计小分子靶向磷酸酶提供了可能性。激酶和磷酸酶的研究进展 (A）磷酸化和去磷酸化的平衡调节；(B）蛋白激酶抑制剂与蛋白磷酸酶抑制剂的临床在研分子变化趋势丝氨酸/苏氨酸磷酸酶（PPPases）可分为7个亚家族，包括PP1、PP2A、PP2B或PP3、PP4、PP5、PP6和PP7。在PPPases亚家族中，PP5和PP7以单体酶的形式工作，而其它亚家族在催化亚基、调节亚基和/或支架亚基的帮助下以全酶的形式工作。 PPPases超家族的催化亚基在序列比对中高度保守。特别是催化亚基中的催化核心含有9个严格保守的氨基酸：6个氨基酸（3个His、2个Asp和1个Asn）与金属离子（包括Mg2+、Mn2+、Fe2+或Zn2+）配位，其中3个氨基酸（2个Arg和1个His）负责磷酸基的结合。虽然它们通过高度保守的催化活性位点发挥去磷酸化的共同机制，但不同的pppase根据其不同的调节亚基或独特的结构特征表现出特异性，这为小分子的合理设计提供了潜在的机会。 pppase参与多种细胞信号通路的调节，如RNA剪接、DNA损伤反应、蛋白质合成、细胞周期进程、有丝分裂、增殖、迁移和凋亡等。超过200种蛋白质被鉴定为PPPases的底物（depod.bios.unifreiburg.de/brènet.php）。尽管大多数底物与pppase有一对一的关系，但实际上只有少数底物被直接分配给一个磷酸酶，形成一个复杂的去磷酸化网络。pppase与许多癌症的发生、发展密切相关。在早期，pppase被简单地鉴定为抑癌蛋白或致癌蛋白。近年来，越来越多的证据表明pppase在不同的癌症中起着不同的作用，这可能是由于pppase调控亚基的多样性所致。鉴于pppase在肿瘤中的重要作用，设计靶向pppase的小分子激活剂或抑制剂可以调控细胞的生长、分化、迁移和增殖，这可能是肿瘤治疗的潜在策略。此外，靶向特定pppase甚至特定亚型和调节亚基的选择性小分子是必要的。根据pppase的结构特点和调节剂的作用机制，pppase的代表性小分子调节剂可分为三类：（1）以催化亚基为靶点的小分子调节剂；（2）以非催化亚基/结构域为靶点的小分子调节剂；（3）以全酶为靶点的小分子调节剂。代表性PPPase调节剂的化学结构代表性的PPPase调制剂的靶点、活性及潜在适应症越来越多的证据表明pppase与癌症密切相关。因此，合理设计高效、特异的小分子靶向pppase用于癌症治疗已成为当务之急。在所有潜在的策略中，尽管带负电荷的结合域和缺乏亚型特异性存在挑战，直接靶向pppase的催化亚单位仍然是一种有效的方法。有趣的是，靶向PPPase催化亚基表面特异性保守的半胱氨酸残基，使共价结合成为可能，并增加了小分子的选择性，这可能为开发具有更高结合效力和特异性的PPPase调节剂提供了另一条可行的途径。以非催化亚基/结构域或全酶为靶点是另一种设计具有更好药物性和选择性的小分子的方法。尽管PPPases活性调控的完整范围尚未被揭示，但上述小分子的成功可为后续肿瘤治疗小分子的开发提供指导和参考。值得注意的是，许多小分子来源于旧药物的新用途，例如PPZ、FK-506、CsA和FTY720等，它们可能成为PPPase调节剂筛选的来源。综上所述，PPPase调节剂是一种很有前途的肿瘤治疗策略，目前已经取得一些进展，但尚未获得成药性分子，我们预见PPPase调节剂在未来抗肿瘤药物的开发中将占有一席之地。