YWHAQ

Summary

YWHAQ (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta, HGNC:12854) is a protein-coding gene on chromosome 2p25.1, encoding 14-3-3 protein theta (P27348). 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 and rat orthologs. This gene is upregulated in patients with amyotrophic lateral sclerosis. It contains in its 5’ UTR a 6 bp tandem repeat sequence which is polymorphic, however, there is no correlation between the repeat number and the disease.

Source: NCBI Gene 10971 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 24 total
• Druggable target: yes
• MANE Select transcript: NM_006826

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12854
Approved symbol	YWHAQ
Name	tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta
Location	2p25.1
Locus type	gene with protein product
Status	Approved
Aliases	HS1, 14-3-3
Ensembl gene	ENSG00000134308
Ensembl biotype	protein_coding
OMIM	609009
Entrez	10971

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 11 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000238081, ENST00000381844, ENST00000446619, ENST00000460093, ENST00000474715, ENST00000862425, ENST00000862426, ENST00000862427, ENST00000862428, ENST00000862429, ENST00000862430, ENST00000932234, ENST00000961210

RefSeq mRNA: 1 — MANE Select: NM_006826 NM_006826

CCDS: CCDS1666

Canonical transcript exons

ENST00000238081 — 6 exons

Exon	Start	End
ENSE00001147659	9630159	9630534
ENSE00001266269	9630941	9630997
ENSE00003532945	9591392	9591515
ENSE00003593078	9588165	9588328
ENSE00003670741	9587414	9587509
ENSE00003842007	9583967	9585345

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 192.7421 / max 1551.1857, expressed in 1827 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26842	166.5015	1826
26838	20.8130	1789
26836	1.7536	941
26835	0.9666	515
26837	0.9091	559
26841	0.8050	530
26839	0.7659	451
26840	0.2275	81

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	99.95	gold quality
male germ cell	CL:0000015	99.93	gold quality
endothelial cell	CL:0000115	99.89	gold quality
pons	UBERON:0000988	99.84	gold quality
parotid gland	UBERON:0001831	99.84	gold quality
superior vestibular nucleus	UBERON:0007227	99.84	gold quality
inferior vagus X ganglion	UBERON:0005363	99.82	gold quality
secondary oocyte	CL:0000655	99.81	gold quality
tibia	UBERON:0000979	99.80	gold quality
penis	UBERON:0000989	99.80	gold quality
hair follicle	UBERON:0002073	99.80	gold quality
choroid plexus epithelium	UBERON:0003911	99.80	gold quality
dorsal root ganglion	UBERON:0000044	99.79	gold quality
trigeminal ganglion	UBERON:0001675	99.79	gold quality
medial globus pallidus	UBERON:0002477	99.78	gold quality
ventral tegmental area	UBERON:0002691	99.78	gold quality
orbitofrontal cortex	UBERON:0004167	99.78	gold quality
mammary duct	UBERON:0001765	99.76	gold quality
epithelium of mammary gland	UBERON:0003244	99.76	gold quality
globus pallidus	UBERON:0001875	99.75	gold quality
subthalamic nucleus	UBERON:0001906	99.75	gold quality
cerebellar vermis	UBERON:0004720	99.75	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.74	gold quality
synovial joint	UBERON:0002217	99.74	gold quality
tendon of biceps brachii	UBERON:0008188	99.74	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.73	gold quality
parietal lobe	UBERON:0001872	99.72	gold quality
visceral pleura	UBERON:0002401	99.72	gold quality
postcentral gyrus	UBERON:0002581	99.72	gold quality
type B pancreatic cell	CL:0000169	99.70	gold quality

Single-cell (SCXA)

Detected in 16 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	45.81
E-CURD-112	yes	42.93
E-HCAD-10	yes	35.26
E-CURD-46	yes	22.63
E-CURD-122	yes	22.38
E-MTAB-9067	yes	20.59
E-GEOD-84465	yes	10.39
E-MTAB-8498	yes	9.62
E-CURD-114	yes	7.75
E-CURD-88	yes	6.24
E-MTAB-6678	yes	4.71
E-MTAB-7051	no	2128.13
E-MTAB-7052	no	1761.32
E-HCAD-5	no	17.31
E-MTAB-8271	no	7.10

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, KAT7, PGR, TP53

miRNA regulators (miRDB)

182 targeting YWHAQ, 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-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6744-5P	99.93	66.82	748

Literature-anchored findings (GeneRIF, showing 40)

