WWP2

Summary

WWP2 (WW domain containing E3 ubiquitin protein ligase 2, HGNC:16804) is a protein-coding gene on chromosome 16q22.1, encoding NEDD4-like E3 ubiquitin-protein ligase WWP2 (O00308). 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.

This gene encodes a member of the Nedd4 family of E3 ligases, which play an important role in protein ubiquitination. The encoded protein contains four WW domains and may play a role in multiple processes including chondrogenesis and the regulation of oncogenic signaling pathways via interactions with Smad proteins and the tumor suppressor PTEN. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 10.

Source: NCBI Gene 11060 — RefSeq curated summary.

At a glance

• GWAS associations: 35
• Clinical variants (ClinVar): 150 total
• MANE Select transcript: NM_001270454

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16804
Approved symbol	WWP2
Name	WW domain containing E3 ubiquitin protein ligase 2
Location	16q22.1
Locus type	gene with protein product
Status	Approved
Aliases	AIP2
Ensembl gene	ENSG00000198373
Ensembl biotype	protein_coding
OMIM	602308
Entrez	11060

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 18 protein_coding, 7 retained_intron, 6 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000356003, ENST00000359154, ENST00000544162, ENST00000561780, ENST00000563618, ENST00000563659, ENST00000566463, ENST00000567161, ENST00000567303, ENST00000567579, ENST00000567986, ENST00000568185, ENST00000568684, ENST00000568818, ENST00000568845, ENST00000569174, ENST00000569297, ENST00000569620, ENST00000569658, ENST00000570104, ENST00000903147, ENST00000903148, ENST00000903149, ENST00000903150, ENST00000903151, ENST00000903152, ENST00000903153, ENST00000903154, ENST00000920129, ENST00000920130, ENST00000920131, ENST00000947408

RefSeq mRNA: 5 — MANE Select: NM_001270454 NM_001270453, NM_001270454, NM_001270455, NM_007014, NM_199424

CCDS: CCDS10885, CCDS58475, CCDS58476, CCDS58477

Canonical transcript exons

ENST00000359154 — 24 exons

Exon	Start	End
ENSE00002625510	69762332	69762391
ENSE00003475661	69840126	69840263
ENSE00003484271	69888039	69888249
ENSE00003485409	69908761	69908850
ENSE00003486918	69935853	69935986
ENSE00003494910	69939341	69939413
ENSE00003504062	69925430	69925484
ENSE00003530777	69842024	69842120
ENSE00003533371	69930130	69930258
ENSE00003534368	69937548	69937652
ENSE00003537351	69929448	69929529
ENSE00003542867	69937118	69937238
ENSE00003555601	69939027	69939123
ENSE00003599855	69936312	69936452
ENSE00003619260	69799174	69799295
ENSE00003619900	69786996	69787080
ENSE00003632669	69931802	69931890
ENSE00003654135	69933970	69934129
ENSE00003673876	69871804	69871931
ENSE00003677794	69798682	69798829
ENSE00003686836	69917709	69917883
ENSE00003690976	69931152	69931227
ENSE00003694478	69931509	69931580
ENSE00003907895	69939841	69941739

