MAP3K6

Summary

MAP3K6 (mitogen-activated protein kinase kinase kinase 6, HGNC:6858) is a protein-coding gene on chromosome 1p36.11, encoding Mitogen-activated protein kinase kinase kinase 6 (O95382). Component of a protein kinase signal transduction cascade.

This gene encodes a serine/threonine protein kinase that forms a component of protein kinase-mediated signal transduction cascades. The encoded kinase participates in the regulation of vascular endothelial growth factor (VEGF) expression. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 9064 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary diffuse gastric adenocarcinoma (Supportive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 275 total — 1 likely-pathogenic
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004672

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6858
Approved symbol	MAP3K6
Name	mitogen-activated protein kinase kinase kinase 6
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	MAPKKK6, ASK2, MEKK6
Ensembl gene	ENSG00000142733
Ensembl biotype	protein_coding
OMIM	604468
Entrez	9064

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 5 retained_intron

ENST00000357582, ENST00000374040, ENST00000470890, ENST00000476509, ENST00000486046, ENST00000493901, ENST00000495230, ENST00000671291, ENST00000891016, ENST00000891017, ENST00000891018, ENST00000954776, ENST00000954777, ENST00000954778

RefSeq mRNA: 2 — MANE Select: NM_004672 NM_001297609, NM_004672

CCDS: CCDS299, CCDS72738

Canonical transcript exons

ENST00000357582 — 29 exons

Exon	Start	End
ENSE00000956097	27360241	27360368
ENSE00000956098	27359858	27359994
ENSE00000956099	27359417	27359522
ENSE00000956100	27358709	27358866
ENSE00001037703	27363442	27363548
ENSE00001037706	27362851	27363021
ENSE00001037707	27361346	27361395
ENSE00001037710	27361520	27361627
ENSE00001037713	27362641	27362753
ENSE00001037716	27362091	27362250
ENSE00001037717	27361705	27361867
ENSE00001037718	27361157	27361252
ENSE00001037721	27360705	27360838
ENSE00001037722	27360921	27361008
ENSE00001600618	27357400	27357576
ENSE00001620649	27358419	27358611
ENSE00001637431	27364204	27364394
ENSE00001659354	27357711	27357876
ENSE00001689261	27364773	27364912
ENSE00001691897	27358181	27358319
ENSE00001747536	27363917	27364085
ENSE00001755515	27364661	27364684
ENSE00001758759	27357009	27357114
ENSE00001791817	27356590	27356749
ENSE00001810757	27355184	27355469
ENSE00001816251	27366258	27366961
ENSE00003479165	27356388	27356500
ENSE00003481175	27355669	27355745
ENSE00003606672	27356026	27356099

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 98.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.1797 / max 62.5784, expressed in 1640 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11225	5.7033	1552
11222	0.2545	101
11224	0.0873	26
11221	0.0750	18
11223	0.0596	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	98.76	gold quality
right lung	UBERON:0002167	98.45	gold quality
skin of abdomen	UBERON:0001416	97.63	gold quality
skin of leg	UBERON:0001511	97.57	gold quality
apex of heart	UBERON:0002098	97.43	gold quality
ectocervix	UBERON:0012249	97.23	gold quality
upper lobe of left lung	UBERON:0008952	97.13	gold quality
left uterine tube	UBERON:0001303	96.91	gold quality
tibial nerve	UBERON:0001323	96.51	gold quality
esophagus mucosa	UBERON:0002469	96.41	gold quality
endocervix	UBERON:0000458	96.22	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.19	gold quality
lower esophagus	UBERON:0013473	96.17	gold quality
omental fat pad	UBERON:0010414	96.14	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.09	gold quality
esophagus	UBERON:0001043	96.07	gold quality
peritoneum	UBERON:0002358	96.06	gold quality
mucosa of stomach	UBERON:0001199	95.68	gold quality
upper lobe of lung	UBERON:0008948	95.68	gold quality
right lobe of thyroid gland	UBERON:0001119	95.61	gold quality
ascending aorta	UBERON:0001496	95.59	gold quality
thoracic aorta	UBERON:0001515	95.56	gold quality
left coronary artery	UBERON:0001626	95.56	gold quality
descending thoracic aorta	UBERON:0002345	95.28	gold quality
right atrium auricular region	UBERON:0006631	95.27	gold quality
tibial artery	UBERON:0007610	95.18	gold quality
aorta	UBERON:0000947	95.17	gold quality
popliteal artery	UBERON:0002250	95.17	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.08	gold quality
minor salivary gland	UBERON:0001830	95.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.53