• Akt promotes cell-cycle progression through the mechanisms of phosphorylation-dependent 14-3-3 binding to p27(Kip1) and cytoplasmic localization. (PMID:12042314)
• Data show that the Yes-associated protein (YAP) associates with 14-3-3 in an Akt-dependent manner. (PMID:12535517)
• 14-3-3tau interacts with FSH receptor (PMID:15196694)
• In transgenic mice with cardiac specific overexpression of dominant negative 14-3-3 protein, 14-3-3 negatively regulates cardiac hypertrophy and fibrosis, possibly through controlling expression of protein kinase C beta 2 in the diabetic myocardium. (PMID:15930726)
• COPI and 14-3-3 specifically bind to the GB1 RSR sequence and that COPI is involved in its intracellular retention (PMID:16176975)
• The 14-3-3 protein forms molecular complex with Hsp60 and PrPC in human CNS under physiological conditions, and this complex might become disintegrated in pathologic process of prion diseases. (PMID:16215457)
• There is a direct functional role for the 14-3-3tau:Tir interaction in E.coli infection. (PMID:16367866)
• In summary, our results show a direct interaction between CPAP and 14-3-3, and this interaction appears to be phosphorylation and cell cycle dependent. (PMID:16516142)
• CSF 14-3-3 assay may represent a useful biologic marker in patients with Guillain-Barre syndrome. (PMID:17190946)
• Regulation of AS160 and interaction with 14-3-3 in skeletal muscle are influenced by resistance exercise and insulin but do not fully explain the effect of resistance exercise on whole-body insulin action. (PMID:17369524)
• ZNF198-FGFR1 activated prosurvival signaling pathways, resulting in elevated phosphorylation of FOXO3a. The phosphorylated residues subsequently sequestered the proapoptotic FOXO3a and BAD to 14-3-3 to prevent apoptosis (PMID:17389761)
• AS160 is a common target of insulin, IGF-1, EGF, PMA and AICAR, these stimuli induce distinctive patterns of phosphorylation and 14-3-3 binding, mediated by at least four protein kinases. (PMID:17617058)
• PKA-phosphorylated NoxA1 is a new binding partner of 14-3-3 protein; this forms the basis of a novel mechanism regulating the formation of ROS by Nox1 and, potentially, other NoxA1-regulated Nox family members (PMID:17913709)
• 14-3-3 proteins could play a role in consolidating and strengthening the effects of phosphorylation on TPH2 and that they may be important for the regulation of serotonin function in the nervous system (PMID:17973628)
• Significant autoantibody reactivity against 14-3-3 theta was also observed in a set consisting of 18 prediagnostic lung cancer sera. (PMID:18089831)
• activation of mTORC1 signalling by phorbol esters does not require PRAS40 to be phosphorylated at Thr(246), bind to 14-3-3 or be released from mTORC1. (PMID:18215133)
• Therefore, our results suggest that the interaction between Sirt2 and 14-3-3 beta/gamma is a novel mechanism for the negative regulation of p53 beside the well-characterized Mdm2-mediated repression. (PMID:18249187)
• the phosphorylation of beta2 integrins on Thr758 acts as a molecular switch to inhibit filamin binding and allow 14-3-3 protein binding to the integrin cytoplasmic domain, thereby modulating T-cell adhesion (PMID:18550856)
• These proteins are important diagnostic biomarkers for CJD, especially in patients with negative 14-3-3 protein findings. (PMID:18626620)
• 14-3-3 exerts combined effects on hMex-3B and acts as a major regulator of the sorting between distinct classes of RNA granules (PMID:18779327)
• Report the occurrence of autoantibodies to annexin I, 14-3-3 theta and LAMR1 in prediagnostic lung cancer sera. (PMID:18794547)
• Analysis of a series of HDAC4 mutants by nuclear import assay suggested that phosphorylation and subsequent 14-3-3 binding reduce nuclear import rather than enhancing nuclear export. (PMID:18952052)
• 14-3-3 protein, together with amino- and carboxyl-terminal sorting signals, control the intracellular traffic of TWIK-related acid-sensitive K+ channel protein (TASK)-1 and TASK-3. (PMID:19139046)
• changes in the expression of five 14-3-3 isoforms (beta, gamma, epsilon, tau, and zeta) during the apoptosis of JURL-MK1 and K562 cells. (PMID:19173300)
• The model of the complex suggests that the forkhead domain of FOXO4 is docked within the central channel of the 14-3-3 protein dimer, consistent with the hypothesis that 14-3-3 masks the DNA binding interface of FOXO4. (PMID:19416966)
• 3CTS contact targeting sequence is involved in the modulation of translocation via its 14-3-3-binding site, in cytoplasmic desequestration via the alpha-helix, and in selective PKCepsilon targeting at the cell-cell contact via Glu-374 (PMID:19429675)
• 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)
• Interaction of Akt-phosphorylated SRPK2 with 14-3-3 mediates cell cycle and cell death in neurons. (PMID:19592491)
• analysis of the interaction between 14-3-3 proteins, the N-terminal region of tyrosine hydroxylase, and negatively charged membranes (PMID:19801645)
• IRSp53 binds to 14-3-3 after phosphorylation in a region that lies between the CRIB and SH3 domains (PMID:19933840)
• Upstream signals couple ASK2 S964 phosphorylation to the ASK1 signalosome through dual engagement of 14-3-3. (PMID:19935702)
• Our findings define genetic markers in 14-3-3tau and CD44 that might improve the treatment and prognosis of soft-tissue sarcomas. (PMID:19996285)
• RASSF1A-mediated cell death is, therefore, tightly controlled by 14-3-3 association. (PMID:20069457)
• The findings of this studies strongly suggest a novel oncogenic role of 14-3-3tau by downregulating p21 in breast cancer. (PMID:20086099)
• Data show that distinct phosphatases dephosphorylate conserved AKT motifs within the FOXO family and that PP2A is entwined in a dynamic interplay with AKT and 14-3-3 to directly regulate FOXO3a subcellular localization and transcriptional activation. (PMID:20110348)
• The PX-RICS-14-3-3zeta/theta complex couples N-cadherin-beta-catenin with dynein-dynactin to mediate its export from the endoplasmic reticulum. (PMID:20308060)
• The 14-3-3 epsilon, zeta and theta may be involved in tumorigenesis of meningioma and be efficient markers for predicting the degree of malignancy in meningioma. (PMID:20388496)
• Data suggest that 14-3-3 serves as a global inhibitor of centralspindlin that allows Aurora B to locally activate clustering and the stable accumulation of centralspindlin between segregating chromosomes. (PMID:20451386)
• novel role for 14-3-3tau in the regulation of Beclin 1 expression and autophagy (PMID:20454448)
• Findings suggest that modulating the C-RAFSer(259)/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for treatment of diseases resulting from an overactive Ras-RAF-MAPK pathway. (PMID:20679480)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ywhaqb	ENSDARG00000023323
danio_rerio	ywhaqa	ENSDARG00000042539
drosophila_melanogaster	14-3-3zeta	FBGN0004907
caenorhabditis_elegans		WBGENE00001502
caenorhabditis_elegans		WBGENE00003920

