WWTR1

Summary

WWTR1 (WW domain containing transcription regulator 1, HGNC:24042) is a protein-coding gene on chromosome 3q25.1, encoding WW domain-containing transcription regulator protein 1 (Q9GZV5). Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. It is a selective cancer dependency (DepMap: 35.4% of cell lines).

Enables transcription coactivator activity. Involved in several processes, including intracellular signal transduction; negative regulation of canonical Wnt signaling pathway; and positive regulation of cell differentiation. Located in cytosol and nuclear body. Is active in nucleus.

Source: NCBI Gene 25937 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 71 total
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 35.4% of screened cell lines
• MANE Select transcript: NM_015472

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24042
Approved symbol	WWTR1
Name	WW domain containing transcription regulator 1
Location	3q25.1
Locus type	gene with protein product
Status	Approved
Aliases	TAZ, DKFZp586I1419
Ensembl gene	ENSG00000018408
Ensembl biotype	protein_coding
OMIM	607392
Entrez	25937

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 22 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000360632, ENST00000460517, ENST00000465804, ENST00000467467, ENST00000471586, ENST00000472417, ENST00000474080, ENST00000475579, ENST00000479238, ENST00000485244, ENST00000485352, ENST00000494754, ENST00000884350, ENST00000884351, ENST00000884352, ENST00000884353, ENST00000884354, ENST00000884355, ENST00000884356, ENST00000884357, ENST00000951294, ENST00000951295, ENST00000951296, ENST00000951297, ENST00000951298, ENST00000951299

RefSeq mRNA: 4 — MANE Select: NM_015472 NM_001168278, NM_001168280, NM_001348362, NM_015472

CCDS: CCDS3144

Canonical transcript exons

ENST00000360632 — 7 exons

Exon	Start	End
ENSE00000779675	149542335	149542537
ENSE00001078038	149656876	149657309
ENSE00001513532	149657765	149658025
ENSE00001927482	149517235	149520989
ENSE00003464373	149527836	149527969
ENSE00003604630	149526013	149526125
ENSE00003784897	149572864	149573000

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.0769 / max 542.5594, expressed in 1454 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45055	38.5183	1443
45035	2.2163	462
45053	1.5796	879
45054	0.8127	579
45052	0.6954	496
45044	0.4094	221
45050	0.3655	161
45042	0.2790	125
45048	0.2051	100
45049	0.1941	75

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	99.06	gold quality
blood vessel layer	UBERON:0004797	99.02	gold quality
cauda epididymis	UBERON:0004360	98.65	gold quality
cranial nerve II	UBERON:0000941	98.53	gold quality
visceral pleura	UBERON:0002401	98.27	gold quality
tendon of biceps brachii	UBERON:0008188	98.23	gold quality
urethra	UBERON:0000057	97.97	gold quality
seminal vesicle	UBERON:0000998	97.97	gold quality
saphenous vein	UBERON:0007318	97.72	gold quality
pleura	UBERON:0000977	97.64	gold quality
colonic epithelium	UBERON:0000397	97.51	gold quality
skin of hip	UBERON:0001554	97.43	gold quality
lower lobe of lung	UBERON:0008949	97.43	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.41	gold quality
vena cava	UBERON:0004087	97.40	gold quality
periodontal ligament	UBERON:0008266	97.34	gold quality
parietal pleura	UBERON:0002400	97.26	gold quality
choroid plexus epithelium	UBERON:0003911	97.26	gold quality
metanephric glomerulus	UBERON:0004736	97.08	gold quality
pigmented layer of retina	UBERON:0001782	97.07	gold quality
cartilage tissue	UBERON:0002418	97.07	gold quality
renal glomerulus	UBERON:0000074	96.96	gold quality
stromal cell of endometrium	CL:0002255	96.89	gold quality
mammary duct	UBERON:0001765	96.88	gold quality
pericardium	UBERON:0002407	96.84	gold quality
nephron tubule	UBERON:0001231	96.74	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.65	gold quality
lower esophagus	UBERON:0013473	96.64	gold quality
penis	UBERON:0000989	96.63	gold quality
superficial temporal artery	UBERON:0001614	96.55	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	582.71
E-MTAB-8142	yes	505.29
E-GEOD-130473	yes	369.95
E-MTAB-8271	yes	301.28
E-HCAD-10	yes	30.34
E-GEOD-81547	yes	28.22
E-MTAB-6701	yes	27.82
E-MTAB-5061	yes	26.26
E-GEOD-84465	yes	21.91
E-HCAD-35	yes	19.23
E-CURD-112	yes	12.94
E-HCAD-9	yes	12.91
E-MTAB-9067	yes	7.68
E-MTAB-9543	yes	7.62
E-GEOD-130148	yes	4.81

