WTIP

Summary

WTIP (WT1 interacting protein, HGNC:20964) is a protein-coding gene on chromosome 19q13.11, encoding Wilms tumor protein 1-interacting protein (A6NIX2). Adapter or scaffold protein which participates in the assembly of numerous protein complexes and is involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, cell-cell adhesion, cell differentiation, prol….

Predicted to enable transcription corepressor activity. Involved in several processes, including miRNA-mediated gene silencing by inhibition of translation; negative regulation of hippo signaling; and response to hypoxia. Acts upstream of or within miRNA-mediated post-transcriptional gene silencing. Located in P-body.

Source: NCBI Gene 126374 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 89 total
• MANE Select transcript: NM_001080436

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20964
Approved symbol	WTIP
Name	WT1 interacting protein
Location	19q13.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000142279
Ensembl biotype	protein_coding
OMIM	614790
Entrez	126374

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000585928, ENST00000590071, ENST00000924107, ENST00000924109, ENST00000954266, ENST00000954267

RefSeq mRNA: 1 — MANE Select: NM_001080436 NM_001080436

CCDS: CCDS59375

Canonical transcript exons

ENST00000590071 — 8 exons

Exon	Start	End
ENSE00000953201	34493263	34493325
ENSE00000953203	34494586	34494637
ENSE00000953206	34493492	34493622
ENSE00001160003	34493037	34493104
ENSE00001160005	34490376	34490477
ENSE00001757670	34495703	34495771
ENSE00002751039	34500129	34512304
ENSE00002832960	34481758	34482641

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 96.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.5984 / max 38.0498, expressed in 1298 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175147	3.5743	1270
175146	0.6199	466
175148	0.4042	250

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	96.30	gold quality
tibial artery	UBERON:0007610	96.29	gold quality
right coronary artery	UBERON:0001625	96.19	gold quality
aorta	UBERON:0000947	95.24	gold quality
ascending aorta	UBERON:0001496	94.03	gold quality
thoracic aorta	UBERON:0001515	93.94	gold quality
coronary artery	UBERON:0001621	93.60	gold quality
left coronary artery	UBERON:0001626	93.60	gold quality
descending thoracic aorta	UBERON:0002345	92.17	gold quality
tibial nerve	UBERON:0001323	89.65	gold quality
right ovary	UBERON:0002118	88.80	gold quality
stromal cell of endometrium	CL:0002255	88.36	gold quality
left ovary	UBERON:0002119	88.31	gold quality
body of uterus	UBERON:0009853	87.97	gold quality
apex of heart	UBERON:0002098	87.26	gold quality
vena cava	UBERON:0004087	87.16	silver quality
omental fat pad	UBERON:0010414	87.08	gold quality
peritoneum	UBERON:0002358	87.06	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.79	gold quality
endocervix	UBERON:0000458	86.74	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.55	gold quality
heart left ventricle	UBERON:0002084	86.04	gold quality
left ventricle myocardium	UBERON:0006566	85.98	gold quality
left uterine tube	UBERON:0001303	85.89	gold quality
cardiac ventricle	UBERON:0002082	85.83	gold quality
upper lobe of left lung	UBERON:0008952	85.66	gold quality
heart	UBERON:0000948	85.50	gold quality
kidney epithelium	UBERON:0004819	85.37	gold quality
myometrium	UBERON:0001296	85.30	gold quality
upper arm skin	UBERON:0004263	85.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.94

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting WTIP, 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-5582-3P	99.86	72.48	4221
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-9903	98.47	66.70	748
HSA-MIR-138-5P	98.43	70.49	1292
HSA-MIR-7161-3P	96.79	68.79	798
HSA-MIR-433-5P	94.67	64.82	99
HSA-MIR-4787-5P	89.08	66.18	88
HSA-MIR-6786-5P	89.01	59.75	103

Literature-anchored findings (GeneRIF, showing 15)

