YWHAH

Summary

YWHAH (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta, HGNC:12853) is a protein-coding gene on chromosome 22q12.3, encoding 14-3-3 protein eta (Q04917). Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways.

This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse, rat and bovine orthologs. This gene contains a 7 bp repeat sequence in its 5’ UTR, and changes in the number of this repeat have been associated with early-onset schizophrenia and psychotic bipolar disorder.

Source: NCBI Gene 7533 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 19 total
• Druggable target: yes
• MANE Select transcript: NM_003405

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12853
Approved symbol	YWHAH
Name	tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000128245
Ensembl biotype	protein_coding
OMIM	113508
Entrez	7533

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000248975, ENST00000397492, ENST00000420430, ENST00000443669, ENST00000471374, ENST00000479649, ENST00000946727

RefSeq mRNA: 1 — MANE Select: NM_003405 NM_003405

CCDS: CCDS13901

Canonical transcript exons

ENST00000248975 — 2 exons

Exon	Start	End
ENSE00000879954	31944535	31944820
ENSE00003679051	31956139	31957603

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 99.6796 / max 2842.0156, expressed in 1827 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191837	59.7215	1824
191836	33.3636	1821
191834	2.8961	1312
191835	1.0447	634
191843	0.7848	340
191839	0.7261	280
191845	0.3707	151
191840	0.2941	101
191844	0.2210	57
191841	0.1394	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
frontal pole	UBERON:0002795	99.97	gold quality
Brodmann (1909) area 10	UBERON:0013541	99.94	gold quality
paraflocculus	UBERON:0005351	99.76	gold quality
prefrontal cortex	UBERON:0000451	99.69	gold quality
middle frontal gyrus	UBERON:0002702	99.60	gold quality
right frontal lobe	UBERON:0002810	99.59	gold quality
cingulate cortex	UBERON:0003027	99.56	gold quality
anterior cingulate cortex	UBERON:0009835	99.56	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.49	gold quality
orbitofrontal cortex	UBERON:0004167	99.41	gold quality
cortical plate	UBERON:0005343	99.38	gold quality
amygdala	UBERON:0001876	99.28	gold quality
pons	UBERON:0000988	99.21	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.18	gold quality
frontal cortex	UBERON:0001870	99.15	gold quality
frontal lobe	UBERON:0016525	99.15	gold quality
cerebellar cortex	UBERON:0002129	99.09	gold quality
cerebellar vermis	UBERON:0004720	99.09	gold quality
cerebellar hemisphere	UBERON:0002245	99.08	gold quality
popliteal artery	UBERON:0002250	99.01	gold quality
tibial artery	UBERON:0007610	99.01	gold quality
ganglionic eminence	UBERON:0004023	98.94	gold quality
cerebellum	UBERON:0002037	98.91	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.91	gold quality
right coronary artery	UBERON:0001625	98.87	gold quality
neocortex	UBERON:0001950	98.85	gold quality
aorta	UBERON:0000947	98.82	gold quality
islet of Langerhans	UBERON:0000006	98.81	gold quality
hypothalamus	UBERON:0001898	98.78	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-MTAB-10855	yes	1114.77
E-MTAB-6653	yes	703.74
E-HCAD-4	yes	136.62
E-HCAD-5	yes	49.20
E-HCAD-35	yes	48.24
E-GEOD-134144	yes	25.57
E-CURD-122	yes	23.23
E-MTAB-9221	yes	20.81
E-HCAD-1	yes	20.57
E-MTAB-7316	yes	12.72
E-CURD-114	yes	11.44
E-CURD-88	yes	9.52
E-MTAB-10553	yes	6.58
E-MTAB-9801	yes	4.01
E-HCAD-30	no	871.70

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, JUN

miRNA regulators (miRDB)

119 targeting YWHAH, 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-3613-3P	100.00	76.36	7965
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-6785-5P	99.82	68.68	4428