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
ASNS	Repression
BAK1	Activation
BAX	Activation
IGFBP1	Unknown
LTBR	Activation
SMAD3	Activation
SOX5	Repression
SOX6	Repression
SOX9	Repression

Upstream regulators (CollecTRI, top): BMP2, METTL3, STAT3

miRNA regulators (miRDB)

177 targeting WWTR1, 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-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-5688	99.96	73.23	4504

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 35.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• coactivates Runx2-dependent gene transcription while repressing PPARgamma-dependent gene transcription; results indicate that TAZ functions as a molecular rheostat that modulates mesenchymal stem cell differentiation (PMID:16099986)
• Decreased osteogenic potential of mesenchymal stem cells of myeloma patients was in part due to TNF-alpha suppressed TAZ expression. (PMID:17927494)
• Seven placental transcripts characterize HELLP-syndrome. (PMID:18374411)
• TAZ plays a role in the migration, invasion, and tumorigenesis of breast cancer cells and thus presents a novel target for the detection and treatment of breast cancer. (PMID:18413727)
• Data demonstrate that in response to TGFbeta stimulation the transcriptional regulator TAZ binds heteromeric Smad2/3-4 complexes and is recruited to TGFbeta response elements. (PMID:18568018)
• These results reveal a novel mechanism for TEADs to regulate nuclear retention and thus the transforming ability of TAZ. (PMID:19324876)
• Disruption of TEAD-TAZ binding or silencing of TEAD expression blocked the function of TAZ to promote cell proliferation and to induce epithelial-mesenchymal transition, demonstrating TEAD as a key downstream effector of TAZ. (PMID:19324877)
• CD138(+) myeloma cells inhibited mRNA expression of TAZ in mesenchymal stem cells, which could be partially reversed by blocking TNF-alpha. (PMID:19538860)
• TAZ mutations are not a cause of thyroid dysgenesis in the series of patients studied. (PMID:19542741)
• data indicate that TNF-alpha enhances osteogenic differentiation of adipocyte mesenchymal stem cells via the activation of NF-kappaB and a subsequent increase of TAZ expression (PMID:20049872)
• The present study was aimed at investigating the role of TAZ in uterine physiology by examining its presence in the human uterine endometrium and its involvement in in vitro decidualization of human stromal fibroblasts. (PMID:20164440)
• the first PDZ domain of zona occludens-1 (ZO-1) and 2 (ZO-2) interacts with the carboxy-terminal PDZ binding motif of TAZ (PMID:20850437)
• Hippo pathway negatively regulates TAZ function by both limiting its nuclear accumulation and promoting its degradation. (PMID:20858893)
• Data show that direct interaction of Wbp2 with TAZ depends on the WW domain of TAZ. (PMID:20972459)
• the activated effectors of the RAS/RAF/MEK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) signalling pathway are involved in the expression of TAZ, supporting the idea that this may also occur in thyroid papillary carcinoma (PMID:21131195)
• PP1A and ASPP2 play a critical role in promoting TAZ function by antagonizing the LATS kinase through TAZ dephosphorylation. (PMID:21189257)
• novel mechanism to restrict the activity of TAZ and YAP through physical interaction with Amot and AmotL1 (PMID:21224387)
• Findings define the TAZ-TEAD-Cyr61/CTGF signaling pathway as an important modifier of the Taxol response in breast cancer cells. (PMID:21349946)
• the presence of a WWTR1-CAMTA1 fusion in all EHE tested from bone, soft tissue, and visceral location (PMID:21584898)
• findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment (PMID:21654799)
• TAZ promotes breast cell growth partially through protecting KLF5 from WWP1-mediated degradation and enhancing KLF5’s activities. (PMID:22045023)