• WTIP monitors slit diaphragm protein assembly as part of a multiple protein complex, linking this specialized adhesion junction to the actin cytoskeleton, and shuttles into the nucleus after podocyte injury (PMID:14736876)
• WTIP is a member of the Ajuba family of LIM-domain containing proteins. Ajuba LIM proteins co-repress E-cadherin expression through interaction with the SNAG domain of Snail/Slug and promote epithelial to mesenchymal differentiation in a Xenopus model. (PMID:18331720)
• Full-length Ror2 recruits Wtip to the cell membrane, a mutant involved in human disease fails to do so. Both genes and proteins show overlapping expression in the mouse embryo. (PMID:19785987)
• Stress signaling pathways initiate WTIP nuclear translocation, and the concomitant loss of WTIP from cell contacts changes podocyte morphology and dynamic actin assembly, suggesting a mechanism that transmits changes in podocyte morphology to the nucleus. (PMID:20086015)
• Report role of WTIP in regulating podocyte phenotype in chronic kidney disease. (PMID:21686224)
• Wtip regulates the stable formation of cell adhesions to both extracellular matrix and neighboring cells and suggest that Wtip is necessary for normal glomerular filtration barrier function (PMID:21900451)
• WTIP interacts with ASXL2 and blocks ASXL2-mediated activation of retinoic acid signaling. (PMID:25065743)
• Nck1 and Nck2 Interact with WTIP. Nck1/2 integrates nephrin with the Hippo kinase cascade through association with the adaptor protein WTIP. (PMID:27033705)
• WTIP interacts with BRCA2 and might be responsible for BRCA2 centrosome localization in cervical cancer cell. (PMID:27535760)
• We show that all three mammalian Ajuba family proteins - AJUBA, LIMD1 and WTIP - exhibit tension-dependent localization to adherens junctions, and that both LATS family proteins, LATS1 and LATS2, exhibit an overlapping tension-dependent junctional localization (PMID:29440237)
• The findings suggest that the UBA2-WTIP fusion is an oncogenic fusion gene, as well as a promising therapeutic target for the treatment of acute myeloid leukemia. (PMID:30179602)
• WTIP impairs AKT phosphorylation and activation, leading to enhanced expression and transcriptional activity of FOXO1, which further increases p21Cip1 and p27Kip1, and decreases cyclin D1, which consequently results in cell cycle arrest. (PMID:30690883)
• The S-phase-induced lncRNA SUNO1 promotes cell proliferation by controlling YAP1/Hippo signaling pathway. (PMID:33108271)
• WTIP upregulates FOXO3a and induces apoptosis through PUMA in acute myeloid leukemia. (PMID:34930905)
• Wnt Signaling Interactor WTIP (Wilms Tumor Interacting Protein) Underlies Novel Mechanism for Cardiac Hypertrophy. (PMID:35671065)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	wtip	ENSDARG00000103607
mus_musculus	Wtip	ENSMUSG00000036459
rattus_norvegicus	Wtip	ENSRNOG00000023296

Paralogs (2): AJUBA (ENSG00000129474), LIMD1 (ENSG00000144791)

Protein

Protein identifiers

Wilms tumor protein 1-interacting protein — A6NIX2 (reviewed: A6NIX2)

All UniProt accessions (2): A6NIX2, K7EKM1

UniProt curated annotations — full annotation on UniProt →

Function. Adapter or scaffold protein which participates in the assembly of numerous protein complexes and is involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, cell-cell adhesion, cell differentiation, proliferation and migration. Positively regulates microRNA (miRNA)-mediated gene silencing. Negatively regulates Hippo signaling pathway and antagonizes phosphorylation of YAP1. Acts as a transcriptional corepressor for SNAI1 and SNAI2/SLUG-dependent repression of E-cadherin transcription. Acts as a hypoxic regulator by bridging an association between the prolyl hydroxylases and VHL enabling efficient degradation of HIF1A. In podocytes, may play a role in the regulation of actin dynamics and/or foot process cytoarchitecture. In the course of podocyte injury, shuttles into the nucleus and acts as a transcription regulator that represses WT1-dependent transcription regulation, thereby translating changes in slit diaphragm structure into altered gene expression and a less differentiated phenotype. Involved in the organization of the basal body. Involved in cilia growth and positioning.

Subunit / interactions. Forms homodimers. Interacts with CD2AP and WT1. Interacts (via LIM domains) with SNAI1 (via SNAG domain), SNAI2/SLUG (via SNAG domain) and SCRT1 (via SNAG domain). Interacts with EIF4E, AGO1, AGO2, DCP2, DDX6, LATS1, LATS2, SAV1, EGLN2/PHD1 and EGLN3/PHD3. Interacts (via LIM domains) with isoform 1 and isoform 3 of VHL. Interacts with ROR2. Following treatment with bacterial lipopolysaccharide (LPS), forms a complex with MAPK8IP3 and dynein intermediate chain. Interacts with PRICKLE3.

Subcellular location. Cell junction. Adherens junction. Nucleus. Cytoplasm. P-body.

Similarity. Belongs to the zyxin/ajuba family.