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 99.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.7790 / max 543.9230, expressed in 1807 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
154855	14.6978	1798
154860	1.5058	400
154859	1.0320	376
154858	0.3972	113
154857	0.0753	51
154861	0.0711	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.68	gold quality
tendon of biceps brachii	UBERON:0008188	97.96	gold quality
ascending aorta	UBERON:0001496	97.86	gold quality
thoracic aorta	UBERON:0001515	97.79	gold quality
descending thoracic aorta	UBERON:0002345	97.42	gold quality
sural nerve	UBERON:0015488	97.35	gold quality
right coronary artery	UBERON:0001625	96.82	gold quality
aorta	UBERON:0000947	96.51	gold quality
popliteal artery	UBERON:0002250	95.55	gold quality
tibial artery	UBERON:0007610	95.53	gold quality
pancreatic ductal cell	CL:0002079	95.40	gold quality
cervix squamous epithelium	UBERON:0006922	95.33	silver quality
endothelial cell	CL:0000115	95.26	gold quality
tendon	UBERON:0000043	94.89	gold quality
coronary artery	UBERON:0001621	94.70	gold quality
esophagus squamous epithelium	UBERON:0006920	94.69	gold quality
left coronary artery	UBERON:0001626	94.53	gold quality
calcaneal tendon	UBERON:0003701	94.26	gold quality
bone marrow cell	CL:0002092	93.99	gold quality
epithelium of esophagus	UBERON:0001976	93.93	gold quality
medial globus pallidus	UBERON:0002477	93.65	gold quality
cartilage tissue	UBERON:0002418	93.42	gold quality
blood	UBERON:0000178	93.34	gold quality
squamous epithelium	UBERON:0006914	93.29	gold quality
blood vessel layer	UBERON:0004797	93.21	gold quality
right uterine tube	UBERON:0001302	93.05	gold quality
palpebral conjunctiva	UBERON:0001812	93.03	gold quality
amniotic fluid	UBERON:0000173	92.84	gold quality
tibial nerve	UBERON:0001323	92.73	gold quality
metanephros cortex	UBERON:0010533	92.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.08
E-MTAB-7249	no	17.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting WWP2, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-942-5P	99.41	68.40	1977
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-4727-5P	99.23	67.55	1154
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-4699-5P	98.99	67.50	1210
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-4646-3P	98.65	66.98	693
HSA-MIR-93-3P	98.15	66.65	1309

Literature-anchored findings (GeneRIF, showing 40)

