WWP1

Summary

WWP1 (WW domain containing E3 ubiquitin protein ligase 1, HGNC:17004) is a protein-coding gene on chromosome 8q21.3, encoding NEDD4-like E3 ubiquitin-protein ligase WWP1 (Q9H0M0). E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.

WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellular functions such as protein degradation, transcription, and RNA splicing. This gene encodes a protein which contains 4 tandem WW domains and a HECT (homologous to the E6-associated protein carboxyl terminus) domain. The encoded protein belongs to a family of NEDD4-like proteins, which are E3 ubiquitin-ligase molecules and regulate key trafficking decisions, including targeting of proteins to proteosomes or lysosomes. Alternative splicing of this gene generates at least 6 transcript variants; however, the full length nature of these transcripts has not been defined.

Source: NCBI Gene 11059 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 83 total
• Phenotypes (HPO): 1
• MANE Select transcript: NM_007013

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17004
Approved symbol	WWP1
Name	WW domain containing E3 ubiquitin protein ligase 1
Location	8q21.3
Locus type	gene with protein product
Status	Approved
Aliases	AIP5, DKFZP434D2111
Ensembl gene	ENSG00000123124
Ensembl biotype	protein_coding
OMIM	602307
Entrez	11059

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 29 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000265428, ENST00000517970, ENST00000518683, ENST00000520374, ENST00000520453, ENST00000520521, ENST00000520798, ENST00000521079, ENST00000521997, ENST00000523863, ENST00000524036, ENST00000882780, ENST00000882781, ENST00000882782, ENST00000882783, ENST00000882784, ENST00000882785, ENST00000882786, ENST00000882787, ENST00000882788, ENST00000882789, ENST00000882790, ENST00000882791, ENST00000882792, ENST00000942569, ENST00000942570, ENST00000942571, ENST00000942572, ENST00000942573, ENST00000942574, ENST00000942575, ENST00000942576, ENST00000942577, ENST00000942578, ENST00000942579, ENST00000942580

RefSeq mRNA: 1 — MANE Select: NM_007013 NM_007013

CCDS: CCDS6242

Canonical transcript exons

ENST00000517970 — 25 exons

Exon	Start	End
ENSE00001019043	86402019	86402203
ENSE00001261227	86461224	86461320
ENSE00001261235	86457921	86458025
ENSE00001261241	86452559	86452679
ENSE00001666690	86461774	86461846
ENSE00002094527	86466794	86468503
ENSE00002117641	86342547	86342930
ENSE00002139517	86368939	86369031
ENSE00003461339	86435633	86435704
ENSE00003481433	86442619	86442778
ENSE00003493871	86448148	86448281
ENSE00003517911	86398342	86398479
ENSE00003518473	86427643	86427817
ENSE00003522105	86380726	86380864
ENSE00003523760	86411538	86411874
ENSE00003529258	86438585	86438673
ENSE00003551170	86430697	86430751
ENSE00003554435	86398572	86398638
ENSE00003567161	86435452	86435527
ENSE00003572042	86431406	86431490
ENSE00003629154	86431615	86431743
ENSE00003651323	86381505	86381629
ENSE00003655679	86448373	86448513
ENSE00003678440	86425223	86425318
ENSE00003694623	86374030	86374120

Expression profiles

Bgee: expression breadth ubiquitous, 301 present calls, max score 99.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3132 / max 275.1558, expressed in 1769 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89639	8.1959	1659
89637	3.5286	1379
89638	1.9094	1063
89636	0.5256	324
89641	0.1191	49
89640	0.0346	8

