ArticleOncogene2011
Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT.
Article in Oncogene, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
48 citing papers in PubMed, 102 citations in OpenAlex.
- HECT ubiquitin ligases as regulators of inflammatory signalling.Cell death and differentiation · 2026Review
- WWP2 in immune surveillance and antigen presentation: context-dependent roles in B cells, T cells, and tumor immune escape.Frontiers in immunology · 2026Review
- circGIGYF1 inhibits stemness and metastasis in colorectal cancer by promoting WWP2-HOXD13 interaction to regulate β-catenin signalling.Communications biology · 2025Article
- Half the Chromosome It Used to Be: Identifying Cancer Treatments Targeting Aneuploid Losses.Genes · 2025Article
- Osteoarthritis as an Enhanceropathy: Gene Regulation in Complex Musculoskeletal Disease.Current rheumatology reports · 2024Review
- Specific isoforms of the ubiquitin ligase gene WWP2 are targets of osteoarthritis genetic risk via a differentially methylated DNA sequence.Arthritis research & therapy · 2024Article
- The cross talk of ubiquitination and chemotherapy tolerance in colorectal cancer.Journal of cancer research and clinical oncology · 2024Review
- TGF-β signaling in health, disease, and therapeutics.Signal transduction and targeted therapy · 2024Review
- Helicobacter pylori-activated fibroblasts as a silent partner in gastric cancer development.Cancer metastasis reviews · 2023Review
- Primate-specific isoform of Nedd4-1 regulates substrate binding via Ser/Thr phosphorylation and 14-3-3 binding.Scientific reports · 2023Article
- The role of NEDD4 related HECT-type E3 ubiquitin ligases in defective autophagy in cancer cells: molecular mechanisms and therapeutic perspectives.Molecular medicine (Cambridge, Mass.) · 2023Review
- WWP2 drives the progression of gastric cancer by facilitating the ubiquitination and degradation of LATS1 protein.Cell communication and signaling : CCS · 2023Article
- The HECT family of E3 ubiquitin ligases and PTEN.Seminars in cancer biology · 2022Review
- WWP2 ameliorates oxidative stress and inflammation in atherosclerotic mice through regulation of PDCD4/HO-1 pathway.Acta biochimica et biophysica Sinica · 2022Article
- Enzymatic analysis of WWP2 E3 ubiquitin ligase using protein microarrays identifies autophagy-related substrates.The Journal of biological chemistry · 2022Article
- E3 Ubiquitin Ligase Regulators of Notch Receptor Endocytosis: From Flies to Humans.Biomolecules · 2022Review
- The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response.Frontiers in physiology · 2022Review
- Postnatal Smad3 Inactivation in Murine Smooth Muscle Cells Elicits a Temporally and Regionally Distinct Transcriptional Response.Frontiers in cardiovascular medicine · 2022Article
- SMADS-Mediate Molecular Mechanisms in Sjögren's Syndrome.International journal of molecular sciences · 2021Review
- Cathepsin S Cleaves BAX as a Novel and Therapeutically Important Regulatory Mechanism for Apoptosis.Pharmaceutics · 2021Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Ubiquitin-dependent mechanisms have emerged as essential regulatory elements controlling cellular levels of Smads and TGFβ-dependent biological outputs such as epithelial-mesenchymal transition (EMT). In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners. We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFβ pathway. Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFβ-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3. Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFβ-dependent transcription and EMT. Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilise Smad7 protein levels and prevent TGFβ-induced EMT. Collectively, our data suggest that WWP2-N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFβ stimulation. Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.