• expression, binding, and functional data all suggest that WWP2 is a candidate to regulate ENaC-mediated Na(+) transport in epithelia (PMID:12167593)
• First demonstration of ubiquitin-protein ligase WWP2 from human lung cDNA library recruited by penton base proteins of adenovirus serotypes Ad2 and Ad3 in vitro and in vivo. (PMID:12450395)
• Data show that WWP2 and Nedd4-2 both bind to the cardiac sodium channel Na(v)1.5, but only Nedd4-2 robustly ubiquitinated and downregulated Na(v)1.5. (PMID:15548568)
• cIAP1 and cIAP2 promote cancer cell survival by functioning as E3 ubiquitin ligases that maintain constitutive ubiquitination of the RIP1 adaptor protein. (PMID:18570872)
• The WWP2 protein is an important regulator for maintaining a proper POU5F1 protein level in human Embryonic Stem Cells. (PMID:19274063)
• AIP2 regulates activation-induced T-cell death by suppressing EGR2-mediated FasL expression via the ubiquitin pathway (PMID:19651900)
• Data show that the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. (PMID:21258410)
• WWP2 controls cellular apoptosis and is required for tumorigenicity of cells (PMID:21532586)
• Koala retrovirus Gag PPPY L-domain interacts with the WW domain(s) of WWP2 and progeny virions are released from cells by utilizing the multivesicular body sorting pathway. (PMID:23651516)
• WWP2-N is downregulated in stage IIIC melanoma and up-regulated in stage II/III prostate cancer, and WWP2-FL and WWP2-C overexpression is associated with early-stage breast cancer. (PMID:23938591)
• Wwp2 acts as a ubiquitin ligase of SRG3. (PMID:24365151)
• Results identify WWP2 as a novel p73-associated protein that ubiquitinates and degrades p73. (PMID:25071155)
• Data provide evidence that the stability of Paip1 can be regulated by ubiquitin-mediated degradation, thus highlighting the importance of WWP2 as a suppressor of translation. (PMID:25266661)
• majority of ovarian carcinomas harbored homozygous or heterozygous deletions in WWP2 locus, and there was an inverse correlation in the expression levels between WWP2 and Notch3 in ovarian carcinomas (PMID:25356737)
• we demonstrate that WWP2 promotes cell adhesion, invasion, and migration in liver cancer by upregulating CXCR3 and CCR5 expression associated with the chemokine signaling pathway. (PMID:26662306)
• WWP2 may represent a novel diagnostic marker and molecular therapeutic target for liver cancer. (PMID:26783238)
• Data suggest that elevated expression of WW domain containing E3 ubiquitin protein ligase 2 (WWP2) may play a role in facilitating the development of lung adenocarcinoma. (PMID:27462019)
• Describe an autoinhibitory mechanism for WWP2 ubiquitin ligase involving a linker-HECT domain interaction. This intramolecular interaction traps the HECT enzyme in its inactive state and can be relieved by linker phosphorylation. (PMID:28475870)
• results provide evidence that WWP2 serves as a positive regulator of osteogenesis by augmenting RUNX2 transactivation in a non-proteolytic mono-ubiquitination manner. (PMID:28500134)
• Our study suggests that WWP2 may play a role in the genesis and development of glioma; it may be a potential biomarker to predict pathological grade and tumor recurrence in patients with glioma. (PMID:29237971)
• The present study suggested that miR32 may effectively inhibit WWP2 expression in human amniotic epithelial stem cells and promote Oct4 overexpression to maintain their pluripotency. (PMID:29393344)
• SNP rs62051384, located within WWP2, showed an association with plantar fascial disorders at genome-wide significance (p<5x10(-8)) with small effects (odds ratios=0.93 and 1.07 per allele, respectively). (PMID:29534260)
• WWP2 is dysregulated in various of tumors, and it promotes carcinogenesis mainly through PTEN/Akt signaling pathway (PMID:30415470)
• findings suggest that WWP2 operates in a DNA-PK-dependent shutoff circuitry for RNAPII clearance that promotes DNA double-strand break repair by protecting the nonhomologous end joining machinery from collision with the transcription machinery (PMID:31048545)
• WWP2 expression level is downregulated in human osteoarthritis cartilage. (PMID:31160553)
• WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFbeta1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFbeta1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2. (PMID:31399586)
• The data reveal a structural platform for Smad substrate selection by WWP2 isoform WW domains that may be significant in the context of WWP2 isoform switching linked to tumorigenesis. (PMID:31546607)
• We found that in addition to influencing catalytic activities, the WW domain linker regions in NEDD4-1 and WWP2 can impact product distribution, including the degree of polyubiquitination and Lys-48 versus Lys-63 linkages. We show that allosteric activation by NDFIP1 or engineered ubiquitin variants is largely mediated by relief of WW domain linker autoinhibition. (PMID:31578285)
• WWP2 promotes proliferation of gastric cancer cells in a PTEN-dependent manner. (PMID:31677789)
• Role of WW domain E3 ubiquitin protein ligase 2 in modulating ubiquitination and Degradation of Septin4 in oxidative stress endothelial injury. (PMID:31924572)
• WWP2 ameliorates acute kidney injury by mediating p53 ubiquitylation and degradation. (PMID:32248569)
• The Tumour Suppressor TMEM127 Is a Nedd4-Family E3 Ligase Adaptor Required by Salmonella SteD to Ubiquitinate and Degrade MHC Class II Molecules. (PMID:32526160)
• ABRO1 stabilizes the deubiquitinase BRCC3 through inhibiting its degradation mediated by the E3 ubiquitin ligase WWP2. (PMID:33107021)
• DKK1 suppresses WWP2 to enhance bortezomib resistance in multiple myeloma via regulating GLI2 ubiquitination. (PMID:34546340)
• Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma. (PMID:34732716)
• Enzymatic analysis of WWP2 E3 ubiquitin ligase using protein microarrays identifies autophagy-related substrates. (PMID:35331737)
• WWP2 overexpression inhibits the antitumor effects of doxorubicin in hepatocellular carcinoma. (PMID:35880837)
• WWP2 ameliorates oxidative stress and inflammation in atherosclerotic mice through regulation of PDCD4/HO-1 pathway. (PMID:35983977)
• WWP2 confers risk to osteoarthritis by affecting cartilage matrix deposition via hypoxia associated genes. (PMID:36208715)
• miR-328-5p Induces Human Intervertebral Disc Degeneration by Targeting WWP2. (PMID:36211818)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Wwp2	ENSMUSG00000031930
rattus_norvegicus	Wwp2	ENSRNOG00000012937

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), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

NEDD4-like E3 ubiquitin-protein ligase WWP2 — O00308 (reviewed: O00308)

Alternative names: Atrophin-1-interacting protein 2, HECT-type E3 ubiquitin transferase WWP2, WW domain-containing protein 2

All UniProt accessions (4): O00308, H3BPJ8, H3BRX8, H3BS79

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. Polyubiquitinates POU5F1 by ‘Lys-63’-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level. Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation.