Top tissues by expression

302 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.33	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.28	gold quality
biceps brachii	UBERON:0001507	99.19	gold quality
body of tongue	UBERON:0011876	98.85	gold quality
caput epididymis	UBERON:0004358	98.84	gold quality
corpus epididymis	UBERON:0004359	98.84	gold quality
tongue	UBERON:0001723	98.61	gold quality
superior surface of tongue	UBERON:0007371	98.60	gold quality
mammary duct	UBERON:0001765	98.57	gold quality
cauda epididymis	UBERON:0004360	98.42	gold quality
pharyngeal mucosa	UBERON:0000355	98.35	gold quality
vastus lateralis	UBERON:0001379	98.29	gold quality
heart right ventricle	UBERON:0002080	98.25	gold quality
diaphragm	UBERON:0001103	98.22	gold quality
lower lobe of lung	UBERON:0008949	98.12	gold quality
trigeminal ganglion	UBERON:0001675	98.09	gold quality
skeletal muscle tissue	UBERON:0001134	98.00	gold quality
cardia of stomach	UBERON:0001162	97.90	gold quality
quadriceps femoris	UBERON:0001377	97.88	gold quality
pons	UBERON:0000988	97.84	gold quality
superficial temporal artery	UBERON:0001614	97.82	gold quality
gluteal muscle	UBERON:0002000	97.57	gold quality
renal medulla	UBERON:0000362	97.46	gold quality
pylorus	UBERON:0001166	97.44	gold quality
epithelium of nasopharynx	UBERON:0001951	97.35	gold quality
nasopharynx	UBERON:0001728	97.33	gold quality
oral cavity	UBERON:0000167	97.31	gold quality
vena cava	UBERON:0004087	97.24	gold quality
epithelium of mammary gland	UBERON:0003244	97.19	gold quality
muscle tissue	UBERON:0002385	97.18	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.59
E-CURD-53	no	100.52

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
ERBB4	Repression
SPART	Unknown
TGFBR1	Repression

Upstream regulators (CollecTRI, top): HIVEP3, TP63

miRNA regulators (miRDB)

155 targeting WWP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 40)