• Study shows that the activity of TAZ, a transducer of the Hippo pathway, is required to sustain self-renewal and tumor-initiation capacities in breast cancer stem cells. (PMID:22078877)
• Results demonstrate that kaempferol fortifies TAZ activity, which enhances RUNX2-mediated osteoblast differentiation and suppresses PPARgamma-stimulated adipocyte differentiation. (PMID:22108137)
• TAZ expression was lower in proneural glioblastomas and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with mesenchymal glioblastomas (PMID:22190458)
• The authors show that YAP and TAZ, the transcriptional co-activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of beta-catenin but through preventing its nuclear translocation. (PMID:22234184)
• Using reverse transcription-polymerase chain reaction (RT-PCR) and subsequent sequencing, we confirmed an identical WWTR1-CAMTA1 fusion transcript product from different nodules in each patient. (PMID:22429593)
• WWTR1 is an oncogene and has an important role in the proliferation of colorectal cancer cells and in tumor growth in vivo. (PMID:22470139)
• High TAZ expression is associated with non-small cell lung cancer. (PMID:22481233)
• a novel mechanism of TAZ regulation and role of TAZ in modulating tissue growth and tumor development in response to PI3K signaling. (PMID:22692215)
• The aim of the present paper was to evaluate Wwox and TAZ, nuclear effectors of Hippo-related pathways, were involved in E-cadherin expression in bone metastases specimens from breast cancer. (PMID:22717556)
• TAZ-dependent secretion of AREG indicates that activation of the EGFR signaling is an important non-cell-autonomous effector of the Hippo pathway, and TAZ as well as its targets may play significant roles in breast tumorigenesis and metastasis. (PMID:22825057)
• Studies indicate that the transcriptional co-activators YAP and TAZ recently emerged as key mediators of the biological effects that are observed in response to extracellular matrix (ECM) elasticity and cell shape. (PMID:22895435)
• NPHP9 promotes signalling through the transcriptional co-activator TAZ. (PMID:23026745)
• TAZ activation is a general feature of Wnt signaling and is functionally relevant to mediate Wnt biological effects. (PMID:23245942)
• Stiffer substrates resulted in upregulation of canonical Wnt modulators, TAZ and sFRP-1, and thus may influence the progression of glaucoma. (PMID:23258147)
• TAZ regulates AXL, and plays an important role in clonogenicity and non-adherent growth in vitro and tumor formation in vivo. (PMID:23372686)
• Considering bone-metastasis specimens, nuclear HIF-1alpha-TAZ co-localisation occurred in neoplastic and supportive cells, such as fibroblasts and endotheliocytes. (PMID:23566416)
• TAZ protein and TEAD transcription factors interaction is functionally important for TAZ-induced cell migration. (PMID:23673366)
• Expression of miR-135b, LZTS1, LATS2 and nuclear TAZ predicts poor outcomes of non-small-cell lung cancer. (PMID:23695671)
• In conclusion, substratum stiffness alters YAP/TAZ expression and YAP localization in trabecularmeshwork cells which then may modulate the expression of extracellular matrix proteins important in glaucoma. (PMID:23727052)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	wwtr1	ENSDARG00000067719
mus_musculus	Wwtr1	ENSMUSG00000027803
rattus_norvegicus	Wwtr1	ENSRNOG00000016617
drosophila_melanogaster	yki	FBGN0034970

Paralogs (1): YAP1 (ENSG00000137693)

Protein

Protein identifiers

WW domain-containing transcription regulator protein 1 — Q9GZV5 (reviewed: Q9GZV5)

Alternative names: Transcriptional coactivator with PDZ-binding motif

All UniProt accessions (8): Q9GZV5, C9J038, C9J337, C9J588, C9JQS8, C9JR84, H7C4Q0, H7C4Z7

