MAP3K3

Summary

MAP3K3 (mitogen-activated protein kinase kinase kinase 3, HGNC:6855) is a protein-coding gene on chromosome 17q23.3, encoding Mitogen-activated protein kinase kinase kinase 3 (Q99759). Component of a protein kinase signal transduction cascade.

This gene product is a 626-amino acid polypeptide that is 96.5% identical to mouse Mekk3. Its catalytic domain is closely related to those of several other kinases, including mouse Mekk2, tobacco NPK, and yeast Ste11. Northern blot analysis revealed a 4.6-kb transcript that appears to be ubiquitously expressed. This protein directly regulates the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by activating SEK and MEK1/2 respectively; it does not regulate the p38 pathway. In cotransfection assays, it enhanced transcription from a nuclear factor kappa-B (NFKB)-dependent reporter gene, consistent with a role in the SAPK pathway. Alternatively spliced transcript variants encoding distinct isoforms have been observed.

Source: NCBI Gene 4215 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebral cavernous malformations 5 (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 110 total
• Phenotypes (HPO): 5
• Druggable target: yes — 28 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002401

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6855
Approved symbol	MAP3K3
Name	mitogen-activated protein kinase kinase kinase 3
Location	17q23.3
Locus type	gene with protein product
Status	Approved
Aliases	MAPKKK3
Ensembl gene	ENSG00000198909
Ensembl biotype	protein_coding
OMIM	602539
Entrez	4215

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 11 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000361357, ENST00000361733, ENST00000577395, ENST00000577597, ENST00000577784, ENST00000577839, ENST00000578622, ENST00000579585, ENST00000581732, ENST00000584573, ENST00000585302, ENST00000963889, ENST00000963890, ENST00000963891, ENST00000963892, ENST00000963893, ENST00000963894

RefSeq mRNA: 4 — MANE Select: NM_002401 NM_001330431, NM_001363768, NM_002401, NM_203351

CCDS: CCDS32701, CCDS32702, CCDS82186, CCDS86624

Canonical transcript exons

ENST00000361733 — 16 exons

Exon	Start	End
ENSE00001257248	63632681	63632802
ENSE00002694611	63693549	63696305
ENSE00002696813	63622417	63622763
ENSE00003465668	63692242	63692419
ENSE00003471935	63685517	63685590
ENSE00003482116	63646034	63646074
ENSE00003507603	63690264	63690412
ENSE00003527091	63657794	63657907
ENSE00003548252	63666940	63667060
ENSE00003564191	63691733	63691862
ENSE00003600230	63688527	63688594
ENSE00003628790	63689544	63689735
ENSE00003631046	63681766	63681899
ENSE00003631629	63652557	63652656
ENSE00003642124	63691102	63691233
ENSE00003693603	63688789	63688881

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 96.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.7020 / max 496.7292, expressed in 1816 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
162211	25.6217	1812
162210	1.0803	629

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.84	gold quality
mononuclear cell	CL:0000842	96.50	gold quality
leukocyte	CL:0000738	96.40	gold quality
granulocyte	CL:0000094	95.46	gold quality
blood	UBERON:0000178	95.42	gold quality
mucosa of stomach	UBERON:0001199	94.66	gold quality
apex of heart	UBERON:0002098	92.46	gold quality
right lung	UBERON:0002167	91.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.68	gold quality
lower esophagus	UBERON:0013473	91.65	gold quality
right coronary artery	UBERON:0001625	91.62	gold quality
popliteal artery	UBERON:0002250	91.61	gold quality
tibial artery	UBERON:0007610	91.59	gold quality
spleen	UBERON:0002106	91.58	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	91.57	gold quality
aorta	UBERON:0000947	91.34	gold quality
descending thoracic aorta	UBERON:0002345	91.24	gold quality
coronary artery	UBERON:0001621	91.19	gold quality
upper lobe of left lung	UBERON:0008952	91.15	gold quality
left coronary artery	UBERON:0001626	91.13	gold quality
tibial nerve	UBERON:0001323	91.12	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.07	gold quality
thoracic aorta	UBERON:0001515	91.03	gold quality
right atrium auricular region	UBERON:0006631	90.94	gold quality
ascending aorta	UBERON:0001496	90.93	gold quality
sural nerve	UBERON:0015488	90.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	90.90	gold quality
heart left ventricle	UBERON:0002084	90.86	gold quality
omental fat pad	UBERON:0010414	90.77	gold quality
cardiac ventricle	UBERON:0002082	90.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