Paralogs (6): YWHAE (ENSG00000108953), YWHAH (ENSG00000128245), YWHAZ (ENSG00000164924), YWHAB (ENSG00000166913), YWHAG (ENSG00000170027), SFN (ENSG00000175793)

Protein

Protein identifiers

14-3-3 protein theta — P27348 (reviewed: P27348)

Alternative names: 14-3-3 protein T-cell, 14-3-3 protein tau, Protein HS1

All UniProt accessions (2): E9PG15, P27348

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 CDK16. Interacts with RGS7 (phosphorylated form). Interacts with SSH1. Interacts with CDKN1B (‘Thr-198’ phosphorylated form); the interaction translocates CDKN1B to the cytoplasm. Interacts with GAB2. 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 RIPOR2 isoform 2. Interacts with INAVA; the interaction increases upon PRR (pattern recognition receptor) stimulation and is required for cellular signaling pathway activation and cytokine secretion. Interacts with MARK2, MARK3 and MARK4. Interacts with MEFV.

Subcellular location. Cytoplasm.

Tissue specificity. Abundantly expressed in brain, heart and pancreas, and at lower levels in kidney and placenta. Up-regulated in the lumbar spinal cord from patients with sporadic amyotrophic lateral sclerosis (ALS) compared with controls, with highest levels of expression in individuals with predominant lower motor neuron involvement.

Post-translational modifications. Ser-232 is probably phosphorylated by CK1.