Subunit / interactions. Interacts with POU5F1, RBP1, EGR2 and SLC11A2. Interacts with SCNN1A, SCNN1B, SCNN1G, WBP1, WBP2 and ATN1. Interacts with ERBB4, NDFIP1 and NDFIP2. Interacts with ARRDC4. Interacts (via WW domains) with ARRDC1 (via PPxY motifs); ubiquitinates ARRDC1. Interacts (via WW domains) with ARRDC2 and ARRDC3. (Microbial infection) Interacts with adenovirus type 2 PIII.

Subcellular location. Nucleus.

Tissue specificity. Detected in heart, throughout the brain, placenta, lung, liver, muscle, kidney and pancreas. Also detected in spleen and peripheral blood leukocytes.

Post-translational modifications. Autoubiquitinated. Ubiquitinated by the SCF(FBXL15) complex, leading to its degradation by the proteasome.

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

Domain organisation. The C2 domain is involved in autoinhibition of the catalytic activity by interacting with the HECT domain. The WW domains mediate interaction with PPxY motif-containing proteins.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. A cysteine residue is required for ubiquitin-thioester formation.

Isoforms (4)

UniProt ID	Names	Canonical?
O00308-1	1	yes
O00308-2	2
O00308-3	3
O00308-4	4

RefSeq proteins (5): NP_001257382, NP_001257383, NP_001257384, NP_008945, NP_955456 (=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: 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 (74 total): helix 23, strand 20, domain 6, turn 6, compositionally biased region 5, sequence conflict 4, splice variant 3, mutagenesis site 3, chain 1, active site 1, modified residue 1, region of interest 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
9EQH	X-RAY DIFFRACTION	2.05
8EI7	X-RAY DIFFRACTION	2.22
5TJ8	X-RAY DIFFRACTION	2.3
4Y07	X-RAY DIFFRACTION	2.51
5TJ7	X-RAY DIFFRACTION	2.6
8EI5	X-RAY DIFFRACTION	2.6
6J1Z	X-RAY DIFFRACTION	2.7
5TJQ	X-RAY DIFFRACTION	2.75
8EI8	X-RAY DIFFRACTION	2.9
8EI6	X-RAY DIFFRACTION	3.62
6RSS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00308-F1	78.67	0.44

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 (1): 838 (glycyl thioester intermediate)

Post-translational modifications (1): 211

Mutagenesis-validated functional residues (3):

Position	Phenotype
498	does not affect fbxl15-mediated ubiquitination.
500	does not affect fbxl15-mediated ubiquitination.
838	abolishes ubiquitination of pou5f1.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-8948751	Regulation of PTEN stability and activity
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus

MSigDB gene sets: 266 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, RNGTGGGC_UNKNOWN, REACTOME_SIGNALING_BY_NOTCH, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GRUETZMANN_PANCREATIC_CANCER_DN, chr16q22, GGGNRMNNYCAT_UNKNOWN, CGGAARNGGCNG_UNKNOWN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, WOTTON_RUNX_TARGETS_UP, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT

GO Biological Process (19): negative regulation of transcription by RNA polymerase II (GO:0000122), transcription by RNA polymerase II (GO:0006366), extracellular transport (GO:0006858), protein ubiquitination (GO:0016567), regulation of monoatomic ion transmembrane transport (GO:0034765), regulation of membrane potential (GO:0042391), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of Notch signaling pathway (GO:0045746), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of transcription by RNA polymerase II (GO:0045944), symbiont entry into host cell (GO:0046718), protein autoubiquitination (GO:0051865), protein K63-linked ubiquitination (GO:0070534), negative regulation of potassium ion export across plasma membrane (GO:1903765), ubiquitin-dependent protein catabolic process (GO:0006511), negative regulation of gene expression (GO:0010629), negative regulation of transporter activity (GO:0032410), protein modification process (GO:0036211), negative regulation of protein transport (GO:0051224)

GO Molecular Function (9): ubiquitin-protein transferase activity (GO:0004842), potassium channel inhibitor activity (GO:0019870), transmembrane transporter binding (GO:0044325), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), ubiquitin protein ligase activity (GO:0061630), transcription regulator inhibitor activity (GO:0140416), protein binding (GO:0005515), transcription factor binding (GO:0008134), transferase activity (GO:0016740)