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1, TCF7L2

miRNA regulators (miRDB)

16 targeting MAP3K6, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-6811-3P	98.62	66.54	944
HSA-MIR-12125	98.59	67.54	1044
HSA-MIR-6882-3P	98.23	67.01	1119
HSA-MIR-6742-3P	97.95	64.50	1490
HSA-MIR-1231	95.10	65.63	663
HSA-MIR-6741-5P	93.86	63.06	437

Literature-anchored findings (GeneRIF, showing 6)

• Apoptosis signal-regulating kinase (ASK) 2 functions as a mitogen-activated protein kinase kinase kinase in a heteromeric complex with ASK1. (PMID:17210579)
• regulation of VEGF by MAP3K6 may play a crucial role in both angiogenesis and tumorigenesis. (PMID:19246638)
• MAP3K6 acts as a tumor suppressor, and studies showing the presence of somatic mutations in MAP3K6 in non-hereditary gastric cancers and gastric cancer cell lines, point towards MAP3K6 variants as a predisposing factor for familial gastric cancer (PMID:25340522)
• Data show that the MAPKKK6 ASK2, a modulator of MAPKKK5 ASK1 signaling, was essential for ASK1-dependent apoptosis, but not for inducing interferon-beta (IFNB) expression. (PMID:26243192)
• MAP3K6 should no longer be considered a gastric cancer (GC) predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility. (PMID:29330337)
• Structure-based mechanism of preferential complex formation by apoptosis signal-regulating kinases. (PMID:32156783)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-1i11.3	ENSDARG00000104760
mus_musculus	Map3k6	ENSMUSG00000028862
rattus_norvegicus	Map3k6	ENSRNOG00000008936
drosophila_melanogaster	Ask1	FBGN0014006
caenorhabditis_elegans		WBGENE00003822

Paralogs (2): MAP3K15 (ENSG00000180815), MAP3K5 (ENSG00000197442)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase 6 — O95382 (reviewed: O95382)

Alternative names: Apoptosis signal-regulating kinase 2

All UniProt accessions (2): O95382, H0Y8A3

UniProt curated annotations — full annotation on UniProt →

Function. Component of a protein kinase signal transduction cascade. Activates the JNK, but not ERK or p38 kinase pathways.

Subunit / interactions. Binds both upstream activators and downstream substrates in multimolecular complexes.

Activity regulation. Activated by phosphorylation on Thr-806. Catalytically active only when complexed with MAP3K5, with MAP3K5 supporting the stability and the active configuration of MAP3K6 and MAP3K6 activating MAP3K5 by direct phosphorylation.

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

Isoforms (3)

UniProt ID	Names	Canonical?
O95382-1	1	yes
O95382-2	2
O95382-3	3

RefSeq proteins (2): NP_001284538, NP_004663* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR025136	MAP3K_TRAF-bd	Domain
IPR043969	MAP3K_PH	Domain
IPR046872	DRHyd-ASK	Domain
IPR046873	HisK-N-like	Domain

Pfam: PF00069, PF13281, PF19039, PF20302, PF20309

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)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
MEK	0.0002–0.0004	6
ATP	0.02–0.394	5

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 (36 total): sequence variant 12, modified residue 5, splice variant 4, compositionally biased region 4, binding site 2, region of interest 2, sequence conflict 2, coiled-coil region 2, chain 1, domain 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95382-F1	75.36	0.28

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): 771 (proton acceptor)

