WWP1

更新于：2025-05-07

基本信息

别名

AIP5、Atrophin-1-interacting protein 5、DKFZP434D2111

+ [7]

简介

E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Ubiquitinates ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and promotes their proteasomal degradation. Ubiquitinates RNF11 without targeting it for degradation. Ubiquitinates and promotes degradation of TGFBR1; the ubiquitination is enhanced by SMAD7. Ubiquitinates SMAD6 and SMAD7. Ubiquitinates and promotes degradation of SMAD2 in response to TGF-beta signaling, which requires interaction with TGIF. Activates the Hippo signaling pathway in response to cell contact inhibition and recruitment to the Crumbs complex at the cell membrane (PubMed:34404733). Monoubiquitinates AMOTL2 which facilitates its interaction with and activation of LATS2 (PubMed:34404733). LATS2 then phosphorylates YAP1, excluding it from the nucleus and therefore ultimately represses YAP1-driven transcription of target genes (PubMed:34404733).

关联

项与 WWP1 相关的药物

AnDC 0003

靶点

WWP1

作用机制

WWP1 modulators [+1]

在研机构-

原研机构

Orum Therapeutics, Inc.

在研适应症-

非在研适应症

肿瘤

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 WWP1 相关的临床结果

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100 项与 WWP1 相关的转化医学

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0 项与 WWP1 相关的专利（医药）

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220

项与 WWP1 相关的文献（医药）

2025-03-01·Journal of Gastroenterology

WWP1 inhibition suppresses the proliferation of pancreatic cancer cells by regulating the PI3K-AKT pathway

Article

作者: Takahashi, Ryota ; Kishikawa, Takahiro ; Miyabayashi, Koji ; Otsuka, Motoyuki ; Yamamoto, Keisuke ; Ijichi, Hideaki ; Notoya, Genso ; Iwata, Takuma ; Fujishiro, Mitsuhiro ; Seimiya, Takahiro ; Yasugi, Kengo

AbstractBackgroundThe proto-oncogene WWP1 is overexpressed in various cancers and contributes to tumor growth and poor prognosis. Recently, WWP1 inhibition was reported to suppress tumor development and cell proliferation by activating the PTEN function. However, the expression profiles and clinical significance of WWP1 in pancreatic ductal adenocarcinoma (PDAC) tissues remain undetermined. Therefore, this study aimed to evaluate the WWP1 expression in PDAC and investigate the therapeutic potential of WWP1 inhibition.MethodsCellular proliferation assays were performed using a doxycycline-inducible shWWP1 expression system. Transcriptome analyses were conducted to identify the altered pathways in WWP1-depleted cells. PTEN ubiquitination by WWP1 was confirmed using immunoprecipitation assays. In vivo xenograft and drug screening assays were performed to evaluate the clinical significance of WWP1 inhibition.ResultsWWP1 was significantly upregulated in PDAC tissues and associated with poor prognosis. WWP1 depletion significantly reduced the proliferation of PDAC cell lines, correlating with the suppression of the PI3K-AKT pathway. Mechanistically, as reported in other cancer types, PTEN is a target of WWP1 in PDAC cells. PTEN silencing abrogated the growth-inhibitory effects in WWP1-depleted cells, suggesting that the anti-tumor effects of WWP1 inhibition are mediated through PTEN activation. In vivo xenograft studies confirmed that WWP1 depletion substantially inhibited tumor growth. Moreover, drug screening assays revealed that WWP1 depletion had an additive effect with the PI3K-AKT pathway inhibitors on hindering tumor growth.ConclusionWWP1 inhibition enhances the anti-tumor effects of PI3K-AKT pathway inhibitors through PTEN activation. Thus, WWP1 could be a potential therapeutic target in PDAC.

2025-02-18·ACS Omega

3,3′-Diindolylmethane (DIM): A Molecular Scaffold for Inhibition of WWP1 and WWP2, Members of the NEDD4 Family HECT E3 Ligases

Article

作者: Angulo, Jesus ; Hughes, Gregory R. ; Monaco, Serena ; Stephenson, G. Richard ; Rigby, Jake M. ; Hemmings, Andrew M. ; Storr, Thomas E. ; Chantry, Andrew ; Dudey, Ashley P.