Literature-anchored findings (GeneRIF, showing 36)

• Results show that three 14-3-3 isoforms, beta, gamma and eta, are DAL-1/Protein 4.1B-binding proteins. (PMID:11996670)
• phosphorylation of 14-3-3 binding site of myeloid leukemia factor 1 by MADM (PMID:12176995)
• Data demonstrate that 14-3-3 proteins are colocalized with Lewy bodies in Parkinson disease, but there was no specific staining for the 14-3-3 eta subunit. (PMID:12480176)
• gremlin 1 is overexpressed in human cancers and interacts with YWHAH protein (PMID:16545136)
• Detection of only 2 (14-3-3 eta and gamma) out of 7 different isoforms in synovial fluid suggests they are specific to the site of joint inflammation (PMID:17611984)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• The association of YWHAH with bipolar disorder in a large sample, consisting of 1211 subjects from 318 nuclear families including 554 affected offspring, was investigated. (PMID:19160447)
• 14-3-3beta, 14-3-3gamma, 14-3-3epsilon, 14-3-3eta and 14-3-3theta isoforms interact with the GPIb-IX complex in platelets (PMID:19558434)
• The 14-3-3 eta, beta, gamma and sigma isoforms were negatively expressed in meningioma (PMID:20388496)
• Data indicate that gene analysis revealed an up-regulation of all four 14-3-3 isoforms beta, eta, gamma, and sigma. (PMID:21416292)
• relocation of p33ING1b from the nucleus to the cytoplasm, where the protein is tethered by 14-3-3eta, participates in tumorigenesis and progression in HNSCC (PMID:21432775)
• This is the first genetic association study of YWHAH with sporadic Creutzfeldt-Jakob disease populations. (PMID:21739144)
• 14-3-3eta may be required for mitotic progression and may be considered as a novel anti-cancer strategy in combination with microtubule inhibitors. (PMID:22562251)
• This study identified YWHAH significantly associated loci with a biologically plausible role in schizophrenia. (PMID:24507884)
• Extracellular 14-3-3eta activates key signalling cascades and induces factors associated with the pathogenesis of rheumatoid arthritis (PMID:24751211)
• 14-3-3 eta isoform colocalizes TDP-43 on the coarse granules in the anterior horn cells of patients with sporadic amyotrophic lateral sclerosis. (PMID:27256400)
• The impact of AKT1 on glucocorticoid receptor (GR)-induced transcriptional activity in cooperation with phospho-serine/threonine-binding protein 14-3-3, was examined. (PMID:27717743)
• Results show that YWHAZ amplification indicates a better survival trend in bladder cancer. Its knockdown promotes both in vitro and in vivo tumorigenesis in bladder cancer and may be a novel biomarker for bladder cancer. (PMID:29512774)
• 14-3-3eta inhibits LDHA by direct interaction in the setting of complex I dysfunction, highlighting the role of 14-3-3eta overexpression and inefficient oxidative phosphorylation in oncocytoma mitochondrial biogenesis. (PMID:29704241)
• 14-3-3eta protein: a promising biomarker for rheumatoid arthritis. (PMID:30022679)
• findings reveal that Akt activity determines the phosphorylation status of TBC1D7 at the phospho-switch Ser-124, which governs binding to either 14-3-3 or beta-TrCP2, resulting in increased or decreased stability of TBC1D7, respectively. (PMID:30143532)
• Study found that 14-3- 3zeta bond to HBx in HBV-positive hepatocellular carcinoma (HCC) cell lines. 14-3- 3zeta- silenced cancer cells displayed weakened migration and invasion, which was accompanied by decreased HBx expression. (PMID:30358169)
• Results uncover a novel function of 14-3-3eta to promote the MDA5-dependent IFNbeta induction pathway by reducing the immunostimulatory potential of viral dsRNA within MDA5 activation signaling pathway. (PMID:30742689)
• Serum 14-3-3eta protein levels in patients with rheumatoid arthritis were significantly higher as compared to healthy individuals (PMID:31333006)
• Proteomic and Interactome Approaches Reveal PAK4, PHB-2, and 14-3-3eta as Targets of Overactivated Cdc42 in Cellular Responses to Genomic Instability. (PMID:31478661)
• 14-3-3eta Protein in Rheumatoid Arthritis: Promising Diagnostic Marker and Independent Risk Factor for Osteoporosis. (PMID:32080735)
• NACHO and 14-3-3 promote expression of distinct subunit stoichiometries of the alpha4beta2 acetylcholine receptor. (PMID:32676916)
• MiR-660-5p promotes the progression of hepatocellular carcinoma by interaction with YWHAH via PI3K/Akt signaling pathway. (PMID:32807493)
• Genomics Links Inflammation With Neurocognitive Impairment in Children Living With Human Immunodeficiency Virus Type-1. (PMID:33373444)
• The significance of serum 14-3-3eta level in rheumatoid arthritis patients. (PMID:33400046)
• YWHAH Genetic Variants are Associated with Increased Hypoxia Inducible Factor-1alpha/Vascular Endothelial Growth Factor in Egyptian Rheumatoid Arthritis Patients. (PMID:35190930)
• Circ_0000144 acts as a miR-1178-3p decoy to promote cell malignancy and angiogenesis by increasing YWHAH expression in papillary thyroid cancer. (PMID:35902926)
• 14-3-3-eta interacts with BCL-2 to protect human endothelial progenitor cells from ox-LDL-triggered damage. (PMID:38100125)
• Mir-142-3P regulates MAPK protein family by inhibiting 14-3-3eta to enhance bone marrow mesenchymal stem cells osteogenesis. (PMID:38129425)
• Temporal regulation of MDA5 inactivation by Caspase-3 dependent cleavage of 14-3-3eta. (PMID:38843304)
• GREM1 Negatively Regulates Osteo-/Dentinogenic Differentiation of Dental Pulp Stem Cells via Association with YWHAH. (PMID:39221981)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ywhah	ENSDARG00000005560
mus_musculus	Ywhah	ENSMUSG00000018965
rattus_norvegicus	Ywhah	ENSRNOG00000055471
drosophila_melanogaster	14-3-3epsilon	FBGN0020238