Ligand- & substrate-binding residues (2): 654–662; 677

Post-translational modifications (5): 806, 964, 984, 1129, 1149

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 113 (showing top): KEGG_MAPK_SIGNALING_PATHWAY, AP2_Q3, GGGTGGRR_PAX4_03, RUTELLA_RESPONSE_TO_CSF2RB_AND_IL4_UP, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, GOBP_JNK_CASCADE, BACH2_01, RUTELLA_RESPONSE_TO_HGF_VS_CSF2RB_AND_IL4_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_12HR_UP, TGANTCA_AP1_C, BIOCARTA_MAPK_PATHWAY, BURTON_ADIPOGENESIS_2, AP2GAMMA_01, PARENT_MTOR_SIGNALING_UP, SCGGAAGY_ELK1_02

GO Biological Process (5): protein phosphorylation (GO:0006468), signal transduction (GO:0007165), JNK cascade (GO:0007254), p38MAPK cascade (GO:0038066), MAPK cascade (GO:0000165)

GO Molecular Function (11): magnesium ion binding (GO:0000287), MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	3
protein kinase activity	2
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
metal ion binding	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

842 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K6	TXN	P10599	566
MAP3K6	JUN	P05412	530
MAP3K6	CUL1	Q13616	491
MAP3K6	YWHAH	Q04917	449
MAP3K6	RBX1	P62877	444
MAP3K6	MAP3K5	Q99683	443
MAP3K6	FBXO24	O75426	440
MAP3K6	CTNNA1	P35221	435
MAP3K6	YWHAQ	P27348	411
MAP3K6	YWHAE	P29360	410
MAP3K6	YWHAB	P31946	410
MAP3K6	HP1BP3	Q5SSJ5	402
MAP3K6	HSPA4	P34932	391
MAP3K6	ARHGAP22	Q7Z5H3	387
MAP3K6	IL20RA	Q9UHF4	367

IntAct

32 interactions, top by confidence:

A	B	Type	Score
MAP3K6	YWHAG	psi-mi:“MI:0914”(association)	0.640
YWHAG	MAP3K6	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
SFN	MAP3K6	psi-mi:“MI:0915”(physical association)	0.560
MAP3K5	MAP3K6	psi-mi:“MI:0914”(association)	0.550
MAP3K6	MAP3K5	psi-mi:“MI:0915”(physical association)	0.550
PRKAB2	PRKAB2	psi-mi:“MI:0914”(association)	0.550
MAP3K6	YWHAE	psi-mi:“MI:0915”(physical association)	0.400
MAP3K6	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
MAP2K3	SUPT5H	psi-mi:“MI:0914”(association)	0.350
MAP2K3	USP9Y	psi-mi:“MI:0914”(association)	0.350
MAP3K6	TGM1	psi-mi:“MI:0914”(association)	0.350
PRKAA2	DFFA	psi-mi:“MI:0914”(association)	0.350
KRT2	IFT56	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
HNRNPCL2	SMCHD1	psi-mi:“MI:0914”(association)	0.350
TNFSF13B	TNPO2	psi-mi:“MI:0914”(association)	0.350
PLEKHO2	MAP3K6	psi-mi:“MI:0914”(association)	0.350
EEF1AKMT3	SMCHD1	psi-mi:“MI:0914”(association)	0.350
UBXN6	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
D2HGDH	ZSWIM8	psi-mi:“MI:0914”(association)	0.350
NPRL2	APAF1	psi-mi:“MI:0914”(association)	0.350
MAPK4	INPPL1	psi-mi:“MI:0914”(association)	0.350
DHFR	FANCA	psi-mi:“MI:0914”(association)	0.350
MAP3K6	PEX5	psi-mi:“MI:0914”(association)	0.350
P4HA2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
SYT1	AP3B1	psi-mi:“MI:0914”(association)	0.350
asnO3	MAP3K6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (67): MAP3K6 (Affinity Capture-RNA), MAP3K6 (Affinity Capture-MS), MAP3K6 (Affinity Capture-MS), MAP3K6 (Affinity Capture-MS), MAP3K6 (Affinity Capture-MS), MAP3K6 (Affinity Capture-MS), MAP3K6 (Affinity Capture-MS), HSP90AA5P (Affinity Capture-MS), HSP90AA4P (Affinity Capture-MS), FKBP5 (Affinity Capture-MS), HSP90AB4P (Affinity Capture-MS), USP4 (Affinity Capture-MS), LIMD1 (Affinity Capture-MS), PCDHA4 (Affinity Capture-MS), RNF123 (Affinity Capture-MS)