GO Cellular Component (6): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
RHO GTPase cycle	3
PTEN Regulation	1
Signaling by NOTCH3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
DNA-templated transcription	2
monoatomic ion transmembrane transport	2
protein ubiquitination	2
regulation of gene expression	2
negative regulation of transport	2
protein binding	2
negative regulation of DNA-templated transcription	1
extracellular region	1
transport	1
protein modification by small protein conjugation	1
regulation of transmembrane transport	1
regulation of monoatomic ion transport	1
regulation of biological quality	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
viral life cycle	1
symbiont entry into host	1
protein polyubiquitination	1
potassium ion export across plasma membrane	1
negative regulation of potassium ion transmembrane transport	1
regulation of potassium ion export across plasma membrane	1
modification-dependent protein catabolic process	1
gene expression	1
negative regulation of macromolecule biosynthetic process	1
transporter activity	1
negative regulation of molecular function	1
protein metabolic process	1
macromolecule modification	1
protein transport	1
regulation of protein transport	1
negative regulation of protein localization	1

Protein interactions and networks

STRING

3440 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WWP2	NDFIP1	Q9BT67	933
WWP2	PTEN	P60484	809
WWP2	ARRDC3	Q96B67	795
WWP2	ARRDC1	Q8N5I2	794
WWP2	POU5F1	P31359	745
WWP2	NDFIP2	Q9NV92	727
WWP2	SMAD7	O15105	698
WWP2	ATN1	P54259	630
WWP2	UBE2S	Q16763	612
WWP2	SPART	Q8N0X7	573
WWP2	CLCN5	P51795	570
WWP2	UBE2K	P27924	559
WWP2	SOX2	P48431	558
WWP2	NOTCH3	Q9UM47	555
WWP2	TP53	P04637	550

IntAct

344 interactions, top by confidence:

A	B	Type	Score
WWP2	HNRNPUL1	psi-mi:“MI:0915”(physical association)	0.870
HNRNPUL1	WWP2	psi-mi:“MI:0915”(physical association)	0.870
WWP2	ARRDC1	psi-mi:“MI:0915”(physical association)	0.850
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
ENTREP1	WWP2	psi-mi:“MI:0915”(physical association)	0.850
WWP2	PDLIM7	psi-mi:“MI:0915”(physical association)	0.800
PDLIM7	WWP2	psi-mi:“MI:0915”(physical association)	0.800
TRAF4	WWP2	psi-mi:“MI:0915”(physical association)	0.780
WWP2	TRAF4	psi-mi:“MI:0915”(physical association)	0.780
SMAD3	WWP2	psi-mi:“MI:0915”(physical association)	0.780
WWP2	ARRDC3	psi-mi:“MI:0915”(physical association)	0.770
ARRDC3	WWP2	psi-mi:“MI:0914”(association)	0.770
WWP2	LGALS9B	psi-mi:“MI:0915”(physical association)	0.740
LGALS9B	WWP2	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (1194): WWP2 (Biochemical Activity), UBE2L3 (Reconstituted Complex), PAIP1 (Affinity Capture-Western), EIF3A (Affinity Capture-Western), PABPC1 (Affinity Capture-Western), PAIP1 (Reconstituted Complex), WWP2 (Reconstituted Complex), PAIP1 (Biochemical Activity), WWP2 (Two-hybrid), WWP2 (Two-hybrid), WWP2 (Two-hybrid), WWP2 (Two-hybrid), WWP2 (Two-hybrid), HNRNPUL1 (Two-hybrid), RUSC1 (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, A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B8N7E5, D3ZBM7, D6C652, E1B7Q7, E1C656, F1LP64, F1N6G5, F8W2M1, G0S9J5, G5E870, H2LBU8, O00308, O08759, O13834, O14326, O15033, P39940, P40985, P46934, P46935, P46937, P46938, P51593, P53119, Q03280, Q05086, Q08CZ0, Q09291, Q0CCL1, Q14669, Q15034, Q15386, Q1K9C4