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional coactivator which acts as a downstream regulatory target in the Hippo signaling pathway that plays a pivotal role in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein STK3/MST2 and STK4/MST1, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. WWTR1 enhances PAX8 and NKX2-1/TTF1-dependent gene activation. In conjunction with YAP1, involved in the regulation of TGFB1-dependent SMAD2 and SMAD3 nuclear accumulation. Plays a key role in coupling SMADs to the transcriptional machinery such as the mediator complex. Regulates embryonic stem-cell self-renewal, promotes cell proliferation and epithelial-mesenchymal transition.

Subunit / interactions. Binds to SLC9A3R2 via the PDZ motif at the plasma membrane. Binds to YWHAZ in vivo and in vitro through the phosphoserine-binding motif RSHSSP. Interacts (via coiled-coil domain) with SMAD2 (via MH1 domain), SMAD3 and SMAD4. Interacts with MED15. Interacts with PAX8 and NKX2-1. Interacts with TEAD1, TEAD2, TEAD3 and TEAD4. Interacts (via WW domain) with PALS1. Interacts with LATS1. Interacts with YAP1 (when phosphorylated at ‘Ser-127’). Interacts (via WW domain) with PRRG4 (via cytoplasmic domain). Interacts (via WW domain) with AMOTL2 (via PPXY motif); the interaction promotes WWTR1/TAZ localization to the cytoplasm and tight junctions, thereby inhibiting its transcriptional coactivator properties. Interacts (via WW domain) with AMOT isoform 1; the interaction facilitates translocation of WWTR1/TAZ to the cytoplasm.

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

Tissue specificity. Highly expressed in kidney, heart, placenta and lung. Expressed in the thyroid tissue.

Post-translational modifications. Phosphorylated by LATS2 and STK3/MST2. Phosphorylation by LATS2 results in creation of 14-3-3 binding sites, retention in the cytoplasm, and functional inactivation. Phosphorylation results in the inhibition of transcriptional coactivation through YWHAZ-mediated nuclear export. Phosphorylated in the nucleus by PRP4K; phosphorylation leads to nuclear exclusion. Ubiquitinated at Lys-46; leading to proteasomal degradation. Deubiquitinated and stabilized by UCHL1 at Lys-46; leading to inhibition of osteoclastogenesis.

Domain organisation. The PDZ-binding motif is essential for stimulated gene transcription. It localizes the protein into both punctate nuclear foci and plasma membrane-associated complexes. Binds to transcription factors via its WW domain.

RefSeq proteins (4): NP_001161750, NP_001161752, NP_001335291, NP_056287* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001202	WW_dom	Domain
IPR036020	WW_dom_sf	Homologous_superfamily
IPR051583	YAP1	Family

Pfam: PF00397

UniProt features (18 total): modified residue 5, mutagenesis site 5, region of interest 2, chain 1, domain 1, cross-link 1, coiled-coil region 1, short sequence motif 1, compositionally biased region 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
6RHC	X-RAY DIFFRACTION	1.2
8R0Z	X-RAY DIFFRACTION	1.2
6RJL	X-RAY DIFFRACTION	1.28
5N5W	X-RAY DIFFRACTION	1.37
5N5T	X-RAY DIFFRACTION	1.8
6SLX	X-RAY DIFFRACTION	1.8
5N5R	X-RAY DIFFRACTION	1.8
5N75	X-RAY DIFFRACTION	1.8
6RJQ	X-RAY DIFFRACTION	1.89
6RP6	X-RAY DIFFRACTION	1.89
6SLW	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZV5-F1	60.36	0.12

Functional residue map

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

Post-translational modifications (6): 295, 311, 46, 62, 89, 105

Mutagenesis-validated functional residues (5):

