YWHAZ

Summary

YWHAZ (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta, HGNC:12855) is a protein-coding gene on chromosome 8q22.3, encoding 14-3-3 protein zeta/delta (P63104). Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. It is a selective cancer dependency (DepMap: 75.1% of cell lines).

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 sheep orthologs. The encoded protein interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. Several transcript variants that differ in the 5’ UTR but that encode the same protein have been identified for this gene.

Source: NCBI Gene 7534 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Moderate, ClinGen) — +1 more curated relationship
• GWAS associations: 8
• Clinical variants (ClinVar): 69 total — 6 pathogenic, 2 likely-pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 75.1% of screened cell lines
• MANE Select transcript: NM_145690

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12855
Approved symbol	YWHAZ
Name	tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta
Location	8q22.3
Locus type	gene with protein product
Status	Approved
Aliases	KCIP-1, 14-3-3-zeta
Ensembl gene	ENSG00000164924
Ensembl biotype	protein_coding
OMIM	601288
Entrez	7534

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 26 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000353245, ENST00000395948, ENST00000395951, ENST00000395953, ENST00000395956, ENST00000395957, ENST00000395958, ENST00000418997, ENST00000419477, ENST00000437293, ENST00000457309, ENST00000480304, ENST00000492736, ENST00000517727, ENST00000518736, ENST00000521309, ENST00000521328, ENST00000521607, ENST00000522542, ENST00000522819, ENST00000523131, ENST00000523848, ENST00000523938, ENST00000908384, ENST00000908385, ENST00000908386, ENST00000908387, ENST00000908388, ENST00000936696, ENST00000936697, ENST00000936698

RefSeq mRNA: 6 — MANE Select: NM_145690 NM_001135699, NM_001135700, NM_001135701, NM_001135702, NM_003406, NM_145690

CCDS: CCDS6290

Canonical transcript exons

ENST00000395958 — 6 exons

Exon	Start	End
ENSE00001523393	100951929	100952020
ENSE00003466350	100924916	100925039
ENSE00003476883	100924135	100924298
ENSE00003739644	100916523	100920752
ENSE00003798443	100948596	100948900
ENSE00003889759	100923955	100924050

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.78.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 357.7658 / max 4742.1963, expressed in 1828 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
94195	106.5228	1824
94194	87.0047	1819
94196	60.1317	1815
94207	41.7668	1780
94205	25.3535	1786
94203	6.6182	1605
94204	5.8622	1603
94202	5.3427	1272
94192	4.3496	1403
94190	2.6113	1390

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	99.78	gold quality
cortical plate	UBERON:0005343	99.77	gold quality
tongue squamous epithelium	UBERON:0006919	99.76	gold quality
esophagus squamous epithelium	UBERON:0006920	99.76	gold quality
gingiva	UBERON:0001828	99.75	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.73	gold quality
squamous epithelium	UBERON:0006914	99.71	gold quality
ganglionic eminence	UBERON:0004023	99.68	gold quality
amniotic fluid	UBERON:0000173	99.67	gold quality
epithelium of esophagus	UBERON:0001976	99.65	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.64	gold quality
penis	UBERON:0000989	99.62	gold quality
prefrontal cortex	UBERON:0000451	99.60	gold quality
oral cavity	UBERON:0000167	99.57	gold quality
colonic mucosa	UBERON:0000317	99.57	gold quality
ventricular zone	UBERON:0003053	99.57	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.55	gold quality
esophagus mucosa	UBERON:0002469	99.54	gold quality
pharyngeal mucosa	UBERON:0000355	99.53	gold quality
hair follicle	UBERON:0002073	99.53	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.52	gold quality
islet of Langerhans	UBERON:0000006	99.51	gold quality
epithelium of nasopharynx	UBERON:0001951	99.51	gold quality
superior frontal gyrus	UBERON:0002661	99.51	gold quality
mammalian vulva	UBERON:0000997	99.50	gold quality
Brodmann (1909) area 9	UBERON:0013540	99.50	gold quality
lower esophagus mucosa	UBERON:0035834	99.50	gold quality
rectum	UBERON:0001052	99.48	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.48	gold quality
monocyte	CL:0000576	99.47	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	1744.07
E-HCAD-35	yes	40.00
E-CURD-122	yes	22.78
E-GEOD-135922	yes	22.31
E-HCAD-10	yes	16.03
E-MTAB-10042	yes	11.15
E-ENAD-20	no	2210.45
E-MTAB-8060	no	1335.79
E-MTAB-8559	no	973.83
E-GEOD-125970	no	7.44
E-GEOD-130148	no	3.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPG

miRNA regulators (miRDB)