ESM2 similar proteins: A0A061IR73, A0A7N9VSG0, A7YSY2, D3KCC4, D3ZU57, D4A2B7, O08644, O15197, O19179, O43542, O75064, O95382, P0C0K6, P0C0K7, P51840, P52785, P52824, P54777, Q02846, Q05932, Q13470, Q13608, Q1HG60, Q3ZBE0, Q4KM32, Q5JZY3, Q643R3, Q6MG64, Q6NVG1, Q6ZPS2, Q76MJ5, Q7TNJ2, Q80SX8, Q8BYG9, Q8IZY2, Q8NFF5, Q8R5G7, Q8TDZ2, Q8WWN8, Q91V24

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

6 interactions.

A	Effect	B	Mechanism
MAP3K6	“up-regulates activity”	MAP3K5	phosphorylation
MAP3K6	“up-regulates activity”	MAP3K6	phosphorylation
MAP3K5	“up-regulates quantity by stabilization”	MAP3K6	binding
MAP3K6	“up-regulates quantity by stabilization”	MAP3K5	phosphorylation
MAP3K6	“up-regulates activity”	MAPK14	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 38 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
Intrinsic Pathway for Apoptosis	5	48.8×	2e-06
Translocation of SLC2A4 (GLUT4) to the plasma membrane	6	30.9×	2e-06
Apoptosis	5	28.0×	2e-05
TP53 Regulates Metabolic Genes	6	25.9×	3e-06
Programmed Cell Death	5	24.4×	3e-05
Transcriptional Regulation by TP53	8	16.6×	2e-06
Membrane Trafficking	8	9.9×	2e-05
Vesicle-mediated transport	8	9.3×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	199
Likely benign	23
Benign	17

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
806105	NM_004672.5(MAP3K6):c.2544del (p.Phe849fs)	Likely pathogenic

SpliceAI

4053 predictions. Top by Δscore:

Variant	Effect	Δscore
1:27355765:C:CT	acceptor_gain	1.0000
1:27356096:GCAG:G	acceptor_gain	1.0000
1:27356097:CAG:C	acceptor_gain	1.0000
1:27356097:CAGC:C	acceptor_gain	1.0000
1:27356100:C:CC	acceptor_gain	1.0000
1:27356383:CTCA:C	donor_gain	1.0000
1:27356386:A:AC	donor_gain	1.0000
1:27356386:ACT:A	donor_loss	1.0000
1:27356387:C:CA	donor_gain	1.0000
1:27356423:T:TA	donor_gain	1.0000
1:27356496:GCAGC:G	acceptor_gain	1.0000
1:27356497:CAGC:C	acceptor_gain	1.0000
1:27356497:CAGCC:C	acceptor_gain	1.0000
1:27356498:AGC:A	acceptor_gain	1.0000
1:27356499:GC:G	acceptor_gain	1.0000
1:27356499:GCCT:G	acceptor_loss	1.0000
1:27356500:CC:C	acceptor_gain	1.0000
1:27356501:C:CC	acceptor_gain	1.0000
1:27356501:CT:C	acceptor_loss	1.0000
1:27356502:T:G	acceptor_loss	1.0000
1:27356509:C:CT	acceptor_gain	1.0000
1:27356511:C:CT	acceptor_gain	1.0000
1:27356512:A:T	acceptor_gain	1.0000
1:27357466:T:TA	donor_gain	1.0000
1:27357572:GCCCC:G	acceptor_gain	1.0000
1:27357573:CCCC:C	acceptor_gain	1.0000
1:27357573:CCCCC:C	acceptor_gain	1.0000
1:27357574:CCC:C	acceptor_gain	1.0000
1:27357574:CCCC:C	acceptor_gain	1.0000
1:27357575:CC:C	acceptor_gain	1.0000