Position	Phenotype
51	loss of interaction with tead4.
89	significant resistance to inhibition by stk3/mst2 and lats2. no effect on binding to prrg4.
111–158	reduced binding to prrg4.
311	partial resistance to inhibition by mst2 and lats2.
394–400	no effect on binding to prrg4.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-2028269	Signaling by Hippo
R-HSA-2032785	YAP1- and WWTR1 (TAZ)-stimulated gene expression
R-HSA-2173795	Downregulation of SMAD2/3:SMAD4 transcriptional activity
R-HSA-2173796	SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription
R-HSA-5578768	Physiological factors
R-HSA-8940973	RUNX2 regulates osteoblast differentiation
R-HSA-8951671	RUNX3 regulates YAP1-mediated transcription
R-HSA-9619665	EGR2 and SOX10-mediated initiation of Schwann cell myelination
R-HSA-9909649	Regulation of PD-L1(CD274) transcription

MSigDB gene sets: 370 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, MODULE_52, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, REACTOME_SIGNALING_BY_TGF_BETA_RECEPTOR_COMPLEX, GOBP_METANEPHROS_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_TO_MESENCHYMAL_TRANSITION, GOBP_NEGATIVE_REGULATION_OF_FAT_CELL_DIFFERENTIATION, GOBP_METANEPHRIC_EPITHELIUM_DEVELOPMENT, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION

GO Biological Process (24): negative regulation of transcription by RNA polymerase II (GO:0000122), osteoblast differentiation (GO:0001649), tissue homeostasis (GO:0001894), heart process (GO:0003015), regulation of DNA-templated transcription (GO:0006355), positive regulation of cell population proliferation (GO:0008284), positive regulation of epithelial to mesenchymal transition (GO:0010718), protein ubiquitination (GO:0016567), stem cell division (GO:0017145), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), glomerulus development (GO:0032835), multicellular organism growth (GO:0035264), hippo signaling (GO:0035329), negative regulation of fat cell differentiation (GO:0045599), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of transcription by RNA polymerase II (GO:0045944), mesenchymal cell differentiation (GO:0048762), cilium assembly (GO:0060271), SMAD protein signal transduction (GO:0060395), kidney morphogenesis (GO:0060993), regulation of metanephric nephron tubule epithelial cell differentiation (GO:0072307), negative regulation of canonical Wnt signaling pathway (GO:0090090), positive regulation of protein localization to nucleus (GO:1900182), regulation of canonical Wnt signaling pathway (GO:0060828)

GO Molecular Function (5): transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), transcription corepressor activity (GO:0003714), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), nuclear body (GO:0016604), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	2
Signal Transduction	1
Generic Transcription Pathway	1
Cardiac conduction	1
RUNX2 regulates bone development	1
Transcriptional regulation by RUNX3	1
Nervous system development	1
Regulation of PD-L1(CD274) expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
cell differentiation	2
positive regulation of cell differentiation	2
positive regulation of DNA-templated transcription	2
transcription coregulator activity	2
ossification	1
multicellular organismal-level homeostasis	1
anatomical structure homeostasis	1
circulatory system process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of multicellular organismal process	1
protein modification by small protein conjugation	1
cell division	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
anatomical structure development	1
nephron development	1
multicellular organismal process	1
developmental growth	1
intracellular signal transduction	1
fat cell differentiation	1
negative regulation of cell differentiation	1
regulation of fat cell differentiation	1
osteoblast differentiation	1
regulation of osteoblast differentiation	1
mesenchyme development	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1

Protein interactions and networks

STRING

1660 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WWTR1	TEAD1	P28347	960
WWTR1	AMOT	Q4VCS5	911
WWTR1	CAMTA1	Q9Y6Y1	864
WWTR1	TBX5	Q99593	856
WWTR1	VGLL3	A8MV65	816
WWTR1	VGLL1	Q99990	804
WWTR1	SAV1	Q9H4B6	789
WWTR1	TEAD4	Q15561	786
WWTR1	RUNX2	Q13950	784
WWTR1	LATS1	O95835	759
WWTR1	VGLL2	Q8N8G2	758
WWTR1	GLIS3	Q8NEA6	742
WWTR1	LATS2	Q9NRM7	710
WWTR1	STK4	Q13043	683
WWTR1	AMOTL2	Q9Y2J4	680