158 targeting YWHAZ, 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-6740-5P	100.00	65.64	932
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 75.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Alpha-synuclein, a small presynaptic protein implicated in Parkinson’s disease and other neurodegenerative disorders, interacts with 14-3-3 and both proteins appear to differentially regulate the activities of important cellular enzymes. (PMID:10407019)
• Identification of 14-3-3zeta as a protein kinase B/Akt substrate. (PMID:11956222)
• 14-3-3 zeta binds with tuberin to regulate phosphorylation of ribosomal protein S6 (PMID:12176984)
• binds cofilin and LIM-domain-containing protein kinase 1 (PMID:12323073)
• TSC2 associates with 14-3-3 in vivo (PMID:12364343)
• role for the 14-3-3zeta/ADAM 22 association in the regulation of cell adhesion and related signaling events (PMID:12589811)
• 14-3-3zeta has a role in MAPKAPK2-mediated phosphorylation, which may represent a novel pathway mediating p38 MAPK-dependent inflammation (PMID:12861023)
• In the presence of 14-3-3, the requirement of two phosphorylated 14-3-3 zeta binding motifs for the complete inhibition of FOXO4 binding to its target DNA is demonstrated. (PMID:14690436)
• Zeta 14-3-3 protein facilitates tau assembly into fibrillar polymers, with polymerization reduced but not abolished, when tau is modified by protein kinase A. (PMID:15036595)
• 14-3-3zeta is a specific substrate for YSK1 that localizes to the Golgi apparatus, and potentially links YSK1 signaling at the Golgi apparatus with protein transport. (PMID:15037601)
• existence of a second major 14-3-3zeta binding site within the cytoplasmic tail of GPIbalpha that has an important functional role in regulating integrin-dependent cell spreading. (PMID:15054037)
• within the tau phosphorylation complex, 14-3-3 connects Ser(9)-phosphorylated GSK3beta to tau and Ser(9)-phosphorylated GSK3beta phosphorylates tau (PMID:15073173)
• EGF-induced co-localization of mouse EGFR and human 14-3-3zeta along the plasma membrane. (PMID:15225635)
• a 14-3-3 zeta implication in the Alzheimer’s neuropathology (PMID:15234461)
• FRET analysis of 14-3-3 protein C-terminal stretch (PMID:15347690)
• YWHAZ gene is a susceptibility gene for paranoid schizophrenia (PMID:15363479)
• Vpr interferes with the suppressive effects of insulin on FOXO-mediated transcription of target genes via 14-3-3. (14-3-3 Protein) (PMID:15616007)
• binding of 14-3-3 to Par3beta is dependent on phosphorylation (PMID:15721295)
• 14-3-3 binds to protein C-terminal domains (PMID:16123035)
• Our data demonstrate that 14-3-3zeta mediates tau phosphorylation by Ser9-phosphorylated GSK3beta in HEK-293 cells. (PMID:17317006)
• Knockdown of 14-3-3 zeta induces at least two isoform-specific phenotypes that are consistent with potential oncogenic activity during tumorigenesis. (PMID:17704798)
• findings suggest that over-expression of 14-3-3zeta is an early event in oral tumorigenesis and may have an important role in its development and progression (PMID:17764575)
• 14-3-3zeta is a granule protein related to atherosclerosis (PMID:17918986)
• Our data support a novel role for 14-3-3zeta in the aggregate formation of nonnative, aggregation-prone proteins. (PMID:18078716)
• 14-3-3zeta has a critical role in anoikis suppression in lung cancer cells (PMID:18162532)
• 14-3-3 zeta protein and butyrylcholinesterase (BCHE) synergistic effects between polymorphisms in tau phosphorylation relate-genes may help in determining the risk profile for AD. (PMID:18290843)
• combined gene effects between 14-3-3 zeta (intron 4, rs 983583) polymorphism and tau (intron 9, rs 2471738) polymorphism might be responsible for susceptibility to Alzheimer disease (PMID:18319590)
• PKC delta in preeclamptic placentas promotes Bax dissociation from 14-3-3 zeta through 14-3-3 zeta phosphorylation. (PMID:18472156)
• structure & properties of wild type 14-3-3zeta & point mutants S58E, S184E, T232E & mutant S58E/S184E/T232E mimicking phosphorylation; mutation mimicking phosphorylation of Ser58 destabilized & mutation of Ser184 induced stabilization of 14-3-3zeta (PMID:18559254)
• 14-3-3epsilon and 14-3-3zeta are identified as Cby-binding partners. (PMID:18573912)
• Immunofluorescent staining for 14-3-3 zeta demonstrated expression of the protein on ascitic and peritumoral macrophages in epithelial ovarian carcinoma patients (PMID:18618111)
• This protein has been found differentially expressed in the temporal lobe from patients with schizophrenia. (PMID:19034380)
• study presents the cellular translocation of 14-3-3 zeta in JC virus(JCV) nonsusceptible progenitors and JCV-susceptible progenitor-derived astrocytes; results suggest that the nuclear presence of 14-3-3 zeta may play a role in JCV infection (PMID:19062179)
• Phosphorylation by cAMP-dependent protein kinase strongly enhanced interaction of tau3 with 14-3-3. (PMID:19138662)
• 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 authors report that phosphorylation leads to the unfolding of the structurally atypical and unstable KH1, creating a site for 14-3-3zeta binding. (PMID:19198587)
• 14-3-3z:Shc scaffolds can act as multivalent signaling nodes for the integration of both phosphoserine/threonine and phosphotyrosine pathways to regulate specific cellular responses. (PMID:19218246)
• These results implicate 14-3-3zeta/tau heterodimers as key regulators of SSH1 activity in keratinocytes and suggest they play a role in cytoskeleton remodeling during cell migration. (PMID:19371722)
• An integrin-alpha4-14-3-3zeta-paxillin ternary complex mediates localised Cdc42 activity and accelerates cell migration. (PMID:19401330)
• 14-3-3zeta mediates resistance of diffuse large B cell lymphoma to an anthracycline-based chemotherapeutic regimen (PMID:19525224)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ywhaz	ENSMUSG00000022285
rattus_norvegicus	Ywhaz	ENSRNOG00000008195
drosophila_melanogaster	14-3-3zeta	FBGN0004907
caenorhabditis_elegans		WBGENE00001502
caenorhabditis_elegans		WBGENE00003920