Indole-3-carbinol (I3C) is a metabolic derivative of glucobrassicin found in cruciferous vegetables. Known for its anticarcinogenic properties, I3C has been shown to target the NEDD4 family HECT E3 ligases, NEDD4-1 and WWP1, yet in vitro confirmation for the latter is lacking. Here, we characterize the interactions of I3C and a set of 17 derivatives with WWP1 and its homologue, WWP2. Saturation transfer difference (STD) NMR analysis confirmed strong interaction of I3C with WWP1 but weaker with WWP2. However, while autoubiquitination activity assays revealed weak inhibition of WWP1, the I3C condensation product, 3,3'-diindolylmethane (DIM), was more potent (IC₅₀ 111.2 μM; 95% CI = 85.1, 145.8). Molecular modeling of DIM to the ubiquitin exosite of both enzymes suggested the WW2 domain makes hydrophobic interactions with the ligand that may contribute to inhibitory action. Taken together, our results suggest future drug lead development should focus on the SAR between WWP1 and DIM.

2025-02-01·iScience

Evolutionary conserved regulation of TFEB stability by the E3 ubiquitin ligase WWP2 modulates response to stress in vivo

Article

作者: Bonnet, Estelle ; Garcia-Sanchez, Juan A ; Munro, Patrick ; Polanowska, Jolanta ; Segui, Fabien ; Torre, Cédric ; Larbret, Frédéric ; Paillier, Guillaume ; Chaintreuil, Paul ; Loubatier, Céline ; Batistic, Ludovic ; Boyer, Laurent ; Doye, Anne ; Visvikis, Orane ; Deckert, Marcel

Transcription factor EB (TFEB) is a key transcription factor that orchestrates the cellular response to stress. Dysregulation of TFEB is associated with a range of human diseases, and understanding the regulatory mechanisms of TFEB is crucial for identifying potential drug targets. In this study, we used Caenorhabditis elegans to screen for E3 ubiquitin ligases regulating the activity of TFEB's homolog, HLH-30, upon pathogenic infection. We identified WWP-1 as a regulator of HLH-30-dependent immune response controlling HLH-30 stability to mediate host defense in vivo. We found that HLH-30 interacts with WWP-1, supporting a model of WWP-1 directly regulating HLH-30. Furthermore, we found that WWP-1's human homolog WWP2 binds TFEB, directly induces TFEB ubiquitination and stabilizes TFEB. Finally, we found that WWP2 is required for TFEB-dependent host response in human monocytes-derived macrophages upon infection. Overall, our work has identified an evolutionarily conserved regulation of TFEB by WWP2 and highlighted its role in modulating stress response.