• First demonstration of ubiquitin-protein ligase WWP1 from human lung cDNA library recruited by penton base proteins of human adenovirus serotypes Ad2 and Ad3 in vitro and in vivo. (PMID:12450395)
• the interaction of nonenveloped viruses with ubiquitin-protein ligases of host cells. (PMID:12450395)
• Data show that the crystal structure of the HECT domain of the human ubiquitin ligase WWP1/AIP5 maintains a two-lobed structure like the HECT domain of the human ubiquitin ligase E6AP. (PMID:12535537)
• WWP1 negatively regulates TGF-beta signaling in cooperation with Smad7. (PMID:15221015)
• KLF5 is a target of the E3 ubiquitin ligase WWP1 for proteolysis in epithelial cells (PMID:16223724)
• Full-length expressed WWP1 could interact in vitro with the cytoplasmic domain of human Notch1, which also regulate the nuclear localization of WWP1. (PMID:16785210)
• these findings identify the first instance of a ubiquitin ligase that causes stabilization of p53 while inactivating its transcriptional activities. (PMID:16924229)
• WWP1 overexpression is a common mechanism involved in the inactivation of TGFbeta function in human cancer. (PMID:17016436)
• genomic aberrations of WWP1 may contribute to the pathogenesis of breast cancer (PMID:17330240)
• the interaction between Gag and WWP1 is required for functions other than Gag ubiquitination (PMID:17609263)
• WWP1 may promote cell proliferation and survival partially through suppressing RNF11-mediated ErbB2 and EGFR downregulation in human cancer cells. (PMID:18724389)
• WWP1 may have a context-dependent role in regulating cell survival through targeting different p63 proteins for degradation. (PMID:18806757)
• analysis of the interaction between ubiquitin ligase WWP1 and Nogo-A (PMID:19035836)
• WWP1 ubiquitinated and caused the degradation of HER4 but not of EGFR, HER2, or HER3. (PMID:19047365)
• Overexpression of WWP1 is associated with the estrogen receptor and insulin-like growth factor receptor 1 in breast carcinoma (PMID:19267401)
• Experiments suggest functions for WWP1 and SPG20 in the regulation of lipid droplet turnover and potential pathological mechanisms in Troyer syndrome. (PMID:19307600)
• WWP1 and its family members suppress the ErbB4 expression and function in breast cancer (PMID:19561640)
• SPG20 interacts with AIP4 and AIP5. (PMID:19580544)
• WWP1 regulates DeltaNp63 transcriptional activity, acting thus as a potential regulator of the proliferation and survival of epithelial-derived cells. (PMID:20951678)
• The authors show that WWP1 changes the ubiquitination status of ARRDC1, suggesting that the arrestins may provide a platform for ubiquitination in PPXY-dependent budding. (PMID:21191027)
• WWP1 depletion-induced apoptosis was rescued by the overexpression of the wild-type WWP1 but not the E3 ligase inactive WWP1-C890A mutant in MCF7 cells. (PMID:21480222)
• WWP1 markedly inhibited the replicative senescence induced by p27(Kip1) by promoting p27(Kip1) degradation. (PMID:21795702)
• WWP1 mutations are not a common cause of human dystroglycanopathy. (PMID:21996799)
• TAZ promotes breast cell growth partially through protecting KLF5 from WWP1-mediated degradation and enhancing KLF5’s activities. (PMID:22045023)
• WWP1 may function as the E3 ligase for several PY motif-containing proteins, such as Smad2, KLF5, p63, ErbB4/HER4, RUNX2, JunB, RNF11, SPG20, and Gag, as well as several non-PY motif containing proteins, such as TbetaR1, Smad4, KLF2, and EPS15. Review. (PMID:22051607)
• WWP1 negatively regulates cell migration to CXCL12 by limiting CXCR4 degradation to promote breast cancer metastasis to bone. (PMID:22266093)
• WWP1 down-regulates AMPKalpha2 under high glucose culture conditions via the ubiquitin-proteasome pathway (PMID:23293026)
• LATS1 is critical in mediating WWP1-induced increased cell proliferation in breast cancer cells. (PMID:23573293)
• results reveal that WWP1 might play an oncogenic role in oral cancer cells. (PMID:23849376)
• Knocking down WWP1 promoted cleaved caspase3 protein and p53 expression in hepatocellular carcinoma cells, and caspase3 inhibition could prevent cell apoptosis induced by the knockdown of WWP1. (PMID:24792179)
• Results suggest that elevated transcription and expression levels of ubiquitin ligase E3s WWP1, Smurf1 and Smurf2 genes may be the mechanisms of occurrence, development and metastasis of prostate cancer. (PMID:25051198)
• Data show that WWP1, which specifically ubiquitinates and degrades DeltaNp73 heterodimerizes with another E3 ligase, WWP2. (PMID:25071155)
• Most notably, WWP1 downregulation both inactivated PTEN-Akt signaling pathway in MKN-45 and AGS cells. our findings suggest that WWP1 acts as an oncogenic factor and should be considered as a novel interfering molecular target for gastric carcinoma (PMID:25293520)
• miR-21 overexpression or WWP1 knockdown in endothelial progenitor cells significantly activates the TGFbeta signaling pathway and inhibits cell proliferation. (PMID:25755729)
• PTPN14, a Pez mammalian homolog, is degraded by overexpressed Su(dx) or Su(dx) homologue WWP1 in mammalian cells. (PMID:25814387)
• The cancer-driven alteration of WWP1 culminates in excessive TbetaRI degradation and attenuated TGFbeta1 cytostatic signaling, a consequence that could conceivably confer tumorigenic properties to WWP1. (PMID:26152726)
• Overexpression of WWP1 promotes tumorigenesis in patients with hepatocellular carcinoma. (PMID:26506518)
• Study shows that WWP1 was upregulated in prostate cancer (PCa) clinical specimens and contributed to cancer cell invasion, indicating that this target of Mir-452 functioned as an oncogene. (PMID:27070713)
• Knock-down of WWP1 abrogates DNA damage-induced down-regulation of DeltaNp63alphaand partially rescues cell apoptosis (PMID:28426804)
• Results show that WWP1 is frequently upregulated in gastric cancer (GC) tissues and cells, and that its 3’-UTR is a putative target of miR-584 which suppresses its protein expression by mRNA degradation. (PMID:28431583)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	wwp1	ENSDARG00000097537
mus_musculus	Wwp1	ENSMUSG00000041058
rattus_norvegicus	Wwp1	ENSRNOG00000006328
drosophila_melanogaster	Su(dx)	FBGN0003557
caenorhabditis_elegans	wwp-1	WBGENE00007009

Paralogs (24): HECW1 (ENSG00000002746), UBE3C (ENSG00000009335), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

NEDD4-like E3 ubiquitin-protein ligase WWP1 — Q9H0M0 (reviewed: Q9H0M0)

Alternative names: Atrophin-1-interacting protein 5, HECT-type E3 ubiquitin transferase WWP1, TGIF-interacting ubiquitin ligase 1, WW domain-containing protein 1