Paralogs (6): YWHAE (ENSG00000108953), YWHAH (ENSG00000128245), YWHAQ (ENSG00000134308), YWHAB (ENSG00000166913), YWHAG (ENSG00000170027), SFN (ENSG00000175793)

Protein

Protein identifiers

14-3-3 protein zeta/delta — P63104 (reviewed: P63104)

Alternative names: Protein kinase C inhibitor protein 1

All UniProt accessions (11): B0AZS6, B7Z2E6, D0PNI1, E5RGE1, E5RIR4, E7ESK7, E7EVZ2, E7EX29, E9PD24, P63104, H0YB80

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. Promotes cytosolic retention and inactivation of TFEB transcription factor by binding to phosphorylated TFEB. Induces ARHGEF7 activity on RAC1 as well as lamellipodia and membrane ruffle formation. In neurons, regulates spine maturation through the modulation of ARHGEF7 activity.

Subunit / interactions. Interacts with CDK16 and BSPRY. Interacts with WEE1 (C-terminal). Interacts with SAMSN1. Interacts with MLF1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with Thr-phosphorylated ITGB2. Interacts with BCL2L11. Homodimer. Heterodimerizes with YWHAE. Homo- and heterodimerization is inhibited by phosphorylation on Ser-58. Interacts with FOXO4, NOXA1, SSH1 and ARHGEF2. Interacts with Pseudomonas aeruginosa exoS (unphosphorylated form). Interacts with BAX; the interaction occurs in the cytoplasm. Under stress conditions, MAPK8-mediated phosphorylation releases BAX to mitochondria. Interacts with phosphorylated RAF1; the interaction is inhibited when YWHAZ is phosphorylated on Thr-232. Interacts with BRAF. Interacts with TP53; the interaction enhances p53 transcriptional activity. The Ser-58 phosphorylated form inhibits this interaction and p53 transcriptional activity. Interacts with ABL1 (phosphorylated form); the interaction retains ABL1 in the cytoplasm. Interacts with PKA-phosphorylated AANAT; the interaction modulates AANAT enzymatic activity by increasing affinity for arylalkylamines and acetyl-CoA and protecting the enzyme from dephosphorylation and proteasomal degradation. It may also prevent thiol-dependent inactivation. Interacts with AKT1; the interaction phosphorylates YWHAZ and modulates dimerization. Interacts with GAB2 and TLK2. Interacts with the ‘Thr-369’ phosphorylated form of DAPK2. Interacts with PI4KB, TBC1D22A and TBC1D22B. Interacts with ZFP36L1 (via phosphorylated form); this interaction occurs in a p38 MAPK- and AKT-signaling pathways. Interacts with SLITRK1. Interacts with AK5, LDB1, MADD, MARK3, PDE1A and SMARCB1. Interacts with MEFV. Interacts with ADAM22 (via C-terminus). (Microbial infection) Interacts with Epstein-Barr virus protein BPLF1 and TRIM25; leading to inhibition of the type-I IFN response.

Subcellular location. Cytoplasm. Melanosome.

Post-translational modifications. The delta, brain-specific form differs from the zeta form in being phosphorylated. Phosphorylation on Ser-184 by MAPK8; promotes dissociation of BAX and translocation of BAX to mitochondria. Phosphorylation on Thr-232; inhibits binding of RAF1. Phosphorylated on Ser-58 by PKA and protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion. Phosphorylation on Ser-58 by PKA; disrupts homodimerization and heterodimerization with YHAE and TP53.

Disease relevance. Popov-Chang syndrome (POPCHAS) [MIM:618428] An autosomal dominant disorder characterized by global developmental delay, impaired intellectual development, poor or absent speech, facial dysmorphism, and behavioral manifestations including autistic-like behavior, self-injurious behavior, fear of social interaction, and poor concentration. Additional features are highly variable and can include seizures, short stature, feeding difficulties, and skin abnormalities. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P63104-1	1	yes
P63104-2	2

RefSeq proteins (6): NP_001129171, NP_001129172, NP_001129173, NP_001129174, NP_003397, NP_663723* (*=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 (38 total): helix 11, modified residue 8, mutagenesis site 6, sequence variant 5, site 2, sequence conflict 2, turn 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

77 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2O02	X-RAY DIFFRACTION	1.5
6F09	X-RAY DIFFRACTION	1.59
7ZIT	X-RAY DIFFRACTION	1.79
9UJ2	X-RAY DIFFRACTION	1.8
6ZFG	X-RAY DIFFRACTION	1.85
6F08	X-RAY DIFFRACTION	1.9
6ZFD	X-RAY DIFFRACTION	1.9
4FJ3	X-RAY DIFFRACTION	1.95
5EXA	X-RAY DIFFRACTION	1.95
8P1H	X-RAY DIFFRACTION	1.95
8A9G	X-RAY DIFFRACTION	1.96
1QJA	X-RAY DIFFRACTION	2
1QJB	X-RAY DIFFRACTION	2
2C1N	X-RAY DIFFRACTION	2
7D8P	X-RAY DIFFRACTION	2
6YMO	X-RAY DIFFRACTION	2.02
5NAS	X-RAY DIFFRACTION	2.08
9FVL	X-RAY DIFFRACTION	2.08
6YO8	X-RAY DIFFRACTION	2.09
5D2D	X-RAY DIFFRACTION	2.1
8WE2	X-RAY DIFFRACTION	2.11
6FNA	X-RAY DIFFRACTION	2.12
6FNC	X-RAY DIFFRACTION	2.12
5ULO	X-RAY DIFFRACTION	2.14
4N7Y	X-RAY DIFFRACTION	2.16
4HKC	X-RAY DIFFRACTION	2.2
4IHL	X-RAY DIFFRACTION	2.2
7D9V	X-RAY DIFFRACTION	2.21
2WH0	X-RAY DIFFRACTION	2.25
4N7G	X-RAY DIFFRACTION	2.25

