# NEDD4
**NEDD4** (NEDD4 E3 ubiquitin protein ligase, also known as NEDD4-1 or RPF1) is a human protein-coding gene and enzyme that attaches ubiquitin to target proteins as the founding member of the NEDD4 family of HECT-type E3 ubiquitin ligases. It functions in the ubiquitin proteasome system of protein degradation and regulates membrane receptors, endocytic machinery components, and the tumor suppressor PTEN.[1](https://www.ncbi.nlm.nih.gov/gene/4734)
| Key fact | Detail |
|---|---|
| Gene | Gene ID 4734, HGNC:7727, protein coding, RefSeq status REVIEWED; also known as NEDD4-1 and RPF1[1](https://www.ncbi.nlm.nih.gov/gene/4734) |
| Location | Chromosome 15q21.3, GRCh38 coordinates 55,826,917 to 55,993,612 (complement strand), 32 exons[1](https://www.ncbi.nlm.nih.gov/gene/4734) |
| Domain architecture | N-terminal calcium- and phospholipid-binding C2 domain, multiple tryptophan-rich WW domains, and a C-terminal HECT ubiquitin ligase catalytic domain[1](https://www.ncbi.nlm.nih.gov/gene/4734) |
| Catalytic mechanism | Accepts ubiquitin from an E2 conjugating enzyme as a thioester on the HECT catalytic cysteine, then transfers it to substrate lysines[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272705/) |
| Substrate recognition | WW domains bind proline-rich PY motifs (L/PPxY) in substrates[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC2824488/) |
| Key substrates | Membrane receptors such as EGFR, IGF-1R, and VEGFR2, plus tumor-related proteins including PTEN, Mdm2, Beclin1, and p21[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10179089/) |
| Expression | Ubiquitous, with highest reported expression in placenta (RPKM 6.4) and liver (RPKM 5.9)[1](https://www.ncbi.nlm.nih.gov/gene/4734) |
## Structure and catalytic mechanism
NEDD4-family proteins share a common modular architecture: an N-terminal C2 domain that binds calcium and phospholipids, two to four WW domains, and a C-terminal HECT domain.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC2824488/) • [5](https://elifesciences.org/articles/828) The C2 domain mediates membrane binding, the WW domains recognize substrates, and the [HECT domain](https://www.edgepedia.org/hect-domain) carries out catalysis.[1](https://www.ncbi.nlm.nih.gov/gene/4734)
The HECT domain, about 350 residues long, works by a two-step mechanism that distinguishes HECT ligases from RING-type E3s. Ubiquitin is transferred from an E2∼ubiquitin intermediate to the E3's catalytic cysteine, forming a labile thioester-linked E3∼ubiquitin intermediate, and is then transferred from the HECT domain onto lysine residues on the substrate.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272705/) • [5](https://elifesciences.org/articles/828) Structural work on the NEDD4-2 HECT domain in complex with an UbcH5B∼ubiquitin adduct showed that the C-terminal lobe rotates about a hinge, shrinking the E2 cysteine-to-HECT cysteine distance to about 8 Å, nearly close enough for direct ubiquitin transfer.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272705/)
**WW domains.** WW domains are compact three-stranded beta-sheet structures of roughly 40 residues, among the smallest functional protein domains known. They are best known for binding PPXY motifs and other proline-rich recognition sequences, and in some cases phosphorylated Ser- or Thr-containing sequences. NEDD4 binds some substrates, such as the EGFR-associated kinase ACK, through its third [WW domain](https://www.edgepedia.org/ww-domain) recognizing a classical PPXY motif.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272705/) The NEDD4 family is defined in MeSH as E3 ligases with four WW domains that transfer ubiquitin specifically to the 63rd lysine residue (Lys-63) of target proteins.[6](https://www.ncbi.nlm.nih.gov/mesh/2023466)
## The NEDD4 family
NEDD4 is the founding member of a family of nine mammalian NEDD4-like E3 ligases, all sharing the C2, WW, and HECT domain organization. The yeast *Saccharomyces cerevisiae* carries out comparable functions with a single orthologue, Rsp5p, while higher eukaryotes evolved several related Nedd4 proteins with specialized roles.[7](https://pubmed.ncbi.nlm.nih.gov/15021885/) The closest relative is NEDD4-2 (NEDD4L), which binds and regulates numerous membrane proteins, including the epithelial sodium channel ENaC and voltage-gated sodium channels, promoting their internalization and turnover.[8](https://www.sciencedirect.com/science/article/pii/S0378111914013286)
The two close relatives differ in substrate preference. Proteome-array comparisons of human NEDD4-1 and NEDD4-2 against about 8,200 human proteins found that several substrates were recognized by both, while others were specific to one: several tyrosine kinases were preferred by NEDD4-1 and some ion channels by NEDD4-2. NEDD4-1 knockdown or knockout led to sustained signaling through substrate tyrosine kinases such as FGFR, indicating that NEDD4-1 suppresses their signaling.[3](https://pmc.ncbi.nlm.nih.gov/articles/PMC2824488/) Despite these substrate differences, the two enzymes show similar E2 specificity: both ubiquitinate substrates strongly with UbcH5b, and optimal ubiquitination by each requires the same E2 enzymes.[9](https://www.sciencedirect.com/science/article/pii/S1357272505003857)
