ArticleThe Journal of biological chemistry2015
Functional Characterization of a WWP1/Tiul1 Tumor-derived Mutant Reveals a Paradigm of Its Constitutive Activation in Human Cancer.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
What it found
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Who cites it
10 citing papers in PubMed, 18 citations in OpenAlex.
- WWP1 gain-of-function drives developmental anoikis through TGFβ pathway during neurodevelopment.Cell death discovery · 2026Article
- WWP1 E3 ligase at the crossroads of health and disease.Cell death & disease · 2023Review
- Ubiquitin-modifying enzymes in Huntington's disease.Frontiers in molecular biosciences · 2023Review
- The emerging role of WWP1 in cancer development and progression.Cell death discovery · 2021Review
- E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression.International journal of molecular sciences · 2021Review
- WW Domain-Containing E3 Ubiquitin Protein Ligase 1: A Self-Disciplined Oncoprotein.Frontiers in cell and developmental biology · 2021Review
- Structural insights into a HECT-type E3 ligase AREL1 and its ubiquitination activitiesThe Journal of biological chemistry · 2019Article
- Emerging roles of HECT-type E3 ubiquitin ligases in autophagy regulation.Molecular oncology · 2019Review
- Specific targeting of the deubiquitinase and E3 ligase families with engineered ubiquitin variants.Bioengineering & translational medicine · 2017Review
- Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although E3 ubiquitin ligases are deemed to play key roles in normal cell function and homeostasis, whether their alterations contribute to cancer pathogenesis remains unclear. In this study, we sought to investigate potential mechanisms that govern WWP1/Tiul1 (WWP1) ubiquitin ligase activity, focusing on its ability to trigger degradation of TGFβ type I receptor (TβRI) in conjunction with Smad7. Our data reveal that the WWP1 protein is very stable at steady states because its autopolyubiquitination activity is silenced due to an intra-interaction between the C2 and/or WW and Hect domains that favors WWP1 monoubiquitination at the expense of its polyubiquitination or polyubiquitination of TβRI. Upon binding of WWP1 to Smad7, this functional interplay is disabled, switching its monoubiquitination activity toward a polyubiquitination activity, thereby driving its own degradation and that of TβRI as well. Intriguingly, a WWP1 point mutation found in human prostate cancer disrupts this regulatory mechanism by relieving the inhibitory effects of C2 and WW on Hect and thereby causing WWP1 hyperactivation. That cancer-driven alteration of WWP1 culminates in excessive TβRI degradation and attenuated TGFβ cytostatic signaling, a consequence that could conceivably confer tumorigenic properties to WWP1.
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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.