157 targeting MAP3K3, 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-3925-3P	100.00	69.95	1237
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-1250-3P	99.96	70.04	4038
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

Literature-anchored findings (GeneRIF, showing 40)

• results established that elevated expression of mitogen-activated protein kinase kinase kinase 3(MEKK3) appears to be a frequent occurrence in breast and ovarian cancers (PMID:14662759)
• MEKK3 signaling and apoptosis is potentiated by TRAF7 (PMID:15001576)
• MEKK3 has a role in NF-kappaB activation by the chemopreventive dithiolethione oltipraz (PMID:15047705)
• RIP-dependent recruitment of MEKK3 plays a specific role in TNF-alpha signaling. (PMID:15572679)
• We find that while hKSR-2 blocks MEKK3 activation, it has little to no effect on other members of the MAP3K family, including MEKK4, TAK1, and Ras-Raf, suggesting that its effects are selective. (PMID:16039990)
• TAK1 is recruited to the TNF-R1 complex via RIP and likely cooperates with MEKK3 to activate NF-kappaB in TNF-alpha signaling (PMID:16260783)
• Serine526 is the only phosphorylation site within the activation loop of MEKK3; phosphorylation occurs in response to exogenous stimuli like osmotic stress. (PMID:16407301)
• TLR8-mediated MEKK3-dependent IKKgamma phosphorylation might play an important role in the activation of IKK complex, leading to IkappaBalpha phosphorylation (PMID:16737960)
• structural details of MEKK3 PB1 and its binding properties with mitogen-activated protein kinase kinase 5, human PB1. (PMID:17985933)
• identifies a potentially important regulatory step in MEKK3 signaling via dephosphorylation of Thr(294), which reduces 14-3-3 binding correlating with MEKK3 pathway activation (PMID:18308725)
• Specific ablation of MEKK3 in T cells of conditional knockout mice does not significantly alter thymic T cell development, but leads to a peripheral T cell homeostasis defect. (PMID:19265138)
• These results strongly suggested that Hsp90 could work as the molecular chaperone of MEKK3. (PMID:19560753)
• The rear end acidic cluster of the p62 PB1 domain is used to organize cytosolic aggregates or speckles-associated TRAF6-p62-MEKK3 complex for control of NF-kappaB activation. (PMID:19903815)
• we report the identification of two regulatory phosphorylation sites at Thr-516 and Ser-520 within the kinase activation loop that is essential for MEKK3-mediated IkappaB kinase beta (IKKbeta)/NF-kappaB activation (PMID:20068038)
• PP2A plays an important role in the termination of LPA-mediated NF-kappaB activation through dephosphorylating and inactivating MEKK3 (PMID:20448038)
• EGFR and MAPK are actively involved in the pathobiology of serous cystic neoplasms of the pancreas. (PMID:20495538)
• The regulation of NHEJ by EGFR was only blocked when ERK was affected by siRNA but not when AKT was knocked down. These data indicate that EGFR modulates DSB repair by regulating NHEJ via MAPK signalling. (PMID:20615764)
• Proliferation of human IVD cells is regulated by exogenous and autocrine growth factors mainly via the MEK/ERK and PI-3K/Akt pathways. (PMID:22105580)
• Alterations in MEKK3 expression occur in early stages of development of esophageal squamous cell carcinoma and are sustained during disease progression. (PMID:24383423)
• We provide evidence for an intimate mutual control of the IKK complex by mitogen-activated protein kinase kinase kinase 3 (MEKK3) and transforming growth factor beta activated kinase 1 (TAK1). (PMID:24418622)
• Inhibitors of apoptosis proteins regulate myogenic differentiation by directly suppressing MEKK2/3-MEK5-ERK5 signaling. (PMID:24975362)
• MEKK3 expression was positively correlated with survivin. (PMID:25040987)
• This study identified an NBR1-MEKK3 complex as a key regulator of JNK signaling and adipose tissue inflammation in obesity. (PMID:25043814)
• MEKK3 expression was significantly higher in patients with renal clear cell carcinoma than in controls. (PMID:25388155)
• Our finding that Verrucous venous malformation contains a MAP3K3 mutation supports our impression that this lesion is a venous anomaly. (PMID:25728774)
• High MEKK3 expression is associated with renal clear cell carcinoma. (PMID:25824786)
• MAP3K3 may potentially not only serve as diagnostic/prognostic markers for patients with lung cancer but also provide an indicator for future investigations into immunomodulatory therapies for lung cancer. (PMID:26088427)
• Polymorphisms in MAP3K3, MMP24 and IGF1R are associated with greater height and act additively on height in children of an admixed population. (PMID:26304632)
• MAP3K3 overexpression is an independent poor prognostic indicator in ovarian carcinoma. (PMID:26997451)
• studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for cerebral cavernous malformations pathogenesis that may be targeted to develop new CCM therapeutics (PMID:27027284)
• All these suggest that the MAP3K M1P site is a potential interacting partner of MAP3K SH3 domain, which may mediate the intermolecular recognition between hPTTG1 and MAP3K. (PMID:27787230)
• Its downstream target MAP3K3 could be a potential therapeutic target for NSCLC. (PMID:29528232)
• MEKK3 KO reduced both EMT and cell migration, the size of 3D colonies and the percentage of CD44(+)/CD24(+)/EpCAM(+) CSC, promoter recruitment of YAP/TAZ and the expression of their target genes. (PMID:29599309)
• Expression of MEKK2 and MEKK3 inhibits medulloblastoma cell proliferation. (PMID:29662197)
• the data revealed the novel role and target of miR505 in NSCLC cells, which may provide novel insights regarding its role in the carcinogenesis of NSCLC and its potential values for clinical applications. (PMID:30628663)
• This study suggests that expression of miR-194 is down-regulated in nasopharyngeal carcinoma, and that miR-194 can directly target MAP3K3 to regulate tumor progression. Given the pivotal involvement of MAP3K3 in nasopharyngeal carcinoma development, targeting miR-194 may be a novel strategy for the treatment of nasopharyngeal carcinoma. (PMID:30652073)
• MEKK3 overexpression prevented the inhibitory effects of miR9 on the viability, migration and invasion of PC cells. (PMID:30896820)
• Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations. (PMID:33729480)
• MEKK3 activates IRF7 to trigger a potent type I interferon induction in response to TLR7/9 signaling. (PMID:33812250)
• Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation. (PMID:33891857)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	map3k3	ENSDARG00000060348
mus_musculus	Map3k3	ENSMUSG00000020700
rattus_norvegicus	Map3k3	ENSRNOG00000061424
drosophila_melanogaster	lic	FBGN0261524
caenorhabditis_elegans		WBGENE00004758
caenorhabditis_elegans		WBGENE00018034
caenorhabditis_elegans		WBGENE00018035