Paralogs (6): YWHAE (ENSG00000108953), YWHAQ (ENSG00000134308), YWHAZ (ENSG00000164924), YWHAB (ENSG00000166913), YWHAG (ENSG00000170027), SFN (ENSG00000175793)

Protein

Protein identifiers

14-3-3 protein eta — Q04917 (reviewed: Q04917)

Alternative names: Protein AS1

All UniProt accessions (4): Q04917, A2IDB1, A2IDB2, F8WEB6

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negatively regulates the kinase activity of PDPK1.

Subunit / interactions. Homodimer. Interacts with many nuclear hormone receptors and cofactors including AR, ESR1, ESR2, MC2R, NR3C1, NRIP1, PPARBP and THRA. Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with ARHGEF28 and CDK16. Weakly interacts with CDKN1B. Interacts with GAB2. Interacts with KCNK18 in a phosphorylation-dependent manner. Interacts with SAMSN1. Interacts with the ‘Ser-241’ phosphorylated form of PDPK1. Interacts with the ‘Thr-369’ phosphorylated form of DAPK2. Interacts with PI4KB, TBC1D22A and TBC1D22B. Interacts with SLITRK1. Interacts with MEFV.

Tissue specificity. Expressed mainly in the brain and present in other tissues albeit at lower levels.

Post-translational modifications. Phosphorylated on Ser-59 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.

Similarity. Belongs to the 14-3-3 family.