IntAct

276 interactions, top by confidence:

A	B	Type	Score
TEAD4	WWTR1	psi-mi:“MI:0915”(physical association)	0.920
TEAD2	YAP1	psi-mi:“MI:0914”(association)	0.820
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
TEAD3	WWTR1	psi-mi:“MI:0915”(physical association)	0.750
WWTR1	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.720
SCRIB	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.710
WWTR1	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.710
WWTR1	LATS1	psi-mi:“MI:0914”(association)	0.640
LATS1	WWTR1	psi-mi:“MI:0915”(physical association)	0.640
WWTR1	CTNNB1	psi-mi:“MI:0915”(physical association)	0.640
WWTR1	CTNNB1	psi-mi:“MI:0914”(association)	0.640
SHANK1	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.620
SNTA1	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.620
WWTR1	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.620
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
WBP2	WWTR1	psi-mi:“MI:0915”(physical association)	0.610
WBP2	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.610
WBP2	WWTR1	psi-mi:“MI:0403”(colocalization)	0.610
WWTR1	DVL3	psi-mi:“MI:0407”(direct interaction)	0.610
PRRG4	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.600
PRRG4	WWTR1	psi-mi:“MI:0915”(physical association)	0.600

BioGRID (466): WWTR1 (Affinity Capture-Western), WWTR1 (Affinity Capture-Western), WWTR1 (Affinity Capture-Western), DVL2 (Affinity Capture-Western), BTRC (Affinity Capture-Western), WWTR1 (Biochemical Activity), WWTR1 (Affinity Capture-Western), WWTR1 (Affinity Capture-Western), WWTR1 (Affinity Capture-MS), AMOTL1 (Affinity Capture-MS), AMOT (Affinity Capture-MS), TEAD1 (Affinity Capture-MS), TEAD3 (Affinity Capture-MS), BTRC (Affinity Capture-MS), FBXW11 (Affinity Capture-MS)

ESM2 similar proteins: A0A096MJY4, A0A486WWJ9, A2ICN5, A2VDZ3, A4UTP7, A8WL06, B7ZR65, H2LBU8, O89038, P10071, P40791, P55197, P55879, Q02078, Q03413, Q03414, Q06413, Q0VGT2, Q14814, Q2KIA0, Q2MJT0, Q32NP8, Q4VYR7, Q5IS56, Q5R444, Q5REW7, Q5U4X3, Q60929, Q61602, Q63943, Q6DFF5, Q6DIF3, Q6F2E7, Q7ZY13, Q8BUR3, Q8CFN5, Q91660, Q91661, Q9DE25, Q9EPK5

Diamond homologs: A0A8C0NGY6, A0A8I3PQN6, A1A5G4, A1CQG2, A1D3C5, A2QQ28, A4IIJ3, B0XQ72, B3LWS4, B3P3M8, B4HEJ6, B4K6I9, B4M5X4, B4NAD3, B4PSQ2, B8N7E5, D6C652, G0S9J5, H2LBU8, O14326, O88382, P39940, P46934, P46935, P46936, P46937, P46938, Q0CCL1, Q19404, Q1L8J7, Q2EJA0, Q2UBP1, Q32NJ6, Q45VV3, Q4L1J4, Q4WTF3, Q54T86, Q5BDP1, Q5F488, Q5RBF2

SIGNOR signaling

56 interactions.