Paralogs (8): MAP2K4 (ENSG00000065559), MAP2K7 (ENSG00000076984), MAP3K4 (ENSG00000085511), MAP2K2 (ENSG00000126934), NEK1 (ENSG00000137601), MAP2K5 (ENSG00000137764), MAP2K1 (ENSG00000169032), MAP3K2 (ENSG00000169967)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase 3 — Q99759 (reviewed: Q99759)

Alternative names: MAPK/ERK kinase kinase 3

All UniProt accessions (6): Q99759, J3KRN4, J3KTC4, J3QRB6, J3QS19, J3QS54

UniProt curated annotations — full annotation on UniProt →

Function. Component of a protein kinase signal transduction cascade. Mediates activation of the NF-kappa-B, AP1 and DDIT3 transcriptional regulators.

Subunit / interactions. Binds both upstream activators and downstream substrates in multimolecular complexes. Part of a complex with MAP2K3, RAC1 and CCM2. Interacts with MAP2K5 and SPAG9.

Post-translational modifications. Phosphorylation at Ser-166 and Ser-337 by SGK1 inhibits its activity.

Disease relevance. Cerebral cavernous malformations 5 (CCM5) [MIM:621032] A form of cerebral cavernous malformations, a congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by phosphorylation on Thr-530.

Similarity. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99759-1	1	yes
Q99759-2	2

RefSeq proteins (4): NP_001317360, NP_001350697, NP_002392, NP_976226 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000270	PB1_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR034879	PB1_MEKK2/3	Domain
IPR053793	PB1-like	Domain

Pfam: PF00069, PF00564

Enzyme classification (BRENDA):

• EC 2.7.11.25 — mitogen-activated protein kinase kinase kinase (BRENDA: 30 organisms, 191 substrates, 74 inhibitors, 12 Km, 12 kcat entries)
• EC 2.7.12.2 — mitogen-activated protein kinase kinase (BRENDA: 38 organisms, 149 substrates, 134 inhibitors, 6 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
MEK	0.0002–0.0004	6
ATP	0.02–0.394	5
ATP	0.0533	1
ERK2	0.0002	1
K52R-[ERK2]	0.0001	1
K53M-[P38ALPHA]	0.0002	1
P38ALPHA	0.0002	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (34 total): modified residue 6, strand 5, sequence variant 4, helix 4, compositionally biased region 3, domain 2, binding site 2, turn 2, region of interest 2, chain 1, splice variant 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
2C60	X-RAY DIFFRACTION	1.25
2O2V	X-RAY DIFFRACTION	1.83
4YL6	X-RAY DIFFRACTION	2.1
4Y5O	X-RAY DIFFRACTION	2.35
2JRH	SOLUTION NMR
2PPH	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99759-F1	67.20	0.38