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P63104-F1	94.42	0.90

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 (8): 232, 1, 3, 58, 68, 184, 207, 210

Mutagenesis-validated functional residues (6):

Position	Phenotype
49	loss of interaction with noxa1.
56–60	abolishes lamellipodia formation and induces filopodia formation.
58	loss of sphingosine-activated pka phosphorylation. promotes homodimerization and heterodimerization with ywhae. enhanced
58	loss of homodimerization. reduced dimerization with ywhae. significantly reduced interaction with p53. no enhancement of
184	on dna damage, loss of mapk8-mediated phosphorylation. loss of binding abl1. attenuates abl1-mediated apoptosis. no loss
232	loss of phosphorylation by ck1.

Function

Pathways and Gene Ontology

Reactome pathways

57 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-3769402	Deactivation of the beta-catenin transactivating complex
R-HSA-392517	Rap1 signalling
R-HSA-430116	GP1b-IX-V activation signalling
R-HSA-450604	KSRP (KHSRP) binds and destabilizes mRNA
R-HSA-512988	Interleukin-3, Interleukin-5 and GM-CSF signaling
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-9013700	NOTCH4 Activation and Transmission of Signal to the Nucleus
R-HSA-9604323	Negative regulation of NOTCH4 signaling
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-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity
R-HSA-109581	Apoptosis
R-HSA-109582	Hemostasis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-114452	Activation of BH3-only proteins
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors

MSigDB gene sets: 526 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_NK_CELL_VS_BCELL_UP, ATF_B, AGGAAGC_MIR5163P, CREL_01, REACTOME_SIGNALING_BY_NOTCH, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_NEURON_RECOGNITION, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, PAX4_01, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, KAAB_FAILED_HEART_ATRIUM_DN

GO Biological Process (27): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), respiratory system process (GO:0003016), protein phosphorylation (GO:0006468), protein targeting (GO:0006605), signal transduction (GO:0007165), synaptic target recognition (GO:0008039), intracellular protein localization (GO:0008104), lung development (GO:0030324), regulation of protein stability (GO:0031647), tube formation (GO:0035148), cellular response to glucose starvation (GO:0042149), negative regulation of apoptotic process (GO:0043066), negative regulation of innate immune response (GO:0045824), establishment of Golgi localization (GO:0051683), ERK1 and ERK2 cascade (GO:0070371), regulation of ERK1 and ERK2 cascade (GO:0070372), regulation of synapse maturation (GO:0090128), Golgi reassembly (GO:0090168), negative regulation of protein localization to nucleus (GO:1900181), negative regulation of TORC1 signaling (GO:1904262), lysosome organization (GO:0007040), cellular response to nutrient levels (GO:0031669), TORC1 signaling (GO:0038202), regulation of programmed cell death (GO:0043067), antibacterial innate immune response (GO:0140367), regulation of lysosome organization (GO:1905671)

GO Molecular Function (14): RNA binding (GO:0003723), protein kinase binding (GO:0019901), protein phosphatase binding (GO:0019903), protein domain specific binding (GO:0019904), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), transmembrane transporter binding (GO:0044325), cadherin binding (GO:0045296), phosphoserine residue binding (GO:0050815), DNA-binding transcription factor binding (GO:0140297), protein sequestering activity (GO:0140311), monooxygenase activity (GO:0004497), protein binding (GO:0005515), kinase activity (GO:0016301)

GO Cellular Component (12): obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), focal adhesion (GO:0005925), vesicle (GO:0031982), melanosome (GO:0042470), extracellular exosome (GO:0070062), blood microparticle (GO:0072562), hippocampal mossy fiber to CA3 synapse (GO:0098686), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Signaling by NOTCH4	2
Activation of BH3-only proteins	1
Membrane Trafficking	1
TCF dependent signaling in response to WNT	1
Adaptive Immune System	1
Platelet activation, signaling and aggregation	1
Regulation of mRNA stability by proteins that bind AU-rich elements	1
Signaling by Interleukins	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
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
cellular anatomical structure	4
anatomical structure formation involved in morphogenesis	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
system process	1
respiratory gaseous exchange by respiratory system	1
phosphorylation	1
protein modification process	1
establishment of protein localization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
neuron recognition	1
macromolecule localization	1
respiratory tube development	1
animal organ development	1
respiratory system development	1
regulation of biological quality	1
tube morphogenesis	1
cellular response to starvation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
negative regulation of response to biotic stimulus	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
innate immune response	1
regulation of innate immune response	1
negative regulation of immune response	1
Golgi localization	1
establishment of localization in cell	1
establishment of organelle localization	1
MAPK cascade	1
regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