RefSeq proteins (1): NP_001073905* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001781	Znf_LIM	Domain
IPR047172	Ajuba-like	Family
IPR047245	Ajuba-like_LIM1	Domain
IPR047247	Ajuba-like_LIM2	Domain
IPR047248	Ajuba-like_LIM3	Domain

Pfam: PF00412

UniProt features (8 total): domain 3, region of interest 2, compositionally biased region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NIX2-F1	65.69	0.09

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

MSigDB gene sets: 80 (showing top): GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_HIPPO_SIGNALING, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_CELL_PROJECTION_ORGANIZATION, GOCC_CELL_CELL_JUNCTION, MARTORIATI_MDM4_TARGETS_FETAL_LIVER_UP, GOBP_REGULATION_OF_TRANSLATION, GOCC_TRANSCRIPTION_REGULATOR_COMPLEX, GOCC_RIBONUCLEOPROTEIN_GRANULE

GO Biological Process (10): response to hypoxia (GO:0001666), regulation of DNA-templated transcription (GO:0006355), cytoskeleton organization (GO:0007010), regulation of cell morphogenesis (GO:0022604), cell projection organization (GO:0030030), miRNA-mediated post-transcriptional gene silencing (GO:0035195), miRNA-mediated gene silencing by inhibition of translation (GO:0035278), negative regulation of hippo signaling (GO:0035331), regulatory ncRNA-mediated gene silencing (GO:0031047), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (3): transcription corepressor activity (GO:0003714), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (6): P-body (GO:0000932), nucleus (GO:0005634), transcription regulator complex (GO:0005667), adherens junction (GO:0005912), cytoplasm (GO:0005737), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to hypoxia	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	2
response to stress	1
response to decreased oxygen levels	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
organelle organization	1
cell morphogenesis	1
regulation of anatomical structure morphogenesis	1
cellular component organization	1
regulatory ncRNA-mediated post-transcriptional gene silencing	1
negative regulation of translation	1
miRNA-mediated post-transcriptional gene silencing	1
hippo signaling	1
regulation of hippo signaling	1
negative regulation of intracellular signal transduction	1
negative regulation of gene expression	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
transcription coregulator activity	1
negative regulation of DNA-templated transcription	1
cation binding	1
binding	1
cytoplasmic ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1
protein-containing complex	1
cell-cell junction	1
intracellular anatomical structure	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

794 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WTIP	RPH3AL	Q9UNE2	837
WTIP	SAV1	Q9H4B6	745
WTIP	RPH3A	Q9Y2J0	728
WTIP	WT1	P19544	612
WTIP	RAB3A	P20336	562
WTIP	PRICKLE3	O43900	538
WTIP	PDLIM2	Q96JY6	527
WTIP	SCGB2B2	Q4G0G5	507
WTIP	ASXL2	Q76L83	475
WTIP	LATS1	O95835	463
WTIP	ASXL3	Q9C0F0	461
WTIP	FN1	P02751	429
WTIP	TTC7B	Q86TV6	418
WTIP	UBA2	Q9UBT2	417
WTIP	DYNC2H1	Q8NCM8	414

IntAct

17 interactions, top by confidence:

A	B	Type	Score
PPP2R3A	WTIP	psi-mi:“MI:0914”(association)	0.640
TRIP6	WTIP	psi-mi:“MI:0914”(association)	0.530
AGO3	WTIP	psi-mi:“MI:0403”(colocalization)	0.520
AGO3	WTIP	psi-mi:“MI:2364”(proximity)	0.520
AGO3	WTIP	psi-mi:“MI:0915”(physical association)	0.520
SCRIB	WTIP	psi-mi:“MI:0407”(direct interaction)	0.440
AGO2	WTIP	psi-mi:“MI:0915”(physical association)	0.400
AGO1	WTIP	psi-mi:“MI:0915”(physical association)	0.400
AGO4	WTIP	psi-mi:“MI:0915”(physical association)	0.400
LATS2	WTIP	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): WTIP (Affinity Capture-MS), WTIP (Affinity Capture-Western), WTIP (Affinity Capture-Western), WTIP (Affinity Capture-Western), WTIP (Affinity Capture-MS), WTIP (Affinity Capture-MS), WTIP (PCA), WTIP (Affinity Capture-Western), BRCA2 (Affinity Capture-Western), WTIP (Reconstituted Complex), WTIP (Affinity Capture-RNA), WTIP (Affinity Capture-MS), WTIP (Affinity Capture-MS), WTIP (Affinity Capture-MS), WTIP (Affinity Capture-Western)

ESM2 similar proteins: A0A8P0N4K0, A5YM72, A6NIK2, A6NIX2, D3KCC4, D3Z7H8, D3ZU57, O08742, O43822, O75427, O95382, P40197, Q02779, Q13470, Q14160, Q149C3, Q15653, Q16584, Q24K06, Q32P44, Q3UGP9, Q505F5, Q5BKY1, Q5I2M8, Q5RKR3, Q5U651, Q66HA1, Q6EMK4, Q6NSJ5, Q6UXK2, Q6UY18, Q76KP1, Q80U72, Q80XI6, Q80ZD5, Q86WK7, Q8C013, Q8K3W2, Q8N1G4, Q8WUA8