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

RefSeq proteins (1): NP_006817* (*=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
IPR042584	14-3-3_theta	Family

Pfam: PF00244

UniProt features (25 total): helix 11, modified residue 9, site 2, chain 1, cross-link 1, sequence conflict 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6BCR	X-RAY DIFFRACTION	1.99
6KZG	X-RAY DIFFRACTION	2
6BCY	X-RAY DIFFRACTION	2.3
6BD1	X-RAY DIFFRACTION	2.35
5IQP	X-RAY DIFFRACTION	2.6
6KZH	X-RAY DIFFRACTION	2.65
2BTP	X-RAY DIFFRACTION	2.8
6BQT	X-RAY DIFFRACTION	2.8
6BD2	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P27348-F1	93.95	0.89

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): 56 (interaction with phosphoserine on interacting protein); 127 (interaction with phosphoserine on interacting protein)

Post-translational modifications (10): 115, 232, 49, 1, 3, 49, 68, 82, 92, 104

Function

Pathways and Gene Ontology

Reactome pathways

35 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-9614399	Regulation of localization of FOXO transcription factors
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-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-114452	Activation of BH3-only proteins
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-9614085	FOXO-mediated transcription
R-HSA-9678108	SARS-CoV-1 Infection
R-HSA-9679506	SARS-CoV Infections

MSigDB gene sets: 387 (showing top): CREL_01, E2F_Q4_01, GOBP_NEGATIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, chr2p25, FAELT_B_CLL_WITH_VH_REARRANGEMENTS_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, RORA1_01, AAGTCCA_MIR422B_MIR422A, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, MORF_UBE2I, MORF_HDAC1, GOBP_PROTEIN_TARGETING, MORF_RAD21, MORF_CDK2

GO Biological Process (7): protein targeting (GO:0006605), signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264), intracellular protein localization (GO:0008104), substantia nigra development (GO:0021762), negative regulation of monoatomic ion transmembrane transport (GO:0034766), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (5): protein domain specific binding (GO:0019904), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), 14-3-3 protein binding (GO:0071889), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), focal adhesion (GO:0005925), membrane (GO:0016020), protein-containing complex (GO:0032991), synapse (GO:0045202), extracellular exosome (GO:0070062)

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
FOXO-mediated transcription	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	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
establishment of protein localization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
macromolecule localization	1
midbrain development	1
neural nucleus development	1
monoatomic ion transmembrane transport	1
negative regulation of transmembrane transport	1
regulation of monoatomic ion transmembrane transport	1
negative regulation of monoatomic ion transport	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
cell-substrate junction	1
cellular_component	1
cell junction	1
extracellular vesicle	1

Protein interactions and networks

STRING

5048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
YWHAQ	MAPT	P10636	903
YWHAQ	YWHAE	P29360	801
YWHAQ	LRP8	Q14114	800
YWHAQ	VLDLR	P98155	788
YWHAQ	APP	P05067	784
YWHAQ	CDC25C	P30307	741
YWHAQ	SNCA	P37840	731
YWHAQ	RELN	P78509	706
YWHAQ	TXNDC9	O14530	697
YWHAQ	BRAF	P15056	686
YWHAQ	TARDBP	Q13148	684
YWHAQ	CDK1	P06493	682
YWHAQ	GSK3B	P49841	669
YWHAQ	APOE	P02649	662
YWHAQ	HSP90AA1	P07900	660

IntAct

606 interactions, top by confidence:

A	B	Type	Score
BRAF	HRAS	psi-mi:“MI:0914”(association)	0.940
YWHAE	YWHAQ	psi-mi:“MI:0407”(direct interaction)	0.920
PTPN3	YWHAQ	psi-mi:“MI:2364”(proximity)	0.850
YWHAB	YWHAQ	psi-mi:“MI:0407”(direct interaction)	0.850
YWHAQ	YWHAG	psi-mi:“MI:0407”(direct interaction)	0.850
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
EGFR	YWHAQ	psi-mi:“MI:0915”(physical association)	0.850
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
ARL3	UNC119B	psi-mi:“MI:0914”(association)	0.730
YWHAQ	CDK14	psi-mi:“MI:0915”(physical association)	0.720
CDK14	YWHAQ	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
TRIM42	YWHAQ	psi-mi:“MI:0915”(physical association)	0.670
YWHAQ	TRIM42	psi-mi:“MI:0915”(physical association)	0.670
PTPN3	MCC	psi-mi:“MI:0914”(association)	0.660
tir	YWHAQ	psi-mi:“MI:0915”(physical association)	0.660
tir	YWHAQ	psi-mi:“MI:0407”(direct interaction)	0.660
tir	KRT18	psi-mi:“MI:0914”(association)	0.660
YWHAQ	tir	psi-mi:“MI:0403”(colocalization)	0.660
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
CDC25A	YWHAQ	psi-mi:“MI:2364”(proximity)	0.570
YWHAQ	YWHAQ	psi-mi:“MI:0407”(direct interaction)	0.560