All UniProt accessions (3): H0YBA4, H0YBS9, Q9H0M0

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Ubiquitinates ERBB4 isoforms JM-A CYT-1 and JM-B CYT-1, KLF2, KLF5 and TP63 and promotes their proteasomal degradation. Ubiquitinates RNF11 without targeting it for degradation. Ubiquitinates and promotes degradation of TGFBR1; the ubiquitination is enhanced by SMAD7. Ubiquitinates SMAD6 and SMAD7. Ubiquitinates and promotes degradation of SMAD2 in response to TGF-beta signaling, which requires interaction with TGIF. Activates the Hippo signaling pathway in response to cell contact inhibition and recruitment to the Crumbs complex at the cell membrane. Monoubiquitinates AMOTL2 which facilitates its interaction with and activation of LATS2. LATS2 then phosphorylates YAP1, excluding it from the nucleus and therefore ultimately represses YAP1-driven transcription of target genes.

Subunit / interactions. Interacts with the Crumbs complex components PALS1 and PATJ; interaction with the Crumbs complex is enhanced by WWP1’s interaction with AMOTL2 and facilitates WWP1 localization to the plasma membrane. Interaction with the Crumbs complex promotes WWP1 monoubiquitination of AMOTL2, which activates the Hippo signaling pathway. Binds KLF2 and HIVEP3. Binds SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2, DRPLA and adenovirus type 2 PIII. Interacts with RNF11. Interacts with SPART. Interacts with ERBB4 isoforms JM-B CYT-1 and JM-A CYT-1. Interacts with SMAD1, SMAD2, SMAD3, SMAD5, SMAD6, SMAD7, TGFBR1 and TGFBR2. Associates with the TGFBR1:TGFBR2 receptor complex in presence of SMAD7. Interacts with SKIL isoform 1. Interacts with TP63 isoform 1 and isoform 2. Interacts with STAMBP and RNF11. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase. Interacts with TGIF. Interacts (via WW domains) with ARRDC1, ARRDC2 and ARRDC3. (Microbial infection) Interacts with HTLV-1 protein Gag. (Microbial infection) Interacts with ebola virus protein VP40.

Subcellular location. Cytoplasm. Cell membrane. Nucleus. Cell junction.

Tissue specificity. Detected in heart, placenta, pancreas, kidney, liver, skeletal muscle, bone marrow, fetal brain, and at much lower levels in adult brain and lung. Isoform 1 and isoform 5 predominate in all tissues tested, except in testis and bone marrow, where isoform 5 is expressed at much higher levels than isoform 1.

Post-translational modifications. Auto-ubiquitinated and ubiquitinated by RNF11.

Activity regulation. Activated by NDFIP1- and NDFIP2-binding.

Domain organisation. The WW domains mediate interaction with PPxY motif-containing proteins.

Induction. Induced at protein level in response to cell-cell contact inhibition, as a result of increased protein stability.

Pathway. Protein modification; protein ubiquitination.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9H0M0-1	1, A	yes
Q9H0M0-2	2, B
Q9H0M0-3	3, C
Q9H0M0-4	4, D
Q9H0M0-5	5, E
Q9H0M0-6	6, F

RefSeq proteins (1): NP_008944* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR000569	HECT_dom	Domain
IPR001202	WW_dom	Domain
IPR024928	E3_ub_ligase_SMURF1	Family
IPR035892	C2_domain_sf	Homologous_superfamily
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR036020	WW_dom_sf	Homologous_superfamily
IPR050409	E3_ubiq-protein_ligase	Family

Pfam: PF00168, PF00397, PF00632

Enzyme classification (BRENDA):

• EC 2.3.2.26 — HECT-type E3 ubiquitin transferase (BRENDA: 14 organisms, 64 substrates, 19 inhibitors, 5 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBC5B]-L-LYSINE	0.0046–0.037	5

UniProt features (89 total): helix 26, strand 22, turn 11, mutagenesis site 10, domain 6, compositionally biased region 5, splice variant 4, region of interest 2, chain 1, active site 1, site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
5HPS	X-RAY DIFFRACTION	2.05
1ND7	X-RAY DIFFRACTION	2.1
6J1X	X-RAY DIFFRACTION	2.3
8EI4	X-RAY DIFFRACTION	2.43
6J1Y	X-RAY DIFFRACTION	2.55
5HPT	X-RAY DIFFRACTION	2.84
9EQK	X-RAY DIFFRACTION	3
2OP7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0M0-F1	76.83	0.42

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 890 (glycyl thioester intermediate); 890 (required for ubiquitin-thioester formation)