RefSeq proteins (1): NP_003396* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000308	14-3-3	Family
IPR023409	14-3-3_CS	Conserved_site
IPR023410	14-3-3_domain	Domain
IPR036815	14-3-3_dom_sf	Homologous_superfamily

Pfam: PF00244

UniProt features (22 total): helix 10, modified residue 3, sequence conflict 3, turn 2, site 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
2C63	X-RAY DIFFRACTION	2.15
7NMZ	X-RAY DIFFRACTION	2.3
2C74	X-RAY DIFFRACTION	2.7
9R2I	ELECTRON MICROSCOPY	3.3
9R2N	ELECTRON MICROSCOPY	3.83

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q04917-F1	95.49	0.91

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): 57 (interaction with phosphoserine on interacting protein); 132 (interaction with phosphoserine on interacting protein)

Post-translational modifications (3): 2, 25, 59

Function

Pathways and Gene Ontology

Reactome pathways

36 pathways

ID	Pathway
R-HSA-111447	Activation of BAD and translocation to mitochondria
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-5625740	RHO GTPases activate PKNs
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-75035	Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex
R-HSA-9735871	SARS-CoV-1 targets host intracellular signalling and regulatory pathways
R-HSA-9755779	SARS-CoV-2 targets host intracellular signalling and regulatory pathways
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-114452	Activation of BH3-only proteins
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-199991	Membrane Trafficking
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5357801	Programmed Cell Death
R-HSA-5653656	Vesicle-mediated transport
R-HSA-5663205	Infectious disease
R-HSA-69473	G2/M DNA damage checkpoint
R-HSA-69481	G2/M Checkpoints
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9678108	SARS-CoV-1 Infection
R-HSA-9679506	SARS-CoV Infections

MSigDB gene sets: 398 (showing top): GOBP_DENDRITE_DEVELOPMENT, GNF2_RTN1, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_GLUCOCORTICOID_METABOLIC_PROCESS, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, GOBP_REGULATION_OF_DENDRITE_MORPHOGENESIS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, HSIAO_HOUSEKEEPING_GENES, PID_NFAT_3PATHWAY, GOBP_NEUROGENESIS

GO Biological Process (13): regulation of sodium ion transport (GO:0002028), glucocorticoid catabolic process (GO:0006713), intracellular protein transport (GO:0006886), signal transduction (GO:0007165), intracellular protein localization (GO:0008104), substantia nigra development (GO:0021762), nuclear receptor-mediated glucocorticoid signaling pathway (GO:0042921), regulation of neuron differentiation (GO:0045664), positive regulation of DNA-templated transcription (GO:0045893), regulation of synaptic plasticity (GO:0048167), negative regulation of dendrite morphogenesis (GO:0050774), membrane depolarization during action potential (GO:0086010), presynaptic modulation of chemical synaptic transmission (GO:0099171)

GO Molecular Function (10): actin binding (GO:0003779), insulin-like growth factor receptor binding (GO:0005159), sodium channel regulator activity (GO:0017080), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), nuclear glucocorticoid receptor binding (GO:0035259), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (10): cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), intercalated disc (GO:0014704), extracellular exosome (GO:0070062), presynapse (GO:0098793), cerebellar granule cell to Purkinje cell synapse (GO:0150048), synapse (GO:0045202), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Activation of BH3-only proteins	1
Membrane Trafficking	1
RHO GTPase Effectors	1
Transcriptional Regulation by TP53	1
G2/M DNA damage checkpoint	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1
MITF-M-regulated melanocyte development	1
Programmed Cell Death	1
Apoptosis	1
Intrinsic Pathway for Apoptosis	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Vesicle-mediated transport	1
RNA Polymerase II Transcription	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
cellular anatomical structure	3
modulation of chemical synaptic transmission	2
cytoplasm	2
synapse	2
sodium ion transport	1
regulation of metal ion transport	1
steroid catabolic process	1
glucocorticoid metabolic process	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
macromolecule localization	1
midbrain development	1
neural nucleus development	1
nuclear receptor-mediated corticosteroid signaling pathway	1
neuron differentiation	1
regulation of cell differentiation	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of biological quality	1
negative regulation of cell projection organization	1
dendrite morphogenesis	1
regulation of dendrite morphogenesis	1
negative regulation of neurogenesis	1
action potential	1
membrane depolarization	1
presynapse	1
cytoskeletal protein binding	1
signaling receptor binding	1
sodium channel activity	1
ion channel regulator activity	1
nuclear receptor binding	1
protein dimerization activity	1