AlphaMissense

8256 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:27359473:T:A	D790V	1.000
1:27360728:C:A	K677N	1.000
1:27360728:C:G	K677N	1.000
1:27358745:G:C	F849L	0.999
1:27358745:G:T	F849L	0.999
1:27358747:A:G	F849L	0.999
1:27358793:C:A	W833C	0.999
1:27358793:C:G	W833C	0.999
1:27358795:A:G	W833R	0.999
1:27358795:A:T	W833R	0.999
1:27359472:G:C	D790E	0.999
1:27359472:G:T	D790E	0.999
1:27359473:T:G	D790A	0.999
1:27359859:T:A	K773I	0.999
1:27359862:A:T	I772K	0.999
1:27359892:A:G	L762S	0.999
1:27358712:A:C	F860L	0.998
1:27358712:A:T	F860L	0.998
1:27358714:A:G	F860L	0.998
1:27358765:C:G	A843P	0.998
1:27358767:A:C	M842R	0.998
1:27358781:G:C	C837W	0.998
1:27358785:C:T	G836D	0.998
1:27359469:G:C	F791L	0.998
1:27359469:G:T	F791L	0.998
1:27359471:A:G	F791L	0.998
1:27359473:T:C	D790G	0.998
1:27359474:C:G	D790H	0.998
1:27359502:G:C	N780K	0.998
1:27359502:G:T	N780K	0.998

dbSNP variants (sampled 300 via entrez): RS1000284785 (1:27356168 T>C), RS1000847152 (1:27360598 T>C), RS1000942999 (1:27366880 G>A,T), RS1001060372 (1:27354826 C>T), RS1001413679 (1:27359149 C>A,T), RS1001535106 (1:27360863 A>C,G), RS1001620960 (1:27367295 C>T), RS1001674709 (1:27361428 C>T), RS1001854903 (1:27355031 C>T), RS1002307346 (1:27354930 G>C), RS1002651557 (1:27365828 T>A), RS1003080896 (1:27357932 C>T), RS1003405038 (1:27356819 G>A,T), RS1003625871 (1:27365002 G>A), RS1003676091 (1:27358337 C>A)

Disease associations

OMIM: gene MIM:604468 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary diffuse gastric adenocarcinoma	Supportive	Autosomal dominant
gastric cancer	Limited	Unknown

Mondo (2): gastric cancer (MONDO:0001056), hereditary diffuse gastric adenocarcinoma (MONDO:0007648)

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1163123 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 13,411 (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
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL3916717	SELONSERTIB	3	1,422
CHEMBL603469	LESTAURTINIB	3
CHEMBL574737	UCN-01	2	2,217
CHEMBL4289017	PF-03814735	1	537
CHEMBL574738	AST-487	1	451

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — STE11 family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 10 [PMID: 23147077]	Inhibition	6.29	pIC50

