ArticleOncotarget2016
NEDL2 regulates enteric nervous system and kidney development in its Nedd8 ligase activity-dependent manner.
Article in Oncotarget, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 19 citations in OpenAlex.
- Determination of Expression and Relationships of Nedd4-Related E3 Ubiquitin Ligase-2 (NEDL2) and Ubiquitin Proteasome System Proteins in Developing Rat Pancreatic Tissue.Anatomia, histologia, embryologia · 2026Article
- Nedl1 knockout ameliorates cognitive impairment and improves epilepsy threshold in pilocarpine-induced epileptic mice.Acta epileptologica · 2025Article
- Identification and validation of shared gene signature of kidney renal clear cell carcinoma and COVID-19.PeerJ · 2024Article
- Age-associated changes in lineage composition of the enteric nervous system regulate gut health and disease.eLife · 2023Article
- HECW2 promotes the progression and chemoresistance of colorectal cancer via AKT/mTOR signaling activation by mediating the ubiquitin-proteasome degradation of lamin B1.Journal of Cancer · 2023Article
- Unraveling the Potential Role of NEDD4-like E3 Ligases in Cancer.International journal of molecular sciences · 2022Review
- The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration.International journal of molecular sciences · 2022Review
- Advances in Cancer Treatment by Targeting the Neddylation Pathway.Frontiers in cell and developmental biology · 2021Review
- Functional role of WW domain-containing proteins in tumor biology and diseases: Insight into the role in ubiquitin-proteasome system.FASEB bioAdvances · 2020Article
- Gut microbiota diversity across ethnicities in the United States.PLoS biology · 2018Article
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The GDNF (Glial cell line-derived neurotrophic factor)/Ret/Akt signaling pathway is essential to the development of ENS (enteric nervous system) as well as kidney. We previously showed that the HECT-type E3 ligase NEDL2 (Nedd4-like ligase 2) is required for the ENS development by activating GDNF/Ret/Akt. However, the underlying mechanism remains unknown. Here we show that in addition to ENS, NEDL2 is also pivotal for kidney development since about 1/3 of Nedl2-deficient mice displayed postnatal unilateral or bilateral kidney hydronephrosis. Double knockout of Nedl1 and Nedl2 in mice leads to postnatal lethal within 2 weeks and the phenotypes resemble those of Nedl2 single knockout mice. Surprisingly, its close member NEDL1 is dispensable for ENS and kidney function and the reason is lack of NEDL1 expression in these systems during early development. Furthermore, biochemical analysis indicated that NEDL2 appears to act like a scaffold protein to recruit SHC, Grb2, PI3K (p110 and p85), PDK1 and Akt together to promote the signaling transduction. Intriguingly, we found that NEDL2 harbours intrinsic Nedd8 ligase activity with cysteine 1341 as the core site. NEDL2 upregulates GDNF-stimulated Akt activity dependent of its Nedd8 ligase activity but not its ubiquitin ligase activity. These findings demonstrate that NEDL2 but not NEDL1 is required for ENS and kidney development in a unique Nedd8 ligase-dependent manner.
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