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Last update 23 Jan 2025

WWP1

Last update 23 Jan 2025

Basic Info

Synonyms

AIP5, Atrophin-1-interacting protein 5, DKFZP434D2111

+ [7]

Introduction

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.

Drugs associated with WWP1

AnDC 0003

Target

WWP1

Mechanism

WWP1 modulators [+1]

Active Org.-

Originator Org.

Orum Therapeutics, Inc.Startup

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with WWP1

100 Translational Medicine associated with WWP1

0 Patents (Medical) associated with WWP1

230

Literatures (Medical) associated with WWP1

09 Jan 2025·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

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

Objective: To investigate the role of WW domain containing E3 ubiquitin protein ligase 1 (WWP1) in enamel development of mice. Methods: Single-cell RNA sequencing data of incisor tissues of postnatal day 7 (P7) mice and mandibular first molar tooth germs of P3.5 mice were used to analyze the expression of Wwp1 in dental epithelial cells. Immunohistochemistry was performed to observe the distribution and expression levels of WWP1 in the epithelium of mouse incisors and mandibular first molar tooth germs. Wwp1 knockout (Wwp1 KO) mice were generated and collected with their control littermates at P1, P7, three mice per group, as well as at P14, P28, 2 months (2M), and 3M, six mice per group. The enamel volumes of molars and incisors were analyzed using micro-CT. Scanning electron microscopy was employed to examine the enamel cross-sections of Wwp1 KO and control mice. Energy dispersive spectroscopy (EDS) was used to analyze the calcium and phosphorus content of the enamel rod of incisors. Immunofluorescence was performed to detect the expression of amelogenin (AMELX) in the ameloblasts of Wwp1 KO and control mice. Additionally, LS-8 ameloblast-like epithelial cells were cultured, and Wwp1 siRNA or overexpression plasmids were transfected to knock down or overexpress WWP1. The protein levels of AMELX were then assessed by Western blotting. Results: Single-cell sequencing result showed a high Wwp1 mRNA expression level in the epithelial cells of mouse incisors and mandibular molar tooth germs. Immunohistochemistry revealed the expression of WWP1 in presecretory, secretory, transitional, and mature ameloblasts. Wwp1 KO mice exhibited enamel developmental defects. The enamel volumes of molars and incisors in Wwp1 KO mice [(0.155±0.016), (0.300±0.017) μm³] were reduced by 23.95% (P<0.001) and 28.31% (P<0.001) compared with the control group [(0.203±0.062), (0.418±0.023) μm³] respectively. Scanning electron microscopy showed disorganized enamel structures in Wwp1 KO incisors and molars. EDS results showed the weight percent of calcium in the enamel rod of incisors decreased in Wwp1 KO mice [(20.74±0.91)%] compared with the control group [(30.30±3.83)%] (P<0.001), and the calcium-to-phosphorus ratio decreased in Wwp1 KO mice (1.93±0.01) compared with the control group (2.02±0.01) (P<0.001). Immunofluorescence showed weaker AMELX expression in ameloblasts of mandibular first molar tooth germs from P1 and P7 Wwp1 KO mice compared with the control group (P<0.001, P<0.001). In LS-8 cells, Wwp1 knocked-down led to a decrease of AMELX protein expression, while WWP1 overexpression resulted in an increased AMELX protein level. Conclusions: WWP1 promotes ameloblast differentiation and enamel matrix mineralization, playing a critical role in enamel formation.

01 Jan 2025·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

Author: 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.

31 Dec 2024·Journal of Enzyme Inhibition and Medicinal Chemistry

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

Article

Author: 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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