Diamond homologs: A0JNI8, A0M8S5, A1ZA47, A2PZF9, A5H447, A6NIX2, A8DZE6, A9LS46, B5DEH0, B7ZUL2, E1BKA3, G5E5X0, G5EEA1, O43294, O60663, O88609, P35688, P37137, P48742, P53411, P53413, P61375, P61376, P61968, P61969, P63006, P63007, P63008, Q04584, Q06BR1, Q07E40, Q0VA45, Q15654, Q15942, Q1JQB5, Q2IBC3, Q3MHZ4, Q3SWZ8, Q3SX26, Q3SX40

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1233 predictions. Top by Δscore:

Variant	Effect	Δscore
19:34490372:CTA:C	acceptor_loss	1.0000
19:34490373:TA:T	acceptor_loss	1.0000
19:34490374:A:AG	acceptor_gain	1.0000
19:34490374:AG:A	acceptor_gain	1.0000
19:34490375:G:GG	acceptor_gain	1.0000
19:34490375:GG:G	acceptor_gain	1.0000
19:34490375:GGC:G	acceptor_gain	1.0000
19:34490375:GGCA:G	acceptor_gain	1.0000
19:34490375:GGCAT:G	acceptor_gain	1.0000
19:34490473:GTGTG:G	donor_gain	1.0000
19:34490475:GTG:G	donor_gain	1.0000
19:34490476:TGGTA:T	donor_loss	1.0000
19:34490477:GGTA:G	donor_loss	1.0000
19:34490478:G:C	donor_loss	1.0000
19:34490478:G:GG	donor_gain	1.0000
19:34490479:T:A	donor_loss	1.0000
19:34493105:G:GG	donor_gain	1.0000
19:34493106:T:A	donor_loss	1.0000
19:34493261:A:AG	acceptor_gain	1.0000
19:34493262:G:GG	acceptor_gain	1.0000
19:34493489:CAGA:C	acceptor_loss	1.0000
19:34493490:A:AG	acceptor_gain	1.0000
19:34493491:G:GG	acceptor_gain	1.0000
19:34493618:CACAC:C	donor_gain	1.0000
19:34493619:ACAC:A	donor_gain	1.0000
19:34493620:CAC:C	donor_gain	1.0000
19:34493621:AC:A	donor_gain	1.0000
19:34493622:CG:C	donor_loss	1.0000
19:34493623:G:C	donor_loss	1.0000
19:34493623:G:GG	donor_gain	1.0000

AlphaMissense

2724 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:34490381:T:A	C225S	1.000
19:34490381:T:C	C225R	1.000
19:34490382:G:A	C225Y	1.000
19:34490382:G:C	C225S	1.000
19:34490383:C:G	C225W	1.000
19:34490390:T:A	C228S	1.000
19:34490390:T:C	C228R	1.000
19:34490391:G:C	C228S	1.000
19:34490391:G:T	C228F	1.000
19:34490444:T:G	Y246D	1.000
19:34490456:T:C	C250R	1.000
19:34490458:C:G	C250W	1.000
19:34490459:T:C	F251L	1.000
19:34490460:T:C	F251S	1.000
19:34490460:T:G	F251C	1.000
19:34490461:C:A	F251L	1.000
19:34490461:C:G	F251L	1.000
19:34490465:T:A	C253S	1.000
19:34490465:T:C	C253R	1.000
19:34490466:G:A	C253Y	1.000
19:34490466:G:C	C253S	1.000
19:34490466:G:T	C253F	1.000
19:34490467:C:G	C253W	1.000
19:34490474:T:C	C256R	1.000
19:34490475:G:A	C256Y	1.000
19:34490475:G:T	C256F	1.000
19:34490476:T:G	C256W	1.000
19:34493060:T:C	F265L	1.000
19:34493062:C:A	F265L	1.000
19:34493062:C:G	F265L	1.000

dbSNP variants (sampled 300 via entrez): RS1000003338 (19:34506668 G>A), RS1000197923 (19:34493687 T>A,C), RS1000378287 (19:34503796 T>G), RS1000429244 (19:34503634 T>G), RS1000472227 (19:34487594 G>A,T), RS1000537100 (19:34492028 A>G), RS1000557962 (19:34500378 C>G,T), RS1000626381 (19:34499468 A>G), RS1000735870 (19:34486444 C>T), RS1000795262 (19:34485761 A>G), RS1000845015 (19:34501610 G>A), RS1000897297 (19:34501346 G>A,C), RS1001012108 (19:34500165 C>A,T), RS1001044576 (19:34490730 G>A,T), RS1001301675 (19:34505721 G>A)

Disease associations

OMIM: gene MIM:614790 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1
leptomycin B	decreases localization	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, decreases expression	1
Niclosamide	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	decreases expression	1
Particulate Matter	increases abundance, increases expression	1
Magnetite Nanoparticles	increases methylation	1

Clinical trials (associated diseases)

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