Mutagenesis-validated functional residues (10):

Position	Phenotype
614	reduces ubiquitin transfer.
621	strongly reduces ubiquitin transfer.
675	reduces ubiquitin transfer.
798	reduces ubiquitin transfer. strongly reduces ubiquitin transfer; when associated with a-845.
804	strongly reduces ubiquitin transfer; when associated with p-806.
806	strongly reduces ubiquitin transfer; when associated with p-804.
845	no effect.
848	abolishes ubiquitin transfer; when associated with a-855.
855	abolishes ubiquitin transfer; when associated with a-848.
890	abolishes monoubiquitination of amotl2.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1253288	Downregulation of ERBB4 signaling
R-HSA-2672351	Stimuli-sensing channels
R-HSA-8939902	Regulation of RUNX2 expression and activity
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 273 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, MULLIGHAN_NPM1_SIGNATURE_3_UP, TGCGCANK_UNKNOWN, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, TTCCGTT_MIR191, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, TGACCTY_ERR1_Q2, GGGTGGRR_PAX4_03, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, MODULE_503

GO Biological Process (8): central nervous system development (GO:0007417), protein ubiquitination (GO:0016567), monoatomic ion transmembrane transport (GO:0034220), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of DNA-templated transcription (GO:0045892), symbiont entry into host cell (GO:0046718), ubiquitin-dependent protein catabolic process (GO:0006511), signal transduction (GO:0007165)

GO Molecular Function (4): ubiquitin-protein transferase activity (GO:0004842), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), anchoring junction (GO:0070161), ubiquitin ligase complex (GO:0000151), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by ERBB4	1
Ion channel transport	1
Transcriptional regulation by RUNX2	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nervous system development	1
system development	1
protein modification by small protein conjugation	1
monoatomic ion transport	1
transmembrane transport	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
viral life cycle	1
symbiont entry into host	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
ubiquitin-like protein transferase activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
extracellular vesicle	1
cell junction	1
intracellular protein-containing complex	1
transferase complex	1

Protein interactions and networks

STRING

2154 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WWP1	SMAD7	O15105	895
WWP1	HIVEP3	Q5T1R4	885
WWP1	USP9X	Q93008	804
WWP1	SPART	Q8N0X7	797
WWP1	ATN1	P54259	743
WWP1	RNF11	Q9Y3C5	642
WWP1	UBE2D1	P51668	622
WWP1	SMAD4	Q13485	617
WWP1	TSG101	Q99816	604
WWP1	SMAD3	P84022	603
WWP1	CALCOCO2	Q13137	590
WWP1	TP53	P04637	589
WWP1	NDFIP1	Q9BT67	576
WWP1	ARRDC3	Q96B67	562
WWP1	ERBB4	Q15303	560
WWP1	TGFBR1	P36897	560

IntAct

123 interactions, top by confidence:

A	B	Type	Score
CPSF6	NUDT21	psi-mi:“MI:0914”(association)	0.890
ARRDC1	WWP2	psi-mi:“MI:0914”(association)	0.850
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
WWP1	SMAD3	psi-mi:“MI:0915”(physical association)	0.810
SMAD3	WWP1	psi-mi:“MI:0915”(physical association)	0.810
ARRDC3	WWP1	psi-mi:“MI:0915”(physical association)	0.800
ARRDC1	WWP1	psi-mi:“MI:0915”(physical association)	0.800
CPSF6	WWP1	psi-mi:“MI:0915”(physical association)	0.780
WWP1	CPSF6	psi-mi:“MI:0915”(physical association)	0.780
ARRDC3	WWP2	psi-mi:“MI:0914”(association)	0.770
ENTREP1	WWP1	psi-mi:“MI:0915”(physical association)	0.660
ARRDC1	NEDD4	psi-mi:“MI:0914”(association)	0.640
WWP1		psi-mi:“MI:0915”(physical association)	0.560
WWP1	FBXL18	psi-mi:“MI:0915”(physical association)	0.560
WWP1	TRAF4	psi-mi:“MI:0915”(physical association)	0.560
FBXL18	WWP1	psi-mi:“MI:0915”(physical association)	0.560
	WWP1	psi-mi:“MI:0915”(physical association)	0.560
TRAF4	WWP1	psi-mi:“MI:0915”(physical association)	0.560
ATXN3	WWP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (452): WWP1 (Biochemical Activity), UBE2L3 (Reconstituted Complex), WWP1 (Two-hybrid), WWP1 (Two-hybrid), WWP1 (Two-hybrid), FBXL18 (Two-hybrid), WWP1 (Protein-peptide), WWP1 (Affinity Capture-MS), WWP1 (Affinity Capture-MS), WWP1 (Affinity Capture-MS), WWP1 (Affinity Capture-MS), WWP1 (Affinity Capture-MS), WWP1 (Affinity Capture-MS), WWP1 (Affinity Capture-MS), ZNF638 (Two-hybrid)