BioGRID (1950): YWHAQ (Affinity Capture-Western), YWHAQ (Affinity Capture-Western), SGK1 (Affinity Capture-Western), MAPT (Affinity Capture-Western), YWHAQ (Affinity Capture-MS), YWHAQ (Affinity Capture-Western), PIK3C3 (Reconstituted Complex), RAF1 (Reconstituted Complex), PIK3R2 (Reconstituted Complex), YWHAQ (Affinity Capture-Western), PIK3R2 (Affinity Capture-Western), YWHAQ (Two-hybrid), YWHAQ (Affinity Capture-Western), DTL (Affinity Capture-Western), YWHAQ (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

10 interactions.

A	Effect	B	Mechanism
YWHAQ	up-regulates	MEF2D	binding
YWHAQ	down-regulates	CDC25C	relocalization
YWHAQ	“down-regulates activity”	NEFL	binding
CSNK2A1	“down-regulates activity”	YWHAQ	phosphorylation
YWHAQ	down-regulates	CDKN1B	binding
BCR	unknown	YWHAQ	phosphorylation
CSNK1A1	“down-regulates activity”	YWHAQ	phosphorylation
YWHAQ	“up-regulates quantity by stabilization”	GEM	binding
YWHAQ	down-regulates	PRKD1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 188 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	7	38.9×	1e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	34.3×	1e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	29.4×	1e-06
Activation of BH3-only proteins	7	25.4×	4e-07
Signaling by RAS mutants	7	21.6×	1e-06
Signaling by high-kinase activity BRAF mutants	9	20.8×	1e-07
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	5	18.9×	1e-04
MAP2K and MAPK activation	9	18.8×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	5	23.4×	4e-04
positive regulation of fibroblast proliferation	9	16.2×	3e-06
regulation of alternative mRNA splicing, via spliceosome	9	13.4×	1e-05
MAPK cascade	13	12.1×	7e-08
intrinsic apoptotic signaling pathway	5	10.9×	7e-03
negative regulation of protein ubiquitination	6	10.4×	4e-03
Ras protein signal transduction	7	8.8×	3e-03
microtubule cytoskeleton organization	10	7.4×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1031 predictions. Top by Δscore:

Variant	Effect	Δscore
2:9585341:CAAAG:C	acceptor_gain	1.0000
2:9585342:AAAG:A	acceptor_gain	1.0000
2:9585343:AAG:A	acceptor_gain	1.0000
2:9585344:AG:A	acceptor_gain	1.0000
2:9585344:AGCTA:A	acceptor_loss	1.0000
2:9585346:C:CC	acceptor_gain	1.0000
2:9585346:CTAGA:C	acceptor_loss	1.0000
2:9587406:CAACT:C	donor_loss	1.0000
2:9587407:AACTC:A	donor_loss	1.0000
2:9587408:ACTCA:A	donor_loss	1.0000
2:9587410:TCA:T	donor_loss	1.0000
2:9587411:CACTG:C	donor_loss	1.0000
2:9587412:A:AC	donor_gain	1.0000
2:9587412:AC:A	donor_loss	1.0000
2:9587413:C:A	donor_loss	1.0000
2:9587413:C:CA	donor_gain	1.0000
2:9587413:CT:C	donor_gain	1.0000
2:9587413:CTG:C	donor_gain	1.0000
2:9587413:CTGTT:C	donor_gain	1.0000
2:9587510:C:CC	acceptor_gain	1.0000
2:9587510:CTGAT:C	acceptor_loss	1.0000
2:9588324:CGTTT:C	acceptor_gain	1.0000
2:9588329:C:CC	acceptor_gain	1.0000
2:9588339:C:CT	acceptor_gain	1.0000
2:9591387:CTTAC:C	donor_loss	1.0000
2:9591388:TTAC:T	donor_loss	1.0000
2:9591389:TA:T	donor_loss	1.0000
2:9591390:A:AC	donor_gain	1.0000
2:9591390:ACG:A	donor_loss	1.0000
2:9591391:C:CG	donor_gain	1.0000