1243 interactions, top by confidence:

A	B	Type	Score
MAP2K1	BRAF	psi-mi:“MI:0914”(association)	0.980
RAF1	YWHAZ	psi-mi:“MI:0407”(direct interaction)	0.970
MAP2K1	RAF1	psi-mi:“MI:0914”(association)	0.960
YWHAZ	MARK3	psi-mi:“MI:0914”(association)	0.940
BRAF	HRAS	psi-mi:“MI:0914”(association)	0.940
BRAF	MAP2K2	psi-mi:“MI:0914”(association)	0.890
YWHAZ	YAP1	psi-mi:“MI:0915”(physical association)	0.880
YWHAZ	YAP1	psi-mi:“MI:0403”(colocalization)	0.880
PTPN3	YWHAQ	psi-mi:“MI:2364”(proximity)	0.850
FOXO3	YWHAZ	psi-mi:“MI:0915”(physical association)	0.850
YWHAH	TSC2	psi-mi:“MI:0914”(association)	0.850
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
RAF1	RAF1	psi-mi:“MI:0914”(association)	0.810
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
MARK3	YWHAE	psi-mi:“MI:0914”(association)	0.790
SIK3	YWHAZ	psi-mi:“MI:0407”(direct interaction)	0.760
YWHAZ	SIK3	psi-mi:“MI:0407”(direct interaction)	0.760
MARK2	YWHAE	psi-mi:“MI:0914”(association)	0.730
ARL3	UNC119B	psi-mi:“MI:0914”(association)	0.730
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
YWHAZ	SIK1	psi-mi:“MI:0407”(direct interaction)	0.680
SIK3	YWHAE	psi-mi:“MI:0914”(association)	0.670
SIK1	YWHAE	psi-mi:“MI:0914”(association)	0.670
PTPN3	MCC	psi-mi:“MI:0914”(association)	0.660
MAST1	YWHAB	psi-mi:“MI:0914”(association)	0.640
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640

BioGRID (2345): YWHAZ (Affinity Capture-Western), YWHAZ (Affinity Capture-Western), DDIT4 (Affinity Capture-Western), TSC2 (Affinity Capture-Western), YWHAZ (Affinity Capture-MS), YWHAZ (Affinity Capture-Western), YWHAZ (Co-localization), YWHAZ (Biochemical Activity), MAPT (Reconstituted Complex), YWHAZ (Affinity Capture-Western), DTL (Affinity Capture-Western), YWHAZ (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), YWHAZ (Affinity Capture-RNA), YWHAZ (Affinity Capture-RNA)

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

15 interactions.

A	Effect	B	Mechanism
AKT1	unknown	YWHAZ	phosphorylation
MAPK10	down-regulates	YWHAZ	phosphorylation
MAPK8	down-regulates	YWHAZ	phosphorylation
MAPK9	down-regulates	YWHAZ	phosphorylation
PRKACA	“down-regulates activity”	YWHAZ	phosphorylation
AKT	unknown	YWHAZ	phosphorylation
PRKCD	“down-regulates activity”	YWHAZ	phosphorylation
MAPKAPK2	“down-regulates activity”	YWHAZ	phosphorylation
CSNK1A1	“down-regulates activity”	YWHAZ	phosphorylation
YWHAZ	“down-regulates activity”	NEFL	binding
JNK	down-regulates	YWHAZ	phosphorylation
PIM1	“up-regulates activity”	YWHAZ	phosphorylation
BCR	unknown	YWHAZ	phosphorylation
YWHAZ	“up-regulates quantity by stabilization”	GEM	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 204 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	6	27.8×	3e-06
Activation of BAD and translocation to mitochondria	5	26.2×	3e-05
Signaling by RAS mutants	8	23.3×	9e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	23.2×	5e-05
Signaling by high-kinase activity BRAF mutants	10	21.9×	1e-08
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	6	21.5×	1e-05
MAP2K and MAPK activation	10	19.7×	1e-08
Signaling by RAF1 mutants	10	19.2×	1e-08

GO biological processes:

GO term	Partners	Fold	FDR
thymus development	7	12.7×	5e-04
negative regulation of extrinsic apoptotic signaling pathway	5	11.3×	7e-03
cellular senescence	7	11.1×	8e-04
MAPK cascade	11	9.1×	2e-05
microtubule cytoskeleton organization	12	7.8×	2e-05
cellular response to oxidative stress	8	6.7×	5e-03
protein phosphorylation	17	6.2×	4e-06
response to oxidative stress	8	5.6×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	16
Likely benign	19
Benign	9

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
3342334	NM_145690.3(YWHAZ):c.379C>T (p.Arg127Cys)	Pathogenic
4082131	E14K	Pathogenic
4082132	NM_145690.3(YWHAZ):c.147A>T (p.Lys49Asn)	Pathogenic
631500	NM_145690.3(YWHAZ):c.434C>T (p.Ser145Leu)	Pathogenic
631501	NM_145690.3(YWHAZ):c.40G>T (p.Glu14Ter)	Pathogenic
631502	NM_145690.3(YWHAZ):c.687_688dup (p.Ser230fs)	Pathogenic
3770190	NM_145690.3(YWHAZ):c.557_558insTTT (p.Glu186delinsAspLeu)	Likely pathogenic
4845382	NM_145690.3(YWHAZ):c.168_184dup (p.Val62fs)	Likely pathogenic