ChEMBL bioactivities

43 potent at pChembl≥5 of 43 total, top 42 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.20	IC50	6.31	nM	CHEMBL5746514
8.19	IC50	6.46	nM	CHEMBL5746514
8.08	IC50	8.32	nM	CHEMBL5937217
7.96	IC50	11	nM	CHEMBL6036447
7.80	IC50	15.8	nM	CHEMBL5812512
7.71	IC50	19.5	nM	CHEMBL6036447
7.04	IC50	90.8	nM	STAUROSPORINE
6.77	Kd	170	nM	LESTAURTINIB
6.70	IC50	200.8	nM	CHEMBL4763562
6.58	IC50	264.4	nM	CHEMBL4764071
6.58	Kd	260	nM	STAUROSPORINE
6.56	IC50	274	nM	STAUROSPORINE
6.47	Kd	335	nM	K-252A
6.42	Kd	378	nM	LESTAURTINIB
6.33	Kd	473	nM	Cerdulatinib Hydrochloride
6.32	IC50	475	nM	STAUROSPORINE
6.29	IC50	510	nM	CHEMBL2205637
6.29	IC50	510	nM	CHEMBL4778541
6.13	IC50	742.4	nM	CHEMBL4759182
5.98	Kd	1038	nM	CHEMBL3752910
5.97	Kd	1060	nM	PF-03814735
5.96	IC50	1091	nM	CHEMBL4776637
5.93	Kd	1185	nM	UCN-01
5.90	ED50	1257	nM	CHEMBL3752910
5.83	IC50	1481	nM	CHEMBL4751918
5.80	Kd	1575	nM	LENVATINIB
5.80	IC50	1591	nM	CHEMBL4749551
5.75	Kd	1800	nM	TAE-684
5.72	Kd	1908	nM	CHEMBL3688339
5.63	IC50	2342	nM	CHEMBL4795965
5.56	IC50	2778	nM	CHEMBL4744931
5.54	IC50	2911	nM	CHEMBL4750857
5.54	IC50	2862	nM	CHEMBL4753203
5.31	IC50	4856	nM	CHEMBL4778358
5.30	IC50	4994	nM	CHEMBL4740051
5.28	IC50	5286	nM	CHEMBL4796925
5.20	IC50	6247	nM	SELONSERTIB
5.17	Kd	6826	nM	CHEMBL5653589
5.14	IC50	7170	nM	CHEMBL4752034
5.10	Kd	8000	nM	CHEMBL1908395
5.10	Kd	8000	nM	AST-487
5.08	ED50	8266	nM	CHEMBL5653589

PubChem BioAssay actives

34 with measured affinity, of 421 total; 29 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
(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	1715276: Inhibition of human MEKK6 using MBP as substrate by [gamma-33P]-ATP assay	ic50	0.0908	uM
(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	507835: Binding affinity to ASK2	kd	0.1700	uM
1-isoquinolin-1-yl-3-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]urea	1691905: Inhibition of ASK2 (unknown origin)	ic50	0.2008	uM
1-[6-[4-[(2R)-1-hydroxypropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]-3-isoquinolin-1-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	0.2644	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-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-nonaene-16-carboxylate	1425050: 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	0.3350	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide;hydrochloride	1425050: 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	0.4730	uM
4-tert-butyl-N-(6-imidazol-1-ylimidazo[1,2-a]pyridin-2-yl)benzamide;hydrochloride	717543: Inhibition of ASK2	ic50	0.5100	uM
1-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3-(7H-purin-2-yl)urea	1691905: Inhibition of ASK2 (unknown origin)	ic50	0.7424	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148695: Binding affinity to human MAP3K6 incubated for 45 mins by Kinobead based pull down assay	kd	1.0382	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	1425050: 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	1.0600	uM
1-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3-pyridin-2-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	1.0910	uM
(2S,3R,4R,6R,18S)-18-hydroxy-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	1425050: 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	1.1850	uM
1-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3-quinazolin-4-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	1.4810	uM
Lenvatinib	1425050: 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	1.5750	uM
1-isoquinolin-3-yl-3-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]urea	1691905: Inhibition of ASK2 (unknown origin)	ic50	1.5910	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	624962: Binding constant for ASK2 kinase domain	kd	1.8000	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425050: 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	1.9080	uM
1-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3-quinolin-2-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	2.3420	uM
1-[5-(1-methylpyrazol-3-yl)-2-pyridinyl]-3-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]urea	1691905: Inhibition of ASK2 (unknown origin)	ic50	2.7780	uM
1-[6-[4-[(2R)-1-hydroxypropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]-3-quinolin-2-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	2.8620	uM
1-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3-quinazolin-2-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	2.9110	uM
1-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3-quinoxalin-2-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	4.8560	uM
1-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]-3-pyrazolo[1,5-a]pyridin-2-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	4.9940	uM
1-[6-[4-[(2R)-1-hydroxypropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]-3-pyrazolo[1,5-a]pyridin-2-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	5.2860	uM
5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)-2-pyridinyl]benzamide	1691905: Inhibition of ASK2 (unknown origin)	ic50	6.2470	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148695: Binding affinity to human MAP3K6 incubated for 45 mins by Kinobead based pull down assay	kd	6.8256	uM
1-[6-[4-[(2R)-1-hydroxypropan-2-yl]-1,2,4-triazol-3-yl]-2-pyridinyl]-3-quinazolin-2-ylurea	1691905: Inhibition of ASK2 (unknown origin)	ic50	7.1700	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624962: Binding constant for ASK2 kinase domain	kd	8.0000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624962: Binding constant for ASK2 kinase domain	kd	8.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
sodium arsenite	increases abundance, increases expression	2
Cisplatin	affects expression, affects cotreatment, increases expression	2
Asbestos, Crocidolite	affects expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases expression	1
trichostatin A	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	increases abundance, affects methylation	1
Am 580	decreases expression	1
2-palmitoylglycerol	increases expression	1
entinostat	increases expression	1
monomethylarsonous acid	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Rosiglitazone	decreases expression	1
Decitabine	affects expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1
Cadmium	increases expression	1
Cannabinoids	affects methylation, increases abundance	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Gallic Acid	increases expression	1