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
WWP2	“down-regulates quantity”	EGR2	ubiquitination
WWP2	“down-regulates quantity”	POU5F1	ubiquitination
WWP2	“down-regulates quantity”	POLR2A	ubiquitination
Ub:E2	“up-regulates activity”	WWP2	ubiquitination
WWP2	“up-regulates activity”	WWP1	binding
WWP2	“down-regulates quantity by destabilization”	TP73	polyubiquitination
WWP2	“down-regulates quantity by destabilization”	PAIP1	ubiquitination
WWP2	“down-regulates quantity by destabilization”	PTEN	ubiquitination
WWP2	“up-regulates activity”	GSC	ubiquitination
WWP2	“down-regulates quantity”	SOX2	ubiquitination
TNK2	“up-regulates activity”	WWP2	phosphorylation
WWP2	“down-regulates quantity”	SLC11A2	ubiquitination
WWP2	“down-regulates quantity by destabilization”	ABI3	polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	110
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

4860 predictions. Top by Δscore:

Variant	Effect	Δscore
16:69763503:TTAC:T	donor_gain	1.0000
16:69786982:T:TA	acceptor_gain	1.0000
16:69786986:T:A	acceptor_gain	1.0000
16:69786991:TACA:T	acceptor_loss	1.0000
16:69786992:A:AG	acceptor_gain	1.0000
16:69786992:ACAGC:A	acceptor_loss	1.0000
16:69786993:C:G	acceptor_gain	1.0000
16:69786993:CAGCT:C	acceptor_loss	1.0000
16:69786994:A:AG	acceptor_gain	1.0000
16:69786994:AGC:A	acceptor_loss	1.0000
16:69786995:G:GT	acceptor_gain	1.0000
16:69786995:GC:G	acceptor_gain	1.0000
16:69786995:GCT:G	acceptor_gain	1.0000
16:69786995:GCTT:G	acceptor_gain	1.0000
16:69786995:GCTTC:G	acceptor_gain	1.0000
16:69787076:GAAAG:G	donor_gain	1.0000
16:69787077:AAAG:A	donor_gain	1.0000
16:69787077:AAAGG:A	donor_loss	1.0000
16:69787078:AAG:A	donor_gain	1.0000
16:69787079:AG:A	donor_gain	1.0000
16:69787080:GG:G	donor_gain	1.0000
16:69787080:GGTG:G	donor_loss	1.0000
16:69787081:G:GA	donor_loss	1.0000
16:69787081:G:GG	donor_gain	1.0000
16:69798678:CCA:C	acceptor_loss	1.0000
16:69798679:CAGT:C	acceptor_loss	1.0000
16:69798680:A:AG	acceptor_gain	1.0000
16:69798680:A:T	acceptor_loss	1.0000
16:69798680:AGT:A	acceptor_gain	1.0000
16:69798680:AGTG:A	acceptor_gain	1.0000

AlphaMissense

5709 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:69908762:T:A	W306R	1.000
16:69908762:T:C	W306R	1.000
16:69908795:T:G	Y317D	1.000
16:69908802:T:A	V319D	1.000
16:69908828:T:A	W328R	1.000
16:69908828:T:C	W328R	1.000
16:69908830:G:C	W328C	1.000
16:69908830:G:T	W328C	1.000
16:69917710:T:A	W336R	1.000
16:69917710:T:C	W336R	1.000
16:69917712:G:C	W336C	1.000
16:69917712:G:T	W336C	1.000
16:69917720:G:C	R339P	1.000
16:69917743:T:G	Y347D	1.000
16:69917755:C:G	H351D	1.000
16:69917776:T:A	W358R	1.000
16:69917776:T:C	W358R	1.000
16:69917778:G:C	W358C	1.000
16:69917778:G:T	W358C	1.000
16:69917785:C:T	P361S	1.000
16:69917786:C:A	P361Q	1.000
16:69925481:T:A	W411R	1.000
16:69925481:T:C	W411R	1.000
16:69925483:G:C	W411C	1.000
16:69925483:G:T	W411C	1.000
16:69929474:T:C	Y421H	1.000
16:69929474:T:G	Y421D	1.000
16:69929486:C:G	H425D	1.000
16:69929505:A:C	Q431P	1.000
16:69929507:T:A	W432R	1.000