Protein interactions and networks

STRING

4278 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
YWHAH	TXNDC9	O14530	833
YWHAH	RAF1	P04049	774
YWHAH	SCN5A	Q14524	727
YWHAH	TPH2	Q8IWU9	710
YWHAH	ARHGEF2	Q92974	697
YWHAH	AKT1S1	Q96B36	677
YWHAH	RIMS1	Q86UR5	663
YWHAH	SELENOW	P63302	656
YWHAH	BMS1	Q14692	650
YWHAH	RCL1	Q9Y2P8	649
YWHAH	YWHAB	P31946	610
YWHAH	TPH1	P17752	606
YWHAH	TSR1	Q2NL82	588
YWHAH	INPP5J	Q15735	585
YWHAH	PRR5	P85299	574

IntAct

612 interactions, top by confidence:

A	B	Type	Score
MAP2K1	RAF1	psi-mi:“MI:0914”(association)	0.960
RAF1	YWHAH	psi-mi:“MI:0915”(physical association)	0.940
BRAF	HRAS	psi-mi:“MI:0914”(association)	0.940
BRAF	NRAS	psi-mi:“MI:0914”(association)	0.860
PTPN3	YWHAQ	psi-mi:“MI:2364”(proximity)	0.850
YWHAH	TSC2	psi-mi:“MI:0914”(association)	0.850
ATXN1	YWHAH	psi-mi:“MI:0915”(physical association)	0.840
LRRK2	YWHAH	psi-mi:“MI:0915”(physical association)	0.830
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
YWHAH	CDK14	psi-mi:“MI:0915”(physical association)	0.780
CDK14	YWHAH	psi-mi:“MI:0915”(physical association)	0.780
ARL3	UNC119B	psi-mi:“MI:0914”(association)	0.730
MARK4	YWHAH	psi-mi:“MI:0915”(physical association)	0.720
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
CGN	YWHAQ	psi-mi:“MI:0914”(association)	0.710
PRKCI	YWHAH	psi-mi:“MI:0915”(physical association)	0.710
BRAF	KRAS	psi-mi:“MI:0914”(association)	0.680
YWHAH	YWHAH	psi-mi:“MI:0407”(direct interaction)	0.670
PTPN3	MCC	psi-mi:“MI:0914”(association)	0.660
CEP170	KIF2A	psi-mi:“MI:2364”(proximity)	0.650
SNCA	YWHAH	psi-mi:“MI:0915”(physical association)	0.650

BioGRID (2010): YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-Western), YWHAH (Affinity Capture-Western), DTL (Affinity Capture-Western), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAH (Affinity Capture-MS)

ESM2 similar proteins: A4K2U9, P27348, P29309, P29310, P29361, P31946, P35213, P61981, P61982, P61983, P63101, P63102, P63103, P63104, P68250, P68252, P68254, P68255, P68509, P68510, P68511, Q04917, Q1HR36, Q20655, Q2F637, Q3SZI4, Q4R572, Q52M98, Q5F3W6, Q5PRD0, Q5R651, Q5RC20, Q5RFJ2, Q5XGC8, Q5XHK2, Q5ZKC9, Q5ZLQ6, Q5ZMD1, Q6NRY9, Q6P4Z5