SpliceAI

1358 predictions. Top by Δscore:

Variant	Effect	Δscore
8:100923949:ACTT:A	donor_loss	1.0000
8:100923952:TACTG:T	donor_loss	1.0000
8:100923953:A:AC	donor_gain	1.0000
8:100923953:ACTGT:A	donor_gain	1.0000
8:100923954:C:CG	donor_gain	1.0000
8:100923954:CT:C	donor_gain	1.0000
8:100923954:CTG:C	donor_gain	1.0000
8:100923954:CTGT:C	donor_gain	1.0000
8:100923954:CTGTC:C	donor_gain	1.0000
8:100924046:AAAGC:A	acceptor_gain	1.0000
8:100924047:AAGC:A	acceptor_gain	1.0000
8:100924048:AGC:A	acceptor_gain	1.0000
8:100924049:GC:G	acceptor_gain	1.0000
8:100924049:GCC:G	acceptor_loss	1.0000
8:100924050:CC:C	acceptor_gain	1.0000
8:100924051:C:CC	acceptor_gain	1.0000
8:100924051:CT:C	acceptor_loss	1.0000
8:100924052:T:G	acceptor_loss	1.0000
8:100924057:T:TC	acceptor_gain	1.0000
8:100924058:T:C	acceptor_gain	1.0000
8:100924133:A:AC	donor_gain	1.0000
8:100924133:ACTGT:A	donor_gain	1.0000
8:100924134:C:CA	donor_gain	1.0000
8:100924134:CTGT:C	donor_gain	1.0000
8:100924134:CTGTC:C	donor_gain	1.0000
8:100924910:GCATA:G	donor_loss	1.0000
8:100924911:CATAC:C	donor_loss	1.0000
8:100924912:ATACC:A	donor_loss	1.0000
8:100924913:TACCT:T	donor_loss	1.0000
8:100924914:A:AC	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000115841 (8:100930647 T>C,G), RS1000130375 (8:100916034 C>T), RS1000182180 (8:100932034 A>C,G), RS1000310937 (8:100946483 G>A,C), RS1000317265 (8:100947839 A>C), RS1000341572 (8:100916303 C>T), RS1000422586 (8:100942862 A>G), RS1000499159 (8:100951706 G>T), RS1000512058 (8:100955344 G>A), RS1000514429 (8:100920027 C>T), RS1000586295 (8:100919743 C>T), RS1000606411 (8:100935234 C>T), RS1000672491 (8:100926193 C>T), RS1000763069 (8:100940520 T>C), RS1000775716 (8:100922679 C>T)

Disease associations

OMIM: gene MIM:601288 | disease phenotypes: MIM:618428

GenCC curated gene-disease

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Moderate	Autosomal dominant
neurodevelopmental disorder	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Moderate	AD

Mondo (3): Popov-Chang syndrome (MONDO:0979865), complex neurodevelopmental disorder (MONDO:0100038), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000253_25	Attention deficit hyperactivity disorder and conduct disorder	5.000000e-06
GCST002783_346	Body mass index	7.000000e-06
GCST003075_133	Cognitive decline rate in late mild cognitive impairment	1.000000e-08
GCST006102_1	Interleukin-10 levels	7.000000e-09
GCST007324_149	Adventurousness	2.000000e-09
GCST007325_282	General risk tolerance (MTAG)	1.000000e-12
GCST007576_178	Chronotype	3.000000e-11
GCST90002385_366	High light scatter reticulocyte count	1.000000e-10

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0007710	cognitive decline measurement
EFO:0004750	interleukin 10 measurement
EFO:0008579	risk-taking behaviour
EFO:0008328	chronotype measurement
EFO:0007986	reticulocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105899 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

2 measured of 2 human assays (2 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4096939	KD	38 nM
CHEMBL4063253	KD	59 nM

ChEMBL bioactivities

26 potent at pChembl≥5 of 29 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.34	Kd	4.526	nM	CHEMBL3752910
8.34	ED50	4.526	nM	CHEMBL3752910
8.14	Kd	7.3	nM	CHEMBL4217121
8.05	Kd	9	nM	CHEMBL4206466
7.75	Kd	18	nM	CHEMBL4218471
7.42	Kd	38	nM	CHEMBL4096939
7.39	Kd	41	nM	CHEMBL4247970
7.23	Kd	59	nM	CHEMBL4063253
7.00	Kd	99	nM	CHEMBL4096528
6.99	Kd	103	nM	CHEMBL4080446
6.46	Kd	350	nM	CHEMBL4061432
6.44	Kd	360	nM	CHEMBL4215246
6.43	Kd	370	nM	CHEMBL4243245
6.29	Kd	510	nM	CHEMBL4073158
6.16	Kd	700	nM	CHEMBL4244843
6.08	IC50	830	nM	CHEMBL4096939
6.00	Kd	1000	nM	CHEMBL4071395
5.94	Kd	1140	nM	CHEMBL4245176
5.91	IC50	1220	nM	CHEMBL4069746
5.48	IC50	3290	nM	CHEMBL4068123
5.23	Kd	5900	nM	CHEMBL4076293
5.19	Kd	6400	nM	CHEMBL4098750
5.07	IC50	8600	nM	CHEMBL4096939
5.05	Kd	9000	nM	CHEMBL4079973
5.03	IC50	9300	nM	CHEMBL119235