A	Effect	B	Mechanism
WWTR1	up-regulates	NKX2-1	binding
WWTR1	up-regulates	MYOD1	binding
14-3-3	down-regulates	WWTR1	binding
WWTR1	up-regulates	SMAD2	binding
WWTR1	“up-regulates activity”	SMAD2	binding
WWTR1	up-regulates	SMAD3	binding
AMOT	down-regulates	WWTR1	relocalization
LATS1	down-regulates	WWTR1	phosphorylation
LATS2	down-regulates	WWTR1	phosphorylation
TJP2	down-regulates	WWTR1	binding
WWTR1	up-regulates	PAX8	binding
WWTR1	up-regulates	TTF1	binding
WWTR1	up-regulates	TEAD1	binding
WWTR1	down-regulates	DVL1	binding
WWTR1	down-regulates	PPARG	binding
WWTR1	up-regulates	RUNX2	binding
WWTR1	down-regulates	Apoptosis
WWTR1	up-regulates	Proliferation
WWTR1	up-regulates	TEAD2	binding
WWTR1	up-regulates	TEAD3	binding
WWTR1	up-regulates	TEAD4	binding
WWTR1	“up-regulates activity”	TEAD	binding
CSNK1E	down-regulates	WWTR1	phosphorylation
SCF-betaTRCP	“down-regulates quantity by destabilization”	WWTR1	ubiquitination
WWTR1	“up-regulates activity”	SMAD3	binding
CSNK1D	down-regulates	WWTR1	phosphorylation
WWTR1	“up-regulates quantity by expression”	LTBR	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 114 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	59.3×	1e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	52.4×	1e-07
YAP1- and WWTR1 (TAZ)-stimulated gene expression	5	49.4×	2e-06
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	43.6×	4e-06
Signaling by Hippo	6	42.4×	4e-07
Activation of BH3-only proteins	6	38.7×	6e-07
Intrinsic Pathway for Apoptosis	6	22.8×	1e-05
FOXO-mediated transcription	5	21.8×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
hippo signaling	7	49.3×	4e-08
establishment or maintenance of epithelial cell apical/basal polarity	8	44.7×	7e-09
receptor clustering	6	36.0×	5e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	5	23.8×	4e-04
protein targeting	6	21.1×	1e-04
epidermal growth factor receptor signaling pathway	6	14.3×	6e-04
cell-cell adhesion	9	8.8×	2e-04
intracellular protein localization	8	8.1×	9e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 1 cancer types — OVT.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2690 predictions. Top by Δscore:

Variant	Effect	Δscore
3:149520829:A:AC	donor_gain	1.0000
3:149520830:C:CC	donor_gain	1.0000
3:149526008:CCTA:C	donor_loss	1.0000
3:149526010:TACC:T	donor_loss	1.0000
3:149526011:ACCTG:A	donor_loss	1.0000
3:149526121:GCCCT:G	acceptor_gain	1.0000
3:149526122:CCCT:C	acceptor_gain	1.0000
3:149526122:CCCTC:C	acceptor_gain	1.0000
3:149526123:CCT:C	acceptor_gain	1.0000
3:149526123:CCTC:C	acceptor_gain	1.0000
3:149526124:CT:C	acceptor_gain	1.0000
3:149526124:CTC:C	acceptor_gain	1.0000
3:149526125:TC:T	acceptor_loss	1.0000
3:149526125:TCT:T	acceptor_gain	1.0000
3:149526126:C:CA	acceptor_loss	1.0000
3:149526126:C:CC	acceptor_gain	1.0000
3:149526127:T:A	acceptor_loss	1.0000
3:149527834:A:AC	donor_gain	1.0000
3:149527834:AC:A	donor_gain	1.0000
3:149527835:C:CC	donor_gain	1.0000
3:149527835:CC:C	donor_gain	1.0000
3:149527977:C:CT	acceptor_gain	1.0000
3:149527978:A:T	acceptor_gain	1.0000
3:149542329:CCATA:C	donor_loss	1.0000
3:149542330:CATA:C	donor_loss	1.0000
3:149542331:ATAC:A	donor_loss	1.0000
3:149542332:TA:T	donor_loss	1.0000
3:149542334:C:A	donor_loss	1.0000
3:149542533:CATCA:C	acceptor_gain	1.0000
3:149542534:ATCA:A	acceptor_gain	1.0000