ESM2 similar proteins: A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B4GEU5, B8N7E5, G0S9J5, G5ECY0, H2L056, O00308, O14326, O42643, P10823, P39055, P39940, P46935, Q0CCL1, Q2TAS2, Q2UBP1, Q45FX5, Q4WTF3, Q5BDP1, Q5RBF2, Q5RD78, Q5U5R9, Q62940, Q757T0, Q8BZZ3, Q8C863, Q8CFI0, Q92462, Q96J02, Q96PU5, Q9CUN6, Q9DBH0, Q9H0M0, Q9HAU4, Q9HCE7

Diamond homologs: A0A8C0NGY6, A0A8I3PQN6, A1A5G4, A1CQG2, A1D3C5, A2QQ28, A4IIJ3, B0XQ72, B3LWS4, B3P3M8, B4HEJ6, B4K6I9, B4M5X4, B4NAD3, B4PSQ2, B8N7E5, D6C652, G0S9J5, H2LBU8, O14326, O88382, O95817, P39940, P46934, P46935, P46936, P46937, P46938, Q0CCL1, Q19404, Q1L8J7, Q2EJA0, Q2UBP1, Q32NJ6, Q4L1J4, Q4WTF3, Q5BDP1, Q5F488, Q5TCQ9, Q62940

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
WWP1	up-regulates	SMAD7	binding
WWP1	“up-regulates activity”	SMAD7	relocalization
WWP1	down-regulates	TGFBR1	ubiquitination
TGIF1	up-regulates	WWP1	binding
WWP1	“up-regulates activity”	SMAD7	ubiquitination
SPART	“up-regulates activity”	WWP1	binding
Ub:E2	“up-regulates activity”	WWP1	ubiquitination
WWP1	“up-regulates activity”	AMOTL2	ubiquitination
WWP2	“up-regulates activity”	WWP1	binding
WWP1	“down-regulates quantity by destabilization”	TP73	polyubiquitination
WWP1	“up-regulates activity”	TP53	ubiquitination
WWP1	“up-regulates activity”	KLF5	ubiquitination
WWP1	“down-regulates quantity”	NDFIP1	ubiquitination
WWP1	“up-regulates quantity by stabilization”	AMOT	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 111 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	5	15.4×	4e-03
DNA-templated transcription	5	11.9×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

83 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4334 predictions. Top by Δscore:

Variant	Effect	Δscore
8:86342926:GCCGG:G	donor_gain	1.0000
8:86342929:GG:G	donor_gain	1.0000
8:86342930:GG:G	donor_gain	1.0000
8:86342931:G:GG	donor_gain	1.0000
8:86342931:GT:G	donor_loss	1.0000
8:86348748:T:TA	acceptor_gain	1.0000
8:86369032:G:GG	donor_gain	1.0000
8:86380724:A:AG	acceptor_gain	1.0000
8:86380725:G:GG	acceptor_gain	1.0000
8:86380860:ACTGT:A	donor_gain	1.0000
8:86380861:CTGT:C	donor_gain	1.0000
8:86380863:GT:G	donor_gain	1.0000
8:86380864:TG:T	donor_loss	1.0000
8:86380865:G:GG	donor_gain	1.0000
8:86380866:T:TC	donor_loss	1.0000
8:86380867:AAGTA:A	donor_loss	1.0000
8:86380868:AGT:A	donor_loss	1.0000
8:86381489:A:AG	acceptor_gain	1.0000
8:86381504:GA:G	acceptor_gain	1.0000
8:86381504:GAAAT:G	acceptor_gain	1.0000
8:86381625:AAAAT:A	donor_gain	1.0000
8:86381626:AAAT:A	donor_gain	1.0000
8:86381626:AAATG:A	donor_loss	1.0000
8:86381627:AAT:A	donor_gain	1.0000
8:86381628:AT:A	donor_gain	1.0000
8:86381628:ATGT:A	donor_loss	1.0000
8:86381629:TGT:T	donor_loss	1.0000
8:86381630:G:GG	donor_gain	1.0000
8:86381631:T:A	donor_loss	1.0000
8:86398336:TTCTA:T	acceptor_loss	1.0000

