ArticleOncotarget2017
Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 45 citations in OpenAlex.
- Hyaluronan: An Architect and Integrator for Cancer and Neural Diseases.International journal of molecular sciences · 2025Review
- Twenty-five years of WWOX insight in cancer: a treasure trove of knowledge.Functional & integrative genomics · 2025Review
- Dissociation of the nuclear WWOX/TRAF2 switch renders UV/cold shock-mediated nuclear bubbling cell death at low temperatures.Cell communication and signaling : CCS · 2024Article
- PMF-GRN: a variational inference approach to single-cell gene regulatory network inference using probabilistic matrix factorization.Genome biology · 2024Article
- Zfra Overrides WWOX in Suppressing the Progression of Neurodegeneration.International journal of molecular sciences · 2024Review
- Hyaluronic Acid as a Modern Approach in Anticancer Therapy-Review.International journal of molecular sciences · 2022Review
- Zfra Inhibits the TRAPPC6AΔ-Initiated Pathway of Neurodegeneration.International journal of molecular sciences · 2022Article
- Review
- Finding New Ways How to Control BACE1.The Journal of membrane biology · 2022Article
- Review
- Review
- Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299.Communications biology · 2021Article
- Review
- Article
- TheExperimental biology and medicine (Maywood, N.J.) · 2020Review
- Pleiotropic tumor suppressor functions of WWOX antagonize metastasis.Signal transduction and targeted therapy · 2020Article
- Functional role of WW domain-containing proteins in tumor biology and diseases: Insight into the role in ubiquitin-proteasome system.FASEB bioAdvances · 2020Article
- Wwox deficiency leads to neurodevelopmental and degenerative neuropathies and glycogen synthase kinase 3β-mediated epileptic seizure activity in mice.Acta neuropathologica communications · 2020Article
- WWOX PossessesCancers · 2019Article
- A p53/TIAF1/WWOX triad exerts cancer suppression but may cause brain protein aggregation due to p53/WWOX functional antagonism.Cell communication and signaling : CCS · 2019Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.
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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.