Diamond homologs: A4K2U9, B8NLM9, O49995, O49998, O65352, O70456, O77642, P27348, P29309, P29310, P29311, P29361, P31946, P31947, P34730, P35213, P41932, P42643, P42644, P42652, P42653, P42654, P42656, P48348, P49106, P52908, P54632, P61981, P61982, P61983, P62258, P62259, P62260, P62261, P62262, P63101, P63102, P63103, P63104, P68250

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
YWHAH	down-regulates	CDKN1B	binding
YWHAH	“down-regulates activity”	KCNK18	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 221 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	30.3×	5e-08
Activation of BAD and translocation to mitochondria	6	29.5×	8e-07
Signaling by RAS mutants	10	27.3×	7e-11
Signaling by high-kinase activity BRAF mutants	13	26.6×	8e-14
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	26.0×	2e-06
Signaling by RAF1 mutants	14	25.2×	5e-14
MAP2K and MAPK activation	13	23.9×	4e-13
RAF activation	11	23.8×	4e-11

GO biological processes:

GO term	Partners	Fold	FDR
centriole replication	5	18.9×	7e-04
microtubule nucleation	5	16.1×	1e-03
insulin-like growth factor receptor signaling pathway	6	15.3×	4e-04
establishment or maintenance of epithelial cell apical/basal polarity	5	15.0×	2e-03
ERK1 and ERK2 cascade	8	13.1×	4e-05
non-motile cilium assembly	7	10.5×	6e-04
thymus development	6	10.4×	2e-03
establishment or maintenance of cell polarity	5	10.3×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

265 predictions. Top by Δscore:

Variant	Effect	Δscore
22:31956126:T:TA	acceptor_gain	1.0000
22:31956127:G:A	acceptor_gain	1.0000
22:31956134:TGCA:T	acceptor_loss	1.0000
22:31956135:GCAG:G	acceptor_loss	1.0000
22:31956136:CAGGT:C	acceptor_loss	1.0000
22:31956137:A:AG	acceptor_gain	1.0000
22:31956137:A:AT	acceptor_loss	1.0000
22:31956138:G:GC	acceptor_loss	1.0000
22:31956138:G:GG	acceptor_gain	1.0000
22:31944818:GCG:G	donor_gain	0.9900
22:31944819:CGGTG:C	donor_loss	0.9900
22:31944820:GGTG:G	donor_loss	0.9900
22:31944821:G:GG	donor_gain	0.9900
22:31944821:GTGA:G	donor_loss	0.9900
22:31944822:T:G	donor_loss	0.9900
22:31947401:A:AG	acceptor_gain	0.9900
22:31956128:G:A	acceptor_gain	0.9900
22:31956134:T:TA	acceptor_gain	0.9900
22:31956138:GGT:G	acceptor_gain	0.9900
22:31944816:AGGCG:A	donor_gain	0.9800
22:31944817:GGCGG:G	donor_gain	0.9800
22:31947402:A:G	acceptor_gain	0.9800
22:31956137:AG:A	acceptor_gain	0.9800
22:31956138:GG:G	acceptor_gain	0.9800
22:31944833:G:GT	donor_gain	0.9700
22:31947400:T:G	acceptor_gain	0.9600
22:31947613:G:GT	donor_gain	0.9600
22:31956137:AGGT:A	acceptor_gain	0.9600
22:31956138:GGTG:G	acceptor_gain	0.9600
22:31956138:GGTGA:G	acceptor_gain	0.9600