AlphaMissense

1616 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:9585340:C:A	W228C	1.000
2:9585340:C:G	W228C	1.000
2:9585342:A:G	W228R	1.000
2:9585342:A:T	W228R	1.000
2:9585344:A:G	L227P	1.000
2:9585344:A:T	L227H	1.000
2:9587418:A:G	L225P	1.000
2:9587420:G:C	N224K	1.000
2:9587420:G:T	N224K	1.000
2:9587421:T:A	N224I	1.000
2:9587422:T:C	N224D	1.000
2:9587423:G:C	D223E	1.000
2:9587423:G:T	D223E	1.000
2:9587424:T:A	D223V	1.000
2:9587424:T:C	D223G	1.000
2:9587424:T:G	D223A	1.000
2:9587425:C:A	D223Y	1.000
2:9587425:C:G	D223H	1.000
2:9587425:C:T	D223N	1.000
2:9587426:T:A	R222S	1.000
2:9587426:T:G	R222S	1.000
2:9587427:C:A	R222I	1.000
2:9587427:C:G	R222T	1.000
2:9587430:A:G	L221P	1.000
2:9587430:A:T	L221H	1.000
2:9587431:G:A	L221F	1.000
2:9587433:A:C	L220W	1.000
2:9587433:A:G	L220S	1.000
2:9587435:C:A	Q219H	1.000
2:9587435:C:G	Q219H	1.000

dbSNP variants (sampled 300 via entrez): RS1000032984 (2:9603085 A>G), RS1000070568 (2:9605368 C>A), RS1000114407 (2:9623491 C>T), RS1000156104 (2:9608691 G>A), RS1000176511 (2:9591229 A>G), RS1000181487 (2:9617239 G>C), RS1000270230 (2:9599727 T>C), RS1000301272 (2:9599970 A>T), RS1000314017 (2:9591103 TA>T), RS1000322524 (2:9587837 G>A), RS1000406998 (2:9602688 C>G,T), RS1000526470 (2:9605227 T>G), RS1000550140 (2:9620228 G>A), RS1000563879 (2:9619951 C>T), RS1000606168 (2:9588248 G>A)

Disease associations

OMIM: gene MIM:609009 | 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
GCST001354_1	Heart rate variability traits	8.000000e-07
GCST003808_2	Non-response to selective serotonin reuptake inhibitors and depression	7.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005658	response to selective serotonin reuptake inhibitor

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3710408 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.70	Kd	20.15	nM	CHEMBL3752910
7.68	ED50	21.11	nM	CHEMBL3752910
7.16	Kd	70	nM	CHEMBL3814675
5.89	Kd	1288	nM	CHEMBL5653589
5.87	ED50	1349	nM	CHEMBL5653589

PubChem BioAssay actives

3 with measured affinity, of 6 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	2149803: Binding affinity to human YWHAQ incubated for 45 mins by Kinobead based pull down assay	kd	0.0202	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	1304818: Binding affinity to GST-tagged 125I-labelled full length human 14-3-3tau 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	2149803: Binding affinity to human YWHAQ incubated for 45 mins by Kinobead based pull down assay	kd	1.2877	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression	2
Air Pollutants	decreases expression, affects expression, increases abundance	2
Ozone	affects expression, increases abundance, affects cotreatment, increases oxidation	2
Valproic Acid	affects cotreatment, increases expression, decreases methylation	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
indole-3-carbinol	decreases phosphorylation	1
sulforaphane	affects binding	1
sodium arsenite	affects binding, decreases reaction	1
triphenyltin	decreases expression	1
AICA ribonucleotide	affects binding, increases reaction	1
1-aminomethylphosphonic acid	decreases expression	1
methacrylaldehyde	increases oxidation, affects cotreatment	1
evodiamine	increases expression	1
phenethyl isothiocyanate	affects binding	1
tributyltinisothiocyanate	decreases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects binding, decreases reaction, increases reaction	1
chloropicrin	decreases expression	1
calfactant	affects cotreatment, increases expression	1
K 7174	decreases expression	1
poly(propyleneimine)	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
bromovanin	increases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3816074	Binding	Binding affinity to GST-tagged 125I-labelled full length human 14-3-3tau expressed in Escherichia coli by solid phase assay	Small molecules that target phosphorylation dependent protein-protein interaction. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B9UH	Abcam A-549 YWHAQ KO	Cancer cell line	Male
CVCL_E0T8	Ubigene HeLa YWHAQ KO	Cancer cell line	Female

Clinical trials (associated diseases)

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