dbSNP variants (sampled 300 via entrez): RS1000000853 (16:69763249 T>C), RS1000001452 (16:69910188 A>G), RS1000018878 (16:69810310 C>T), RS1000019091 (16:69893908 C>T), RS1000039828 (16:69846276 A>C,G,T), RS1000053707 (16:69792025 G>A,C), RS1000068068 (16:69810045 C>A), RS1000073470 (16:69904876 T>A,C), RS1000086023 (16:69803838 G>T), RS1000098105 (16:69891088 G>A), RS1000100617 (16:69848712 A>G), RS1000109215 (16:69837630 A>G), RS1000120139 (16:69807633 A>G), RS1000146646 (16:69931119 G>A,T), RS1000165658 (16:69924912 C>T)

Disease associations

OMIM: gene MIM:602308 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

35 associations (top):

Study	Trait	p-value
GCST001739_2	IgE levels	1.000000e-06
GCST002541_110	Menarche (age at onset)	1.000000e-11
GCST005558_2	Plantar fascial disorders	2.000000e-08
GCST005830_15	Hand grip strength	7.000000e-16
GCST005951_13	Body mass index	5.000000e-11
GCST006479_41	Diverticular disease	4.000000e-06
GCST006613_95	Triglycerides	7.000000e-11
GCST006925_4	Knee osteoarthritis	3.000000e-11
GCST007268_54	Diastolic blood pressure	4.000000e-16
GCST007269_293	Pulse pressure	1.000000e-33
GCST007293_28	Body fat distribution (arm fat ratio)	3.000000e-12
GCST007293_6	Body fat distribution (arm fat ratio)	5.000000e-06
GCST007293_62	Body fat distribution (arm fat ratio)	2.000000e-17
GCST007295_15	Body fat distribution (leg fat ratio)	3.000000e-06
GCST007295_99	Body fat distribution (leg fat ratio)	5.000000e-06
GCST007429_155	Lung function (FVC)	1.000000e-18
GCST007432_160	FEV1	7.000000e-19
GCST008058_134	Estimated glomerular filtration rate	1.000000e-15
GCST008059_146	Estimated glomerular filtration rate	1.000000e-11
GCST008163_419	Height	2.000000e-06
GCST008662_17	Lung function in never smokers (low FEV1 vs high FEV1)	3.000000e-07
GCST008803_13	Smoking behaviour (cigarette pack-years)	6.000000e-09
GCST008839_484	Height	6.000000e-20
GCST009963_15	Cataracts (operation)	8.000000e-11
GCST010204_68	Low density lipoprotein cholesterol levels	5.000000e-09
GCST010659_1	Waist circumference	2.000000e-08
GCST010660_7	Triglyceride levels	7.000000e-06
GCST010703_100	Brain morphology (MOSTest)	2.000000e-40
GCST011364_26	Myocardial infarction	2.000000e-08
GCST011703_25	Smoking initiation	5.000000e-09

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:1001909	Plantar Fasciitis
EFO:0006941	grip strength measurement
EFO:0004340	body mass index
EFO:0009959	diverticular disease
EFO:0004530	triglyceride measurement
EFO:0006336	diastolic blood pressure
EFO:0005763	pulse pressure measurement
EFO:0004341	body fat distribution
EFO:0004312	vital capacity
EFO:0004314	forced expiratory volume
EFO:0009115	tobacco smoke exposure measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004346	neuroimaging measurement
EFO:0005670	smoking initiation
EFO:0004980	appendicular lean mass
EFO:0004309	platelet count
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases methylation	4
sodium arsenite	increases expression, decreases expression, increases abundance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
heclin	decreases activity, decreases expression, decreases reaction	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
beta-lapachone	decreases expression, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	decreases methylation	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
Resveratrol	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arsenic	decreases expression, increases abundance	1
Atrazine	increases expression	1
Folic Acid	decreases expression	1
Methapyrilene	increases methylation	1
Oxygen	decreases expression, decreases reaction, increases reaction	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Selenomethionine	affects expression	1

Cellosaurus cell lines

1 cell lines: 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C3L1	N/Tert-1 WWP2	Telomerase immortalized cell line	Male

Clinical trials (associated diseases)

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