## Physiological roles
NEDD4 was originally identified as a neuronally expressed, developmentally downregulated gene, and it is highly expressed in the central nervous system, where it has a physiological role in neuronal development. In mouse models, NEDD4 regulates dendrite formation and arborization in hippocampal and cortical neurons: it forms a complex with the Traf2 and NCK interacting kinase (TNIK) and Rap2A, and its mono- and di-ubiquitination of Rap2A reduces downstream signaling to promote dendrite growth. NEDD4-mediated ubiquitination and downregulation of PTEN in axons also promotes axon branching in vivo.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC6639052/)
More broadly, the family regulates receptor internalization and lysosomal degradation, and NEDD4-family ligases also function as part of the ESCRT complex in virus release.[6](https://www.ncbi.nlm.nih.gov/mesh/2023466) NEDD4 mediates receptor-regulated endocytosis along with proteasomal degradation, affecting cell growth and other cellular processes.[11](https://mdpi-res.com/d_attachment/ijms/ijms-23-12380/article_deploy/ijms-23-12380.pdf?version=1665910793)
## Role in cancer
Abnormal regulation of NEDD4 has been implicated in cancer development and progression. It acts in tumorigenesis through ubiquitination-mediated degradation of multiple substrates, affecting cell proliferation, apoptosis, cell cycle, migration, invasion, epithelial-mesenchymal transition, cancer stem cells, and drug resistance; findings are supported by knockout mouse models and human tumor tissue studies.[12](https://pubmed.ncbi.nlm.nih.gov/32171886/)
**PTEN regulation.** A central example is NEDD4's action on the tumor suppressor PTEN: NEDD4 degrades PTEN through poly-ubiquitination and dictates its nuclear localization through mono-ubiquitination, and it is well known to initiate and promote cancer through this mechanism.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10179089/) NEDD4 also regulates the cellular localization and stability of membrane receptors relevant to tumorigenesis, including IGF-1R, VEGFR2, and EGFR.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC10179089/) Overexpression of NEDD4-family members has been reported in several cancers, including Nedd4 in prostate and bladder cancer, and the family modulates signaling pathways involved in tumorigenesis such as TGF-beta, EGF, IGF, VEGF, SDF-1, and TNF-alpha.[13](https://pubmed.ncbi.nlm.nih.gov/17726579/)
**Therapeutic interest.** Because NEDD4-family substrate recognition is mediated by WW domains near the HECT domain, this architecture has been a target for inhibitor design. A fragment screen against the NEDD4-1 HECT domain yielded two electrophilic fragments that selectively reacted with the noncatalytic cysteine Cys627 in an exosite of the ligase, confirmed by mass spectrometry and mutational analysis.[14](https://pmc.ncbi.nlm.nih.gov/articles/PMC6471174/) Reviews of glioma, one of the most common brain cancers, have discussed NEDD4's involvement in these tumors and its potential as a pharmacological target.[15](https://www.sciencedirect.com/science/article/pii/S2405844025013775)
## References
1. [NEDD4 NEDD4 E3 ubiquitin protein ligase [Homo sapiens], NCBI Gene ID 4734](https://www.ncbi.nlm.nih.gov/gene/4734)
2. [Molecular Mechanisms of Ubiquitin-Dependent Membrane Traffic, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272705/)
3. [Comparison of substrate specificity of the ubiquitin ligases Nedd4 and Nedd4-2 using proteome arrays, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC2824488/)
4. [Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10179089/)
5. [Mechanism of ubiquitin ligation and lysine prioritization by a HECT E3, eLife](https://elifesciences.org/articles/828)
6. [Nedd4 Ubiquitin Protein Ligases, MeSH, NCBI](https://www.ncbi.nlm.nih.gov/mesh/2023466)
7. [The Nedd4 family of E3 ubiquitin ligases: functional diversity within a common modular architecture, PubMed](https://pubmed.ncbi.nlm.nih.gov/15021885/)
8. [NEDD4-2 (NEDD4L): The ubiquitin ligase for multiple membrane proteins, Gene](https://www.sciencedirect.com/science/article/pii/S0378111914013286)
9. [The ubiquitin-protein ligases Nedd4 and Nedd4-2 show similar ubiquitin-conjugating enzyme specificities, Molecular and Cellular Biochemistry via ScienceDirect](https://www.sciencedirect.com/science/article/pii/S1357272505003857)
10. [NEDD4: The founding member of a family of ubiquitin-protein ligases, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6639052/)
11. [Unraveling the Potential Role of NEDD4-like ligases, International Journal of Molecular Sciences](https://mdpi-res.com/d_attachment/ijms/ijms-23-12380/article_deploy/ijms-23-12380.pdf?version=1665910793)
12. [NEDD4 E3 ligase: Functions and mechanism in human cancer, Seminars in Cancer Biology](https://pubmed.ncbi.nlm.nih.gov/32171886/)
13. [The Nedd4-like family of E3 ubiquitin ligases and cancer, PubMed](https://pubmed.ncbi.nlm.nih.gov/17726579/)
14. [Developing Small-Molecule Inhibitors of HECT-Type Ubiquitin Ligases for Therapeutic Applications, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC6471174/)
15. [The potential of pharmacological intervention targeting NEDD4 in glioma, Heliyon](https://www.sciencedirect.com/science/article/pii/S2405844025013775)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Enzyme classes and activities › Ubiquitination and protein-modification enzymes › Ubiquitin conjugation machinery › HECT-domain E3 ligases*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license