项与 WWP1 相关的新闻（医药）

2025-04-26

·今日头条

首次证明！温州医科大学发文：可实现癌症放射增敏的新治疗靶点

【导读】宫颈鳞状细胞癌（CESC）是女性中最常见的癌症之一，放疗一直被用作主要治疗手段。然而，其疗效受到固有和获得性放射抵抗的限制。 4月22日，温州医科大学研究团队在期刊《Cell Death Discovery》上发表了研究论文，题为“HSP90 regulates dCK stability and inhibits ionizing radiation-induced ferroptosis in cervical cancer cells”，本研究中，研究人员发现dCK通过提高 SLC7A11 的活性和稳定性来抑制胰岛素抵抗（IR）诱导的铁死亡。利用数据库，研究人员预测 NEDD4L 可能是 dCK 的潜在泛素连接酶，而 WWP1/2 可能是 NEDD4L 的潜在泛素连接酶。本研究结果表明，HSP90通过招募泛素连接酶 WWP1/2 抑制 NEDD4L，从而调节 dCK 的稳定性。总之，本研究揭示了 HSP90-WWP1/WWP2-NEDD4L-dCK-SLC7A11 轴是 HeLa 细胞中 IR 诱导铁死亡的关键调节因子。这些发现为宫颈癌的放射增敏潜在策略提供了宝贵的见解。 https://www.nature.com/articles/s41420-025-02388-x#Abs1 背景知识 01 宫颈鳞状细胞癌（CESC）是全球育龄妇女癌症死亡的第二大原因。放疗一直是宫颈癌的主要治疗方法，尤其是对于局部晚期病例。然而，其固有的和获得的放射抵抗性导致预后不良，这在临床环境中是一个紧迫的问题。作为一种细胞毒性疗法，电离辐射（IR）通过在肿瘤细胞中诱导 DNA 双链断裂（DSBs）来发挥其治疗作用。当暴露于高能 IR 时，肿瘤细胞被破坏，导致各种类型的细胞死亡。铁死亡是一种最近发现的铁依赖性非凋亡性细胞死亡形式，其特征是细胞毒性脂质过氧化物的积累。许多研究表明，铁死亡在诸如放疗等癌症治疗中具有前景。然而，放疗与宫颈癌铁死亡之间的关系仍未明确。 dCK敲低促进了 HeLa 细胞的放射敏感性 02 研究人员分析了癌症基因组图谱（TCGA）数据库中dCK的表达水平，并证实其在宫颈鳞状细胞癌（CESC）组织中显著升高。通过 Kaplan-Meier 曲线显示，dCK 水平高与 CESC 患者的不良预后相关。结果表明 dCK 的上调具有时间依赖性。因此，研究人员通过转染 dCK shRNA 构建了稳定的 HeLa 细胞敲低模型，并检测了转染效率。经辐射照射后，dCK 敲低细胞在 48 小时的细胞死亡率显著增加。此外，dCK 敲低显著抑制了暴露于辐射的 HeLa 细胞的增殖。同样，集落形成实验表明 dCK 敲低增加了 HeLa 细胞的放射敏感性。综上所述，这些结果表明 dCK 敲低促进了辐射诱导的细胞死亡，并增强了 HeLa 细胞的放射敏感性。 dCK敲低促进了辐射诱导的 HeLa 细胞铁死亡 03 众所周知，辐射可导致多种细胞死亡形式。为了确定辐射处理后诱导的细胞死亡类型，研究人员将不同的细胞死亡抑制剂应用于 dCK 敲低的 HeLa 细胞。随后，这些细胞接受了 4 Gy 的辐射。Fer-1 减轻了辐射诱导的细胞死亡，这表明 dCK 敲低可能促进辐射诱导的铁死亡。研究人员进行了多项测试以确认 dCK 敲低是否促进辐射诱导的铁死亡。正如预期的那样，与对照组相比，dCK 敲低的 HeLa 细胞内 Fe2+浓度显著升高；这种效应可能因辐射治疗而增强。然后，与 shControl 相比，经辐射或厄拉司汀处理后，通过 BODIPY C11 染色检测到的 dCK 敲低 HeLa 细胞的脂质过氧化显著增加，而这一现象可通过 Fer-1 逆转。此外，研究人员发现经辐射处理后，dCK 敲低的 HeLa 细胞中 PTGS2（铁死亡标志物）的 mRNA 表达增加，在铁死亡诱导剂和氧化应激诱导剂处理的细胞中也观察到了这种升高。同样，GPX4 的 mRNA 水平降低。这些发现表明，辐射诱导的铁死亡因 dCK 敲低而得到促进。 dCK敲低促进了辐射诱导的铁死亡结论 04 通过本研究，研究人员得出结论：dCK可能是提高 HeLa 细胞放射敏感性的新治疗靶点，HSP90抑制剂可能有助于提高宫颈癌放疗的效果。参考资料： https://www.nature.com/articles/s41420-025-02388-x#Abs1 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。责任声明：本稿件如有错误之处，敬请联系转化医学网客服进行修改事宜！微信号：zhuanhuayixue 热门推荐活动点击免费报名 🕓 浙江｜2025年5月9日 ▶ 首届精准医学国际学术研讨会暨队列研究先锋计划颁奖仪式 🕓 上海｜2025年6月12-15日 ▶ 第七届上海国际癌症大会暨第十八届全国医学生物技术研讨会暨第六届中德双边论坛 🕓 上海｜2025年7月17-18日 ▶ 第四届长三角体外诊断产业高峰论坛 🕓 北京｜2025年9月19-20日 ▶ 第六届单细胞技术应用研讨会暨空间组学前沿研讨会 🕓 上海｜2025年11月14-15日 ▶ 第二届中国类器官转化医学大会点击对应文字查看详情

细胞疗法