ArticleEMBO reports2017
Allosteric auto-inhibition and activation of the Nedd4 family E3 ligase Itch.
Article in EMBO reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 71 citations in OpenAlex.
- HECT-type ubiquitin ligases: Emerging principles in the era of full-length structures.The Journal of biological chemistry · 2026Review
- MAML1 drives Notch and Hedgehog oncogenic pathways by inhibiting Itch activity in triple-negative breast cancer.Cell death and differentiation · 2026Article
- Identification and validation of an interaction between the E3 ubiquitin ligase WWP1 and the Transcriptional Co-Activator WBP2 in the human heart.Biology open · 2026Article
- Structure and mechanism of the HECT ligase HECTD3.Nature communications · 2026Article
- PARG inhibition suppresses breast cancer progression and potentiates immunoresponse through MTDH degradation mediated by E3 ligase ITCH-dependent ubiquitination.NPJ breast cancer · 2025Article
- The role of HECT-type E3 ubiquitin ligases in DNA damage response and repair.Cell death discovery · 2025Review
- SRAS1.1 E3 ligase mediates DSK2A degradation to regulate autophagy and drought tolerance in Arabidopsis.EMBO reports · 2025Article
- Structural basis of ubiquitin ligase Nedd4-2 autoinhibition and regulation by calcium and 14-3-3 proteins.Nature communications · 2025Article
- Chemical Tools for Probing the Ub/Ubl Conjugation Cascades.Chembiochem : a European journal of chemical biology · 2025Review
- Role and therapeutic potential of the NEDD4 family in breast cancer.Frontiers in pharmacology · 2025Review
- The Nedd4L ubiquitin ligase is activated by FCHO2-generated membrane curvature.The EMBO journal · 2024Article
- Protein semisynthesis reveals plasticity in HECT E3 ubiquitin ligase mechanisms.Nature chemistry · 2024Article
- Article
- Structural insights into the functional mechanism of the ubiquitin ligase E6AP.Nature communications · 2024Article
- Myofibrillogenesis Regulator-1 Regulates the Ubiquitin Lysosomal Pathway of Notch3 Intracellular Domain Through E3 Ubiquitin-Protein Ligase Itchy Homolog in the Metastasis of Non-Small Cell Lung Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Structural snapshots along K48-linked ubiquitin chain formation by the HECT E3 UBR5.Nature chemical biology · 2024Article
- TMEM55B links autophagy flux, lysosomal repair, and TFE3 activation in response to oxidative stress.Nature communications · 2024Article
- Review
- Feedback regulation of ubiquitination and phase separation of HECT E3 ligases.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Unraveling the Potential Role of NEDD4-like E3 Ligases in Cancer.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Nedd4 family E3 ligases are key regulators of cell growth and proliferation and are often misregulated in human cancers and other diseases. The ligase activities of Nedd4 E3s are tightly controlled via auto-inhibition. However, the molecular mechanism underlying Nedd4 E3 auto-inhibition and activation is poorly understood. Here, we show that the WW domains proceeding the catalytic HECT domain play an inhibitory role by binding directly to HECT in the Nedd4 E3 family member Itch. Our structural and biochemical analyses of Itch reveal that the WW2 domain and a following linker allosterically lock HECT in an inactive state inhibiting E2-E3 transthiolation. Binding of the Ndfip1 adaptor or JNK1-mediated phosphorylation relieves the auto-inhibition of Itch in a WW2-dependent manner. Aberrant activation of Itch leads to migration defects of cortical neurons during development. Our study provides a new mechanism governing the regulation of Itch.
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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.