AlphaMissense

6059 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:86430748:T:A	W462R	1.000
8:86430748:T:C	W462R	1.000
8:86430750:G:C	W462C	1.000
8:86430750:G:T	W462C	1.000
8:86431435:T:G	Y473D	1.000
8:86431438:T:C	F474L	1.000
8:86431440:T:A	F474L	1.000
8:86431440:T:G	F474L	1.000
8:86431468:T:A	W484R	1.000
8:86431468:T:C	W484R	1.000
8:86431469:G:C	W484S	1.000
8:86431470:G:C	W484C	1.000
8:86431470:G:T	W484C	1.000
8:86431478:C:A	P487Q	1.000
8:86431646:T:A	W502R	1.000
8:86431646:T:C	W502R	1.000
8:86431679:T:G	Y513D	1.000
8:86431682:T:C	F514L	1.000
8:86431684:T:A	F514L	1.000
8:86431684:T:G	F514L	1.000
8:86431686:T:A	V515D	1.000
8:86438613:G:C	R593T	1.000
8:86438613:G:T	R593M	1.000
8:86438624:T:G	Y597D	1.000
8:86438648:G:A	G605R	1.000
8:86438648:G:C	G605R	1.000
8:86438649:G:A	G605E	1.000
8:86438652:T:A	L606H	1.000
8:86438652:T:C	L606P	1.000
8:86438673:G:T	R613I	1.000

dbSNP variants (sampled 300 via entrez): RS1000000027 (8:86407902 T>C), RS1000019789 (8:86370018 A>T), RS1000033336 (8:86363565 G>A), RS1000063775 (8:86460933 T>C), RS1000085164 (8:86363804 A>G), RS1000089404 (8:86459707 C>T), RS1000105093 (8:86453456 T>G), RS1000139341 (8:86389261 T>A,C), RS1000208252 (8:86389466 G>T), RS1000318480 (8:86420648 A>G), RS1000330040 (8:86369832 G>A), RS1000333834 (8:86465451 C>T), RS1000345669 (8:86427716 C>T), RS1000366157 (8:86359916 G>A), RS1000415098 (8:86460672 A>G)

Disease associations

OMIM: gene MIM:602307 | disease phenotypes: MIM:194200

GenCC curated gene-disease

Mondo (1): Wolff-Parkinson-White syndrome (MONDO:0008685)

Orphanet (1): NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001716	Wolff-Parkinson-White syndrome

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008058_126	Estimated glomerular filtration rate	2.000000e-16

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, decreases expression	2
Valproic Acid	decreases methylation, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	affects binding, increases reaction	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	increases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Coumestrol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Selenium	decreases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TY27	HAP1 WWP1 (-) 1	Cancer cell line	Male
CVCL_TY28	HAP1 WWP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

8 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00251121	Not specified	COMPLETED	Routine Mini-invasive Electrophysiology Study for Patients Feeling Tachycardia, With a Negative Holter ECG
NCT00873470	Not specified	TERMINATED	Wolff-Parkinson-White Syndrome Anterograde Refractory Period of Accessory Duct
NCT03207373	Not specified	TERMINATED	Stress ECG Test for the Evaluation of the Risk of Sudden Cardiac Death in a Paediatric Cohort With WPW Pattern
NCT03301935	Not specified	COMPLETED	Risk Assessment in Patients With Symptomatic- and Asymptomatic Preexcitation
NCT03816033	Not specified	UNKNOWN	Cryotherapy Versus Radiofrequency Catheter Ablation Research Program
NCT04106622	Not specified	UNKNOWN	Accessory Pathway Antegrade Effective Refractory Period Among WPW Patients: the Risk in Relation to the Location
NCT06349109	Not specified	COMPLETED	Physical Activity in Children With Wolff-Parkinson-White Syndrome
NCT07435181	Not specified	NOT_YET_RECRUITING	Comparative Outcomes of Radiofrequency Ablation of Concealed and Manifest Accessory Pathways: a Single Center, Retrospective Observational Study