AlphaMissense

2650 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:149520813:A:G	W399R	1.000
3:149520813:A:T	W399R	1.000
3:149526089:A:C	S314R	1.000
3:149526089:A:T	S314R	1.000
3:149526091:T:G	S314R	1.000
3:149526093:T:A	D313V	1.000
3:149542345:A:G	L254P	1.000
3:149572964:C:A	R156S	1.000
3:149572964:C:G	R156S	1.000
3:149572965:C:A	R156M	1.000
3:149572968:G:T	P155H	1.000
3:149572969:G:A	P155S	1.000
3:149572971:T:C	D154G	1.000
3:149572976:C:A	W152C	1.000
3:149572976:C:G	W152C	1.000
3:149572977:C:G	W152S	1.000
3:149572978:A:G	W152R	1.000
3:149572978:A:T	W152R	1.000
3:149656879:A:G	L143P	1.000
3:149656881:G:C	F142L	1.000
3:149656881:G:T	F142L	1.000
3:149656882:A:G	F142S	1.000
3:149656883:A:G	F142L	1.000
3:149656886:A:C	Y141D	1.000
3:149656917:C:A	W130C	1.000
3:149656917:C:G	W130C	1.000
3:149656918:C:G	W130S	1.000
3:149656919:A:G	W130R	1.000
3:149656919:A:T	W130R	1.000
3:149657151:G:C	F52L	1.000

dbSNP variants (sampled 300 via entrez): RS1000009609 (3:149642153 G>A), RS1000032549 (3:149723819 T>C), RS1000043353 (3:149597254 C>T), RS1000043886 (3:149660857 A>G), RS1000063712 (3:149629720 A>C,G), RS1000103956 (3:149519904 T>A,C), RS1000111810 (3:149644983 A>G), RS1000116494 (3:149632935 C>G), RS1000142838 (3:149644790 G>A), RS1000182366 (3:149672140 A>G), RS1000188455 (3:149714294 G>T), RS1000189161 (3:149542617 G>A,T), RS1000190366 (3:149632667 T>C), RS1000191512 (3:149714355 C>G,T), RS1000191797 (3:149629965 G>GCC)

Disease associations

OMIM: gene MIM:607392 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001949_14	Preeclampsia	3.000000e-06
GCST008839_190	Height	1.000000e-12
GCST010687_5	Polycystic ovary syndrome	8.000000e-07
GCST012048_28	Triglyceride levels	3.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6193795 (PROTEIN-PROTEIN INTERACTION)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3811715	WWTR1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
trichostatin A	increases expression, affects cotreatment	3
Acetaminophen	decreases expression, increases expression	3
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	3
methylmercuric chloride	increases expression	2
bisphenol A	increases localization, decreases expression, affects reaction, increases expression, increases lipidation (+1 more)	2
sodium arsenite	increases abundance, increases expression	2
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, decreases expression	2
Vorinostat	affects cotreatment, increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	affects cotreatment, decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
Particulate Matter	decreases expression, increases abundance, decreases stability	2
aristolochic acid I	decreases expression	1
caulerpin	decreases expression	1
IBS008738	affects expression, increases stability	1
FR900359	increases phosphorylation	1
dicrotophos	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
deoxynivalenol	increases expression	1
glycidyl methacrylate	decreases expression	1
terbufos	increases methylation	1
methylparaben	decreases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
zinc chromate	increases abundance, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5588739	Binding	PROTAC activity at TAZ/VHL in human Huh-7 cells assessed as induction of TAZ degradation at 5 to 20 uM incubated for 24 hrs by Western blot analysis	Exploring Degradation of Intrinsically Disordered Protein Yes-Associated Protein Induced by Proteolysis TArgeting Chimeras. — J Med Chem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B8RT	Abcam HCT 116 WWTR1 KO	Cancer cell line	Male
CVCL_B9CH	Abcam MCF-7 WWTR1 KO	Cancer cell line	Female
CVCL_B9UC	Abcam A-549 WWTR1 KO	Cancer cell line	Male
CVCL_B9VX	Abcam HeLa WWTR1 KO	Cancer cell line	Female
CVCL_TY29	HAP1 WWTR1 (-) 1	Cancer cell line	Male
CVCL_XV15	HAP1 WWTR1 (-) 2	Cancer cell line	Male
CVCL_YE50	MUSIi012-A-1	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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