PubChem BioAssay actives

25 with measured affinity, of 55 total; 22 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	2149804: Binding affinity to human YWHAZ incubated for 45 mins by Kinobead based pull down assay	kd	0.0045	uM
(4aR,6S,7R,8R,8aS)-6-[[(1E,3R,8R,9R,10R,11S,14R)-9,14-dihydroxy-14-(methoxymethyl)-3,10-dimethyl-6-propan-2-yl-8-tricyclo[9.3.0.03,7]tetradeca-1,6-dienyl]oxy]-2,2-dimethyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol	1373967: Binding affinity to 14-3-3zeta (unknown origin) assessed as stabilization of protein-protein interaction between 14-3-3zeta and fluorescein-labeled phosphopeptide by measuring Kd of FAM-KRSHpSV-COOH at 40 uM by fluorescence polarization assay (Rvb = 470 +/- 20 nM)	kd	0.0073	uM
(1R,2E,4R,7S,8R,9R,10R)-10-[[(1S,2R,4S,5R,6R,8S,9S)-5-hydroxy-2-(methoxymethyl)-9-methyl-9-[(2S)-oxiran-2-yl]-3,7,10,11-tetraoxatricyclo[6.2.1.01,6]undecan-4-yl]oxy]-4-(methoxymethyl)-1,8-dimethyl-12-propan-2-yltricyclo[9.3.0.03,7]tetradeca-2,11-diene-4,9-diol	1373967: Binding affinity to 14-3-3zeta (unknown origin) assessed as stabilization of protein-protein interaction between 14-3-3zeta and fluorescein-labeled phosphopeptide by measuring Kd of FAM-KRSHpSV-COOH at 40 uM by fluorescence polarization assay (Rvb = 470 +/- 20 nM)	kd	0.0090	uM
(4aR,6S,7R,8R,8aS)-6-[[(1E,3R,8R,9R,10R,11S,14S)-9-hydroxy-14-(methoxymethyl)-3,10-dimethyl-6-propan-2-yl-8-tricyclo[9.3.0.03,7]tetradeca-1,6-dienyl]oxy]-2,2-dimethyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol	1373967: Binding affinity to 14-3-3zeta (unknown origin) assessed as stabilization of protein-protein interaction between 14-3-3zeta and fluorescein-labeled phosphopeptide by measuring Kd of FAM-KRSHpSV-COOH at 40 uM by fluorescence polarization assay (Rvb = 470 +/- 20 nM)	kd	0.0180	uM
2-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[2-[[(2S)-2-acetamido-5-amino-5-oxopentanoyl]amino]acetyl]amino]-2-(1-adamantyl)-5-(carboxymethyl)-8,21-dimethyl-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-3-amino-3-oxopropyl]propanedioic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	0.0380	uM
(3S)-4-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[[(2S,5S,8S,11S,24S)-5-(carboxymethyl)-24-[[2-[[(2S)-2,5-diamino-5-oxopentanoyl]amino]acetyl]amino]-8,11,24-trimethyl-2-(2-methylpropyl)-3,6,9,25-tetraoxo-1,4,7,10-tetrazacyclopentacosane-11-carbonyl]amino]-4-oxobutanoic acid	1393199: Binding affinity to human full length 14-3-3zeta by fluorescence polarization assay	kd	0.0410	uM
(3S)-3-[[(2S)-2-[[(2S,5S,8S,21S)-2-(1-adamantyl)-21-[[2-[[(2S)-5-amino-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-5-(carboxymethyl)-8,21-dimethyl-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	0.0590	uM
2-[(2S)-3-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[2-[[(2S)-5-amino-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-5-(carboxymethyl)-8,21-dimethyl-2-(2-methylpropyl)-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-3-oxopropyl]propanedioic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	0.0990	uM
(3S)-3-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[2-[[(2S)-5-amino-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-5-(carboxymethyl)-8,21-dimethyl-2-(2-methylpropyl)-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	0.1030	uM
(3S)-3-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[(2R)-2-[[(2S)-5-amino-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-(carboxymethyl)-8,21-dimethyl-2-(2-methylpropyl)-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	0.3500	uM
(4aR,6S,7R,8R,8aS)-6-[[(1E,3R,8R,9R,10R,11S,14R)-9-hydroxy-14-methoxy-14-(methoxymethyl)-3,10-dimethyl-6-propan-2-yl-8-tricyclo[9.3.0.03,7]tetradeca-1,6-dienyl]oxy]-2,2-dimethyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol	1373967: Binding affinity to 14-3-3zeta (unknown origin) assessed as stabilization of protein-protein interaction between 14-3-3zeta and fluorescein-labeled phosphopeptide by measuring Kd of FAM-KRSHpSV-COOH at 40 uM by fluorescence polarization assay (Rvb = 470 +/- 20 nM)	kd	0.3600	uM
(3S)-4-[[(2S)-1-[(E)-[2-[[(1E,3R,8R,9R,10R,11S,14S)-6-[(2S)-1-acetyloxypropan-2-yl]-8,9-dihydroxy-14-(methoxymethyl)-3,10-dimethyl-4-tricyclo[9.3.0.03,7]tetradeca-1,6-dienyl]oxymethyl]phenyl]methylideneamino]oxy-3-methylbutan-2-yl]amino]-3-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[2-[[5-(dimethylamino)naphthalen-1-yl]sulfonylamino]acetyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-oxobutanoic acid	1393203: Binding affinity to recombinant human His-tagged 14-3-3zeta expressed in Escherichia coli K12 by ITC method	kd	0.3700	uM
(3S)-3-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[2-[[(2S)-5-amino-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-5-(3-amino-3-oxopropyl)-8,21-dimethyl-2-(2-methylpropyl)-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	0.5100	uM