AlphaMissense

1625 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:31944773:G:C	A14P	1.000
22:31944782:G:C	A17P	1.000
22:31944788:C:A	R19S	1.000
22:31944789:G:C	R19P	1.000
22:31944802:G:A	M23I	1.000
22:31944802:G:C	M23I	1.000
22:31944802:G:T	M23I	1.000
22:31956176:G:C	R42P	1.000
22:31956180:T:A	N43K	1.000
22:31956180:T:G	N43K	1.000
22:31956182:T:C	L44P	1.000
22:31956185:T:C	L45P	1.000
22:31956187:T:C	S46P	1.000
22:31956188:C:T	S46F	1.000
22:31956193:G:C	A48P	1.000
22:31956194:C:A	A48D	1.000
22:31956194:C:T	A48V	1.000
22:31956196:T:G	Y49D	1.000
22:31956199:A:C	K50Q	1.000
22:31956199:A:G	K50E	1.000
22:31956200:A:C	K50T	1.000
22:31956200:A:T	K50M	1.000
22:31956201:G:C	K50N	1.000
22:31956201:G:T	K50N	1.000
22:31956202:A:G	N51D	1.000
22:31956203:A:T	N51I	1.000
22:31956204:T:A	N51K	1.000
22:31956204:T:G	N51K	1.000
22:31956209:T:A	V53D	1.000
22:31956211:G:C	G54R	1.000

dbSNP variants (sampled 300 via entrez): RS1000525777 (22:31943833 T>C), RS1000676669 (22:31952072 T>TA), RS1000693389 (22:31946173 G>C), RS1000748624 (22:31951795 G>T), RS1000907369 (22:31955590 G>A), RS1001019861 (22:31955868 T>C), RS1001139522 (22:31949506 T>A), RS1001408077 (22:31957797 CAT>C), RS1001423906 (22:31949294 C>T), RS1001469236 (22:31942596 G>A), RS1002086654 (22:31952986 C>A), RS1002361681 (22:31954992 G>C), RS1002472124 (22:31943840 TG>T), RS1002586684 (22:31943546 C>A), RS1002911727 (22:31954461 ACT>A)

Disease associations

OMIM: gene MIM:113508 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003262_877	Post bronchodilator FEV1	5.000000e-06
GCST009379_304	Type 2 diabetes	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3708585 (SINGLE PROTEIN), CHEMBL5291962 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 12 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.68	Kd	20.86	nM	CHEMBL3752910
7.66	ED50	21.7	nM	CHEMBL3752910
7.16	Kd	70	nM	CHEMBL3814675
7.00	Kd	99.23	nM	CHEMBL5653589
6.99	ED50	103.2	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 27 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149802: Binding affinity to human YWHAH incubated for 45 mins by Kinobead based pull down assay	kd	0.0209	uM
(2S)-1-[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-carbamimidamido-2-[[(2S)-1-[(2S)-2-[[(2R)-2-[[(2S)-3-(1H-imidazol-5-yl)-2-[[(2S)-pyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-sulfanylpropanoyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]-4-carboxybutanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-4-methylsulfanylbutanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylpentanoyl]pyrrolidine-2-carboxylic acid	1304819: Binding affinity to GST-tagged 125I-labelled 14-3-3eta (unknown origin) expressed in Escherichia coli by solid phase assay	kd	0.0700	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149802: Binding affinity to human YWHAH incubated for 45 mins by Kinobead based pull down assay	kd	0.0992	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	3
bisphenol F	increases expression, affects cotreatment	2
bisphenol A	affects expression, decreases expression	2
sodium arsenite	decreases expression	2
Arsenic Trioxide	affects binding, decreases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	decreases expression	2
aristolochic acid I	increases expression	1
moringin	affects cotreatment, increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	affects expression	1
sodium bichromate	decreases expression	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
nickel sulfate	increases expression	1
cupric oxide	decreases expression	1
dibenzo(a,l)pyrene	decreases expression	1
phenethyl isothiocyanate	affects binding	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
27-hydroxycholesterol	decreases reaction, affects reaction, decreases expression, increases expression, increases activity (+2 more)	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3816075	Binding	Binding affinity to GST-tagged 125I-labelled 14-3-3eta (unknown origin) expressed in Escherichia coli by solid phase assay	Small molecules that target phosphorylation dependent protein-protein interaction. — Bioorg Med Chem

Clinical trials (associated diseases)

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