预约演示

更新于：2025-01-23

WWP1

更新于：2025-01-23

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.

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.初创企业

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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230

项与 WWP1 相关的文献（医药）

2025-01-09·Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology

[WWP1 plays a positive role in ameloblast differentiation and enamel formation in mice].

Article

作者: Lin, J X ; Fu, J ; Yuan, G H ; Feng, H ; Liu, Y ; Niu, J X ; Chen, Z

目的： 研究含有WW结构域的E3泛素蛋白连接酶1（WWP1）在小鼠牙釉质形成中的作用。 方法： 对出生后（P）7 d（P7）小鼠切牙和P3.5小鼠下颌第一磨牙牙胚的单细胞RNA测序数据进行可视化，分析Wwp1在小鼠牙上皮中的整体表达情况。采用免疫组化染色观察WWP1在不同时期小鼠切牙和下颌第一磨牙牙胚上皮中的表达。构建Wwp1基因敲除（Wwp1 KO）小鼠。分别收集P1、P7 Wwp1 KO及同窝对照小鼠各3只，P14、P28、2和3个月的Wwp1 KO及同窝对照小鼠各6只。采用显微CT分析小鼠磨牙及切牙的牙釉质形成量。采用扫描电镜观察小鼠切牙和磨牙牙釉质断面结构。能谱分析检测切牙断面釉柱表面钙磷含量。采用免疫荧光检测小鼠釉原蛋白（AMELX）表达。培养类成釉上皮细胞LS-8，转染Wwp1 siRNA或过表达质粒，采用蛋白质印迹法检测AMELX的表达。 结果： 单细胞测序数据显示，Wwp1在小鼠切牙和下颌第一磨牙牙胚上皮细胞中高表达。免疫组织化学染色显示，小鼠切牙和磨牙牙胚中WWP1高表达于分泌前期、分泌期、过渡期和成熟期的成釉细胞。不同于对照小鼠，Wwp1 KO小鼠下颌切牙呈现不透明白垩色。Wwp1 KO小鼠磨牙和切牙牙釉质体积［分别为（0.155±0.016）、（0.300±0.017）μm³］较对照小鼠［分别为（0.203±0.062）、（0.418±0.023）μm³］显著降低23.95%（P<0.001）和28.31%（P<0.001）。扫描电镜观察显示，Wwp1 KO小鼠釉柱低平、松散、结构紊乱。能谱分析结果显示，Wwp1 KO小鼠切牙牙釉质断面钙元素的质量百分比［（20.74±0.91）%］和钙磷比（1.93±0.01）均显著低于对照小鼠［分别为（30.30±3.83）%和2.02±0.01］（均P<0.001）。免疫荧光结果显示，P1和P7的Wwp1 KO小鼠下颌第一磨牙牙胚成釉细胞中AMELX表达均显著低于对照小鼠（均P<0.001）。在LS-8细胞中敲低或过表达WWP1分别使AMELX蛋白表达下降或上升。 结论： WWP1对小鼠牙釉质有促进成釉细胞分化和釉基质矿化的作用，从而可以促进牙釉质的正常发育。.

2025-01-01·Molecular Oncology

Thioredoxin‐interacting protein (TXNIP) is a substrate of the NEDD4‐like E3 ubiquitin‐protein ligase WWP1 in cellular redox state regulation of acute myeloid leukemia cells

Article

作者: Melino, Gerry ; Agostini, Massimiliano ; Zhou, Ji ; Smirnov, Artem ; Pecorari, Rosalba ; Candi, Eleonora ; Moriconi, Valeria ; Shi, Yufang ; Li, Yanan ; Zhang, Jinping ; Rinalducci, Sara ; Bernassola, Francesca ; Timperio, Anna Maria ; Giovannini, Sara ; De Antoni, Anna ; Fierro, Claudia ; Fiorilli, Claudia ; Corigliano, Federica

The HECT‐type E3 ubiquitin WWP1 (also known as NEDD4‐like E3 ubiquitin‐protein ligase WWP1) acts as an oncogenic factor in acute myeloid leukemia (AML) cells. WWP1 overexpression in AML confers a proliferative advantage to leukemic blasts (abnormal immature white blood cells) and counteracts apoptotic cell death and differentiation. In an effort to elucidate the molecular basis of WWP1 oncogenic activities, we identified WWP1 as a previously unknown negative regulator of thioredoxin‐interacting protein (TXNIP)‐mediated reactive oxygen species (ROS) production in AML cells. TXNIP inhibits the disulfide reductase enzymatic activity of thioredoxin (Trx), impairing its antioxidant function and, ultimately, leading to the disruption of cellular redox homeostasis. In addition, TXNIP restricts cell growth and survival by blocking glucose uptake and metabolism. Here, we found that WWP1 directly interacts with TXNIP, thus promoting its ubiquitin‐dependent proteasomal proteolysis. As a result, accumulation of TXNIP in response to WWP1 inactivation in AML blasts reduces Trx activity and increases ROS production, hence inducing cellular oxidative stress. Increased ROS generation in WWP1‐depleted cells culminates in DNA strand breaks and subsequent apoptosis. Coherently with TXNIP stabilization following WWP1 inactivation, we also observed an impairment of both glucose up‐take and consumption. Hence, a contribution to the increased cell death observed in WWP1‐depleted cells also possibly arises from the attenuation of glucose up‐take and glycolytic flux resulting from TXNIP accumulation. Future studies are needed to establish whether TXNIP‐dependent deregulation of redox homeostasis in WWP1‐overexpressing blasts may affect the response of leukemic cells to chemotherapeutic drugs.

2024-12-31·Journal of Enzyme Inhibition and Medicinal Chemistry

Expanding the inhibitor space of the WWP1 and WWP2 HECT E3 ligases

Article

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

The HECT E3 ubiquitin ligases 1 (WWP1) and 2 (WWP2) are responsible for the ubiquitin-mediated degradation of key tumour suppressor proteins and are dysregulated in various cancers and diseases. Here we expand their limited inhibitor space by identification of NSC-217913 displaying a WWP1 IC₅₀ of 158.3 µM (95% CI = 128.7, 195.1 µM). A structure-activity relationship by synthesis approach aided by molecular docking led to compound 11 which displayed increased potency with an IC₅₀ of 32.7 µM (95% CI = 24.6, 44.3 µM) for WWP1 and 269.2 µM (95% CI = 209.4, 347.9 µM) for WWP2. Molecular docking yielded active site-bound poses suggesting that the heterocyclic imidazo[4,5-b]pyrazine scaffold undertakes a π-stacking interaction with the phenolic group of tyrosine, and the ethyl ester enables strong ion-dipole interactions. Given the therapeutic potential of WWP1 and WWP2, we propose that compound 11 may provide a basis for future lead compound development.

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