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 (1): 489 (proton acceptor)

Ligand- & substrate-binding residues (2): 391; 368–376

Post-translational modifications (6): 147, 166, 250, 312, 337, 340

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9020702	Interleukin-1 signaling
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-168256	Immune System
R-HSA-446652	Interleukin-1 family signaling
R-HSA-449147	Signaling by Interleukins

MSigDB gene sets: 292 (showing top): REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, TGCACTT_MIR519C_MIR519B_MIR519A, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, PID_IL1_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, FOXO4_01, AP2_Q3, CAGCTG_AP4_Q5, SOX9_B1, PID_TNF_PATHWAY, BLALOCK_ALZHEIMERS_DISEASE_UP, GATA1_01

GO Biological Process (7): MAPK cascade (GO:0000165), blood vessel development (GO:0001568), intracellular signal transduction (GO:0035556), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), protein autophosphorylation (GO:0046777), positive regulation of p38MAPK cascade (GO:1900745), protein phosphorylation (GO:0006468)

GO Molecular Function (10): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Interleukin-1 family signaling	1
Immune System	1
Signaling by Interleukins	1
Cytokine Signaling in Immune system	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
protein kinase activity	2
cellular anatomical structure	2
intracellular signaling cassette	1
vasculature development	1
anatomical structure development	1
signal transduction	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
protein phosphorylation	1
p38MAPK cascade	1
positive regulation of MAPK cascade	1
regulation of p38MAPK cascade	1
phosphorylation	1
protein modification process	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
MAPK cascade	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cytoplasm	1

Protein interactions and networks

STRING

3136 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K3	CCM2	Q9BSQ5	984
MAP3K3	MAP2K5	Q13163	866
MAP3K3	ITGB1BP1	O14713	835
MAP3K3	PDCD10	Q9BUL8	833
MAP3K3	KRIT1	O00522	821
MAP3K3	TRAF7	Q6Q0C0	728
MAP3K3	AKT1	P31749	702
MAP3K3	CCM2L	Q9NUG4	696
MAP3K3	TRAF4	Q9BUZ4	689
MAP3K3	TRAF6	Q9Y4K3	664
MAP3K3	RHOA	P06749	584
MAP3K3	NBR1	Q14596	577
MAP3K3	MAP2K3	P46734	558
MAP3K3	MAP3K7	O43318	549
MAP3K3	IL17RA	Q96F46	538

IntAct

239 interactions, top by confidence:

A	B	Type	Score
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
MAP3K3	TRAF7	psi-mi:“MI:0915”(physical association)	0.750
MAP3K3	TRAF7	psi-mi:“MI:0403”(colocalization)	0.750
CCM2	MAP3K3	psi-mi:“MI:0407”(direct interaction)	0.720
CCM2	MAP3K3	psi-mi:“MI:0915”(physical association)	0.720
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
MAP3K3	TCP1	psi-mi:“MI:0914”(association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
EGFR	MAP3K3	psi-mi:“MI:0915”(physical association)	0.550
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
NS	MAP3K3	psi-mi:“MI:0915”(physical association)	0.370
MAP3K3	GLRX3	psi-mi:“MI:0915”(physical association)	0.370
MAP3K3	GTF2I	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
	AHRR	psi-mi:“MI:0914”(association)	0.350
	AURKA	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
YWHAZ	SPEG	psi-mi:“MI:0914”(association)	0.350

BioGRID (155): MAP3K3 (Affinity Capture-MS), GLRX3 (Two-hybrid), MAP3K3 (Two-hybrid), MAP3K3 (Affinity Capture-Western), NBR1 (Affinity Capture-Western), MAP3K3 (Affinity Capture-Western), MAP3K3 (Affinity Capture-Western), MAP3K3 (Reconstituted Complex), MAP3K3 (Affinity Capture-MS), MAP3K3 (Affinity Capture-MS), MAP3K3 (Affinity Capture-MS), MAP3K3 (Affinity Capture-MS), MAP3K3 (Affinity Capture-MS), MAP3K3 (Affinity Capture-MS), MAP2K5 (Co-localization)

ESM2 similar proteins: A2VDU3, A7E3S4, A8XJW8, E9PUQ8, F1QGZ6, O35346, O43318, O54748, P04049, P05625, P09560, P0C8E4, P11345, P11346, P27966, P33886, P34152, P34908, P42331, Q00944, Q04982, Q05397, Q07192, Q07292, Q08BR4, Q16760, Q21029, Q3UVC0, Q56R14, Q5R5M7, Q5RFL3, Q5U2Z7, Q61083, Q61084, Q61097, Q61UC4, Q62073, Q69Z98, Q6GPK9, Q6VAB6

Diamond homologs: A0A078CGE6, A0A194W8T8, A2AQW0, A2QHV0, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A7A1P0, A8XJW8, A9RVK2, A9SY39, B0LT89, B0XXN8, B5VNQ3, C4YRB7, E9Q3S4, F4HRJ4, G4N7X0, G4NDR3, H2L099, O00506, O14047, O14305, O22040, O22042, O24527, O54748, O61122, O61125, O81472, O95382, P0CY23, P0CY24, P23561, P27636, P28829

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
SGK1	“down-regulates activity”	MAP3K3	phosphorylation
MAP3K3	up-regulates	RCAN1	phosphorylation
MAP3K3	up-regulates	MAP2K5	phosphorylation
TRAF7	up-regulates	MAP3K3	binding
MAP3K3	up-regulates	MAP3K3	phosphorylation
PPP2CA	down-regulates	MAP3K3	dephosphorylation
MAP3K3	“up-regulates activity”	IKBKB	phosphorylation
MAP3K3	“up-regulates activity”	SQSTM1	phosphorylation
MAP3K3	“up-regulates activity”	MAP2K3	phosphorylation
MAP3K3	“up-regulates activity”	MAP2K4	binding
MAP3K3	up-regulates	MAP2K6
WDR62	“up-regulates activity”	MAP3K3	relocalization
MAP3K3	“up-regulates quantity by stabilization”	WDR62	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 178 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
Prefoldin mediated transfer of substrate to CCT/TriC	22	61.0×	3e-34
Formation of tubulin folding intermediates by CCT/TriC	16	47.7×	4e-22
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	16	46.0×	8e-22
Chaperonin-mediated protein folding	16	33.9×	4e-19
Gap junction trafficking and regulation	10	33.5×	5e-12
Gap junction trafficking	10	33.5×	5e-12
RHOBTB2 GTPase cycle	10	33.5×	5e-12
Activation of BAD and translocation to mitochondria	6	32.2×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of telomere maintenance via telomerase	9	38.8×	2e-10
actin filament-based movement	7	33.0×	2e-07
protein refolding	8	29.4×	4e-08
microtubule-based process	5	29.2×	5e-05
chaperone-mediated protein complex assembly	6	24.8×	1e-05
binding of sperm to zona pellucida	8	19.8×	7e-07
protein folding	30	18.2×	2e-26
response to unfolded protein	10	17.7×	4e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	78
Likely benign	2
Benign	17

Top pathogenic / likely-pathogenic (0)

SpliceAI

2878 predictions. Top by Δscore:

Variant	Effect	Δscore
17:63622762:GG:G	donor_gain	1.0000
17:63622763:GG:G	donor_gain	1.0000
17:63622763:GGT:G	donor_loss	1.0000
17:63622764:G:GA	donor_loss	1.0000
17:63622764:G:GG	donor_gain	1.0000
17:63622765:T:A	donor_loss	1.0000
17:63632679:A:AG	acceptor_gain	1.0000
17:63632679:AGAC:A	acceptor_gain	1.0000
17:63632680:G:GC	acceptor_gain	1.0000
17:63632680:GA:G	acceptor_gain	1.0000
17:63632680:GAC:G	acceptor_gain	1.0000
17:63632680:GACG:G	acceptor_gain	1.0000
17:63632680:GACGA:G	acceptor_gain	1.0000
17:63646071:GGCG:G	donor_gain	1.0000
17:63646072:GCGG:G	donor_gain	1.0000
17:63646075:G:GG	donor_gain	1.0000
17:63652554:CA:C	acceptor_loss	1.0000
17:63652554:CAGAA:C	acceptor_gain	1.0000
17:63652555:A:AG	acceptor_gain	1.0000
17:63652555:AGAAT:A	acceptor_gain	1.0000
17:63652556:G:GG	acceptor_gain	1.0000
17:63652556:GA:G	acceptor_gain	1.0000
17:63652556:GAA:G	acceptor_gain	1.0000
17:63652556:GAAT:G	acceptor_gain	1.0000
17:63652556:GAATT:G	acceptor_gain	1.0000
17:63652655:AGGTG:A	donor_loss	1.0000
17:63652656:GGTGA:G	donor_loss	1.0000
17:63652657:GTGAG:G	donor_loss	1.0000
17:63652658:T:G	donor_loss	1.0000
17:63657779:T:G	acceptor_gain	1.0000

AlphaMissense

4133 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:63657825:T:C	L100P	1.000
17:63681873:T:C	F204L	1.000
17:63681874:T:C	F204S	1.000
17:63681875:C:A	F204L	1.000
17:63681875:C:G	F204L	1.000
17:63690276:C:A	P359H	1.000
17:63690284:T:A	W362R	1.000
17:63690284:T:C	W362R	1.000
17:63690305:G:C	G369R	1.000
17:63690306:G:A	G369D	1.000
17:63690306:G:T	G369V	1.000
17:63690311:G:C	G371R	1.000
17:63690311:G:T	G371C	1.000
17:63690317:T:A	F373I	1.000
17:63690317:T:C	F373L	1.000
17:63690319:C:A	F373L	1.000
17:63690319:C:G	F373L	1.000
17:63690320:G:C	G374R	1.000
17:63690321:G:A	G374D	1.000
17:63690327:T:A	V376D	1.000
17:63690337:C:G	C379W	1.000
17:63690363:T:C	L388P	1.000
17:63690366:C:A	A389D	1.000
17:63690371:A:C	K391Q	1.000
17:63690371:A:G	K391E	1.000
17:63690373:G:C	K391N	1.000
17:63690373:G:T	K391N	1.000
17:63691115:T:A	L409Q	1.000
17:63691115:T:C	L409P	1.000
17:63691124:A:T	E412V	1.000

dbSNP variants (sampled 300 via entrez): RS1000005239 (17:63681622 A>G), RS1000104024 (17:63659491 A>G), RS1000113176 (17:63675322 T>C), RS1000169674 (17:63660787 A>G), RS1000177595 (17:63672532 G>T), RS1000231301 (17:63675012 T>C), RS1000282280 (17:63631295 C>T), RS1000332965 (17:63634551 A>T), RS1000347202 (17:63678468 G>A), RS1000399765 (17:63678747 C>T), RS1000437969 (17:63668645 G>A), RS1000510930 (17:63626094 A>T), RS1000559235 (17:63659721 A>G,T), RS1000634433 (17:63672777 C>T), RS1000684382 (17:63677158 C>T)

Disease associations

OMIM: gene MIM:602539 | disease phenotypes: MIM:621032

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebral cavernous malformations 5	Strong	Autosomal dominant

Mondo (2): verrucous hemangioma (MONDO:0018734), cerebral cavernous malformations 5 (MONDO:0975952)

Orphanet (1): Verrucous hemangioma (Orphanet:464318)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0001442	Typified by somatic mosaicism
HP:0002170	Intracranial hemorrhage
HP:0003581	Adult onset
HP:0003621	Juvenile onset
HP:0033522	Cerebral cavernous malformation

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000175_9	Height	7.000000e-07
GCST001263_30	Height	6.000000e-10
GCST001290_7	Height	5.000000e-10
GCST002702_102	Height	9.000000e-14
GCST008163_454	Height	4.000000e-07
GCST010988_65	Adult body size	6.000000e-11
GCST012226_810	Waist circumference adjusted for body mass index	6.000000e-09
GCST90000025_607	Appendicular lean mass	8.000000e-24
GCST90020028_1439	Hip circumference adjusted for BMI	3.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0004980	appendicular lean mass
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5970 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

28 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 433,097 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL180022	NERATINIB	4	9,404
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL939	GEFITINIB	4	117,814
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL572881	MOTESANIB	3	4,642
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL3545396	BMS-690514	2	567
CHEMBL475251	R-406	2
CHEMBL495727	AT-9283	2
CHEMBL572878	TOZASERTIB	2
CHEMBL607707	PELITINIB	2
CHEMBL1908397	KW-2449	1
CHEMBL2140408	AMG-900	1
CHEMBL4289017	PF-03814735	1
CHEMBL494089	GSK-690693	1

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — STE11 family

Binding affinities (BindingDB)

1 measured of 10 human assays (13 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
6-(3-ethoxyphenyl)-3-thiophen-2-yl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole	EC50	1100 nM

ChEMBL bioactivities

56 potent at pChembl≥5 of 57 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.22	Kd	6	nM	LESTAURTINIB
8.12	IC50	7.55	nM	STAUROSPORINE
7.96	IC50	10.9	nM	STAUROSPORINE
7.62	Kd	24.04	nM	CHEMBL5653589
7.57	Kd	27	nM	CHEMBL4554938
7.47	Kd	34	nM	NINTEDANIB
7.46	IC50	34.8	nM	CHEMBL4554938
7.45	ED50	35.82	nM	CHEMBL5653589
7.42	IC50	38.4	nM	CHEMBL4554938
7.32	IC50	48.2	nM	STAUROSPORINE
7.27	Kd	54	nM	BOSUTINIB
6.96	Kd	110	nM	CRIZOTINIB
6.92	Kd	120	nM	KW-2449
6.89	Kd	130	nM	NERATINIB
6.82	Kd	150	nM	RUXOLITINIB
6.82	Kd	150	nM	R-406
6.77	Kd	170	nM	RUBOXISTAURIN
6.68	Kd	210	nM	MIDOSTAURIN
6.66	Kd	220	nM	SUNITINIB
6.66	Kd	220	nM	CHEMBL1908395
6.61	Kd	246	nM	PF-03814735
6.55	Kd	280	nM	DASATINIB
6.52	Kd	300	nM	SU-014813
6.50	Kd	320	nM	TAE-684
6.46	Kd	345	nM	AT-9283
6.37	Kd	430	nM	CHEMBL386051
6.36	Kd	442	nM	CHEMBL3688339
6.26	Kd	546	nM	BMS-690514
6.19	Kd	640	nM	CHEMBL1241674
6.13	IC50	738	nM	CHEMBL5559304
6.06	Kd	880	nM	GSK-690693
5.96	Kd	1089	nM	Cerdulatinib Hydrochloride
5.89	Kd	1300	nM	FEDRATINIB
5.88	Kd	1311	nM	BOSUTINIB
5.82	Kd	1500	nM	CGP-52421
5.72	Kd	1900	nM	TOZASERTIB
5.68	Kd	2094	nM	PELITINIB
5.68	Kd	2100	nM	GEFITINIB
5.68	Kd	2100	nM	MOTESANIB
5.64	Kd	2300	nM	ERLOTINIB
5.64	Kd	2300	nM	CANERTINIB
5.62	Kd	2386	nM	LESTAURTINIB
5.56	Kd	2747	nM	AMG-900
5.55	Kd	2800	nM	AXITINIB
5.55	Kd	2800	nM	STAUROSPORINE
5.50	Kd	3133	nM	CHEMBL4443828
5.49	Kd	3264	nM	SUNITINIB
5.32	Kd	4800	nM	FORETINIB
5.27	Kd	5349	nM	NINTEDANIB
5.23	Kd	5900	nM	PHA-665752

PubChem BioAssay actives

53 with measured affinity, of 495 total; 42 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
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507599: Binding affinity to MAP3K3	kd	0.0060	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715275: Inhibition of human MEKK3 using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0076	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148692: Binding affinity to human MAP3K3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0240	uM
4-[(2,9-dimethyl-8-oxo-6-thia-2,9,12,14-tetrazatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),4,10,12-pentaen-13-yl)amino]benzenesulfonamide	2189152: Binding affinity to MAP3K3 (unknown origin) assessed as dissociation constant	kd	0.0270	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624865: Binding constant for MAP3K3 kinase domain	kd	0.0340	uM
Bosutinib	624865: Binding constant for MAP3K3 kinase domain	kd	0.0540	uM
Crizotinib	624865: Binding constant for MAP3K3 kinase domain	kd	0.1100	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624865: Binding constant for MAP3K3 kinase domain	kd	0.1200	uM
Neratinib	624865: Binding constant for MAP3K3 kinase domain	kd	0.1300	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624865: Binding constant for MAP3K3 kinase domain	kd	0.1500	uM
Ruxolitinib	624865: Binding constant for MAP3K3 kinase domain	kd	0.1500	uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione	624865: Binding constant for MAP3K3 kinase domain	kd	0.1700	uM
Midostaurin	507599: Binding affinity to MAP3K3	kd	0.2100	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624865: Binding constant for MAP3K3 kinase domain	kd	0.2200	uM
Sunitinib	507599: Binding affinity to MAP3K3	kd	0.2200	uM
N-[2-[4-[[4-(cyclobutylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-11-azatricyclo[6.2.1.02,7]undeca-2(7),3,5-trien-11-yl]-2-oxoethyl]acetamide	1425047: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.2460	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	624865: Binding constant for MAP3K3 kinase domain	kd	0.2800	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	624865: Binding constant for MAP3K3 kinase domain	kd	0.3000	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624865: Binding constant for MAP3K3 kinase domain	kd	0.3200	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1425047: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.3450	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624865: Binding constant for MAP3K3 kinase domain	kd	0.4300	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425047: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.4420	uM
(3R,4R)-4-amino-1-[[4-(3-methoxyanilino)pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol	1425047: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.5460	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624865: Binding constant for MAP3K3 kinase domain	kd	0.6400	uM
N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-[2-(3,5-dimethoxyanilino)pyrimidin-4-yl]-1-methylpyrazole-5-carboxamide	2075974: Inhibition of MAP3K3 (unknown origin)	ic50	0.7380	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	624865: Binding constant for MAP3K3 kinase domain	kd	0.8800	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide;hydrochloride	1425047: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.0890	uM
Fedratinib	624865: Binding constant for MAP3K3 kinase domain	kd	1.3000	uM
N-[(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide	507599: Binding affinity to MAP3K3	kd	1.5000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	624865: Binding constant for MAP3K3 kinase domain	kd	1.9000	uM
(E)-N-[4-(3-chloro-4-fluoroanilino)-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide	1425047: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.0940	uM
N-(3,3-dimethyl-1,2-dihydroindol-6-yl)-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide	624865: Binding constant for MAP3K3 kinase domain	kd	2.1000	uM
Gefitinib	624865: Binding constant for MAP3K3 kinase domain	kd	2.1000	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	624865: Binding constant for MAP3K3 kinase domain	kd	2.3000	uM
Erlotinib	624865: Binding constant for MAP3K3 kinase domain	kd	2.3000	uM
N-[4-[[3-(2-aminopyrimidin-4-yl)-2-pyridinyl]oxy]phenyl]-4-(4-methylthiophen-2-yl)phthalazin-1-amine	1425047: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.7470	uM
Axitinib	624865: Binding constant for MAP3K3 kinase domain	kd	2.8000	uM
2,5-difluoro-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]benzenesulfonamide	1573306: Binding affinity to MAP3K3 in SILAC-labeled human MDA-MB-231 cells lysate by mass spectrometry based kinAffinity assay	kd	3.1330	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624865: Binding constant for MAP3K3 kinase domain	kd	4.8000	uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one	624865: Binding constant for MAP3K3 kinase domain	kd	5.9000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148692: Binding affinity to human MAP3K3 incubated for 45 mins by Kinobead based pull down assay	kd	8.1461	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	624865: Binding constant for MAP3K3 kinase domain	kd	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Vorinostat	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
moringin	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
bufalin	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
diallyl disulfide	affects expression	1
allyl sulfide	affects expression	1
diallyl trisulfide	affects expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	affects expression	1
2-palmitoylglycerol	increases expression	1
ON 01910	affects expression	1
Decitabine	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Glyphosate	decreases expression	1
Arsenicals	decreases expression	1
Caffeine	affects phosphorylation	1
Cannabidiol	increases expression	1
Chelating Agents	affects binding, increases expression	1
Copper	increases expression, affects binding	1
Diethylhexyl Phthalate	increases methylation, increases abundance	1
Estradiol	increases expression	1
Manganese	decreases expression, increases abundance	1
Menthol	decreases expression	1
Mercuric Chloride	decreases expression	1
Plant Extracts	decreases expression	1

ChEMBL screening assays

189 unique, capped per target: 189 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1038686	Binding	Inhibition of MEKK3	Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. — J Med Chem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7Y5	Abcam Raji MAP3K3 KO	Cancer cell line	Male
CVCL_B9YV	Abcam THP-1 MAP3K3 KO	Cancer cell line	Male
CVCL_C7AL	Abcam PC-3 MAP3K3 KO	Cancer cell line	Male
CVCL_D7UB	Ubigene A-549 MAP3K3 KO	Cancer cell line	Male
CVCL_D8Q1	Ubigene HCT 116 MAP3K3 KO	Cancer cell line	Male
CVCL_SW67	HAP1 MAP3K3 (-)	Cancer cell line	Male
CVCL_VP06	HEK293-HM3	Transformed cell line	Female

Clinical trials (associated diseases)

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