ChEMBL screening assays

103 unique, capped per target: 103 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1168790	Binding	Inhibition of ASK2 at 1 uM	Synthesis and structure-activity relationships of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines as potent and selective inhibitors of the anaplastic lymphoma kinase. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7UC	Ubigene A-549 MAP3K6 KO	Cancer cell line	Male
CVCL_D9JF	Ubigene HEK293 MAP3K6 KO	Transformed cell line	Female
CVCL_SW72	HAP1 MAP3K6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00558155	PHASE4	COMPLETED	The Impact of Immunostimulating Nutrition on the Outcome of Surgery
NCT00576940	PHASE4	COMPLETED	Standard and Immunostimulating Enteral Nutrition in Surgical Patients
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT01038154	PHASE4	UNKNOWN	Study to Evaluate the Efficacy of Pravastatin on Survival and Recurrence of Advanced Gastroesophageal Cancer
NCT01234272	PHASE4	COMPLETED	Comparison of the Analgesic Effect Between Intrathecal Morphine and IV-fentanyl Patient Controlled Analgesia (ITM-IVPCA) and Epidural PCA (PCEA) in Patients Undergoing Gastrectomy -Randomized Allocation Study-
NCT01260194	PHASE4	TERMINATED	A Study of Herceptin (Trastuzumab) in Combination With Standard Chemotherapy in Patients With HER Positive Metastatic Gastric Cancer
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01401075	PHASE4	COMPLETED	RCT With Adjuvant Mistletoe Treatment in Gastric Cancer Patients
NCT01471756	PHASE4	COMPLETED	Improving Complete Endoscopic Mucosal Resection (EMR) of Colorectal Neoplasia
NCT01766765	PHASE4	UNKNOWN	Early Jejunostomy Nutrition Minimizes Time to Chemotherapy
NCT01910948	PHASE4	UNKNOWN	Perioperative Application of Omega-3 Polyunsaturated Fatty Acids in Gastric Cancer Patients
NCT01927328	PHASE4	UNKNOWN	Iron Replacement in Oesophagogastric Neoplasia
NCT01962272	PHASE4	COMPLETED	The Effect of Nutritional Counseling for Cancer Patients
NCT01962376	PHASE4	UNKNOWN	Preoperative Chemotherapy With Bevacizumab For Potentially Resectable Gastric Cancer With Liver Metastasis
NCT02047994	PHASE4	RECRUITING	Multicentric Randomized Study of H. Pylori Eradication and Pepsinogen Testing for Prevention of Gastric Cancer Mortality
NCT02235246	PHASE4	COMPLETED	The Effect of Perioperative Intravenous Magnesium on Pain After Endoscopic Submucosal Dissection for Gastric Neoplasm: Prospective Randomized Double-blind Placebo Controlled Study
NCT02366819	PHASE4	SUSPENDED	Genetic Analysis-Guided Irinotecan Hydrochloride Dosing of mFOLFIRINOX in Treating Patients With Locally Advanced Gastroesophageal or Stomach Cancer
NCT02401971	PHASE4	UNKNOWN	Irinotecan Plus Thalidomide in Second Line Advanced Gastric Cancer
NCT02458573	PHASE4	COMPLETED	Comparison of the Effects of Continuous Epidural Analgesia and Continuous Intravenous Analgesia on Postoperative Bowel Movement in Patients Undergoing Laparoscopic Gastrectomy
NCT02638584	PHASE4	COMPLETED	Effects of Ilaprazole on Ulcer Healing Rate and Prevention of Gastrointestinal Bleeding in the Patients Undergone ESD.
NCT02776527	PHASE4	UNKNOWN	A Clinical Trial of Maintenance Treatment of Apatinib in Advanced Gastric Cancer Patients Have Completed Postoprative Adjuvant Chemotherapy
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03550482	PHASE4	COMPLETED	Oncoxin® and Quality of Life in Cancer Patients
NCT03609892	PHASE4	COMPLETED	Helicobacter Rescue Therapy With Berberine Plus Amoxicillin Quadruple Therapy Versus Tetracycline Plus Furazolidone Quadruple Therapy
NCT03642093	PHASE4	UNKNOWN	HOPE - A Study to Evaluate the Effect of a Prehabilitation Program on GI Cancer Patients Planning to Undergo Surgery
NCT03733639	PHASE4	UNKNOWN	Tisseel® as a Reinforcement of Esophagojejunal Anastomoses
NCT04168346	PHASE4	NOT_YET_RECRUITING	Preoperative Intravenous Iron Therapy in Patients With Gastric Cancer
NCT04209933	PHASE4	COMPLETED	Helicobacter Pylori Eradication With Different Bismuth Quadruple Therapies
NCT04591028	PHASE4	WITHDRAWN	A Study to Evaluate Indocyanine Green Lymphangiography to Improve Lymphadenectomy in Gastric Cancer Patients
NCT04607057	PHASE4	UNKNOWN	Supplemental Parenteral Nutrition During Postgastrectomy in Nutritionally at Risk Patient
NCT04660123	PHASE4	COMPLETED	A Real World Study of Bismuth Colloidal Pectin Granules Quadruple Therapy for H. Pylori Eradication
NCT04678492	PHASE4	COMPLETED	Helicobacter Rescue Therapy With High-dose Esomeprazole and Amoxicillin Dual Therapy Versus Bismuth-containing Quadruple Therapy
NCT04697186	PHASE4	COMPLETED	Helicobacter Pylori Eradication With Berberine Plus Amoxicillin Triple Therapy Versus Bismuth-containing Quadruple Therapy
NCT05029453	PHASE4	UNKNOWN	Apatinib Combined With Chemotherapy Versus Chemotherapy in Second-line Gastric Cancer Receiving Prior Anti-PD-1 Therapy
NCT05183126	PHASE4	RECRUITING	Pharmacokinetic Study of Skeletal Muscle Area-based Paclitaxel Infusion in Patients With Cancer
NCT05354856	PHASE4	TERMINATED	The Effect of Chemoradiotherapy on Gastric Perfusion in Patients With Gastric Cancer.
NCT05410535	PHASE4	COMPLETED	To Evaluate Efficacy of Ursodeoxycholic Acid (UDCA) for the Prevention of Gallstone Formation After Gasterectomy
NCT05498766	PHASE4	NOT_YET_RECRUITING	Effect and Safety of Huaier Granule Versus SOX Regimen in Gastric Cancer Patients
NCT05518929	PHASE4	COMPLETED	Hypoxia During Gastroenterological Endoscope Procedures Sedated With Ciprofol In Overweight Or Obesity Patients