[(2S)-2-[(1E,3R,4S,8R,9R,10R,11S,14S)-8-[(2S,3R,4S,5R,6R)-4-acetyloxy-3,5-dihydroxy-6-(2-methylbut-3-en-2-yloxymethyl)oxan-2-yl]oxy-4,9-dihydroxy-14-(methoxymethyl)-3,10-dimethyl-6-tricyclo[9.3.0.03,7]tetradeca-1,6-dienyl]propyl] acetate	1397076: Binding affinity to human GST-tagged 14-3-3zeta expressed in Escherichia coli assessed as Kd for 14-3-3zeta binding to H+-ATPase peptide motif by isothermal titration calorimetric method	kd	0.7000	uM
(3S)-3-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[2-[[(2S)-5-amino-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-5-(carboxymethyl)-8,21-dimethyl-2-(2-methylpropyl)-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-(2-fluorophenyl)-2-methyl-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	1.0000	uM
(3S)-4-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2,5-diamino-5-oxopentanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoic acid	1393199: Binding affinity to human full length 14-3-3zeta by fluorescence polarization assay	kd	1.1400	uM
(3S)-3-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[2-[[(2S)-2-acetamido-5-amino-5-oxopentanoyl]amino]acetyl]amino]-5-(carboxymethyl)-8,21-dimethyl-2-(2-methylpropyl)-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	1471564: Inhibition of TAMRA-labeled cRaf peptide binding to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr by fluorescence polarization assay	ic50	1.2200	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-acetamido-5-amino-5-oxopentanoyl]amino]acetyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid	1471564: Inhibition of TAMRA-labeled cRaf peptide binding to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr by fluorescence polarization assay	ic50	3.2900	uM
(3S)-3-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[2-[[(2S)-5-amino-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-5-(carboxymethyl)-2-(1H-indol-3-ylmethyl)-8,21-dimethyl-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	5.9000	uM
(3S)-3-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[2-[[(2S)-5-amino-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-8,21-dimethyl-2-(2-methylpropyl)-5-[3-[(N-nitrocarbamimidoyl)amino]propyl]-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	6.4000	uM
(3S)-3-[[(2S)-2-[[(2S,5S,8S,21S)-21-[[2-[[(2S)-5-amino-2-[[2-[2-[2-[(3’,6’-dihydroxy-3-oxospiro[2-benzofuran-1,9’-xanthene]-5-yl)carbamothioylamino]ethoxy]ethoxy]acetyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-5-(carboxymethyl)-8,21-dimethyl-2-(2-methylpropyl)-3,6,22-trioxo-1,4,7-triazacyclodocosane-8-carbonyl]amino]-4-methylpentanoyl]amino]-4-[[(2S)-1-[[(2R)-1-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-oxobutanoic acid	1471563: Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	kd	9.0000	uM
4-[[4-formyl-5-hydroxy-6-methyl-3-(phosphonooxymethyl)-2-pyridinyl]diazenyl]benzoic acid	1393200: Binding affinity to GST-tagged 14-3-3-zeta (unknown origin) expressed in Escherichia coli BL21(DE3) assessed as inhibition of interaction with PRAS40 in African green monkey COS7 cells preincubated with protein followed by cell addition by ELISA	ic50	9.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
methacrylaldehyde	affects cotreatment, increases oxidation, decreases expression, increases abundance	2
evodiamine	increases expression	2
Arsenic Trioxide	decreases expression, increases expression, decreases response to substance	2
Acrolein	increases abundance, affects cotreatment, increases oxidation, decreases expression	2
Cadmium	increases palmitoylation, increases expression, decreases reaction, increases abundance	2
Copper	affects binding, decreases expression	2
Ozone	decreases expression, increases abundance, affects cotreatment, increases oxidation	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cadmium Chloride	decreases reaction, increases abundance, increases palmitoylation, increases expression	2
aristolochic acid I	decreases expression, increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
titanium dioxide	increases phosphorylation	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	decreases expression, increases expression	1
afimoxifene	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
2-bromopalmitate	increases palmitoylation, decreases reaction, increases abundance	1
manganese chloride	decreases expression, affects methylation	1
triacsin C	increases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression, decreases reaction	1
S-1,2-dichlorovinyl-N-acetylcysteine	affects expression	1
phenethyl isothiocyanate	affects binding	1
tamibarotene	affects expression	1
thrombin receptor-activating peptide SFLLRNPNDKY	decreases reaction, increases secretion	1
CD 437	decreases expression	1
chloropicrin	decreases expression	1

ChEMBL screening assays

23 unique, capped per target: 23 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4026607	Binding	Binding affinity to 14-3-3zeta (1 to 230 residues) (unknown origin) after 1 hr using FITC labeled compound by fluorescence polarization assay	Structure-Based Design of Non-natural Macrocyclic Peptides That Inhibit Protein-Protein Interactions. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D6A8	HyCyte HEK293T KO-hYWHAZ	Transformed cell line	Female
CVCL_VF81	NERCe002-A-3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism