MAP2K6

Summary

MAP2K6 (mitogen-activated protein kinase kinase 6, HGNC:6846) is a protein-coding gene on chromosome 17q24.3, encoding Dual specificity mitogen-activated protein kinase kinase 6 (P52564). Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.

This gene encodes a member of the dual specificity protein kinase family, which functions as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein phosphorylates and activates p38 MAP kinase in response to inflammatory cytokines or environmental stress. As an essential component of p38 MAP kinase mediated signal transduction pathway, this gene is involved in many cellular processes such as stress induced cell cycle arrest, transcription activation and apoptosis.

Source: NCBI Gene 5608 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 31 total
• Druggable target: yes — 16 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002758

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6846
Approved symbol	MAP2K6
Name	mitogen-activated protein kinase kinase 6
Location	17q24.3
Locus type	gene with protein product
Status	Approved
Aliases	MEK6, MKK6, SAPKK3, MAPKK6, CRCMSL
Ensembl gene	ENSG00000108984
Ensembl biotype	protein_coding
OMIM	601254
Entrez	5608

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000359094, ENST00000586641, ENST00000588110, ENST00000589295, ENST00000589647, ENST00000590474, ENST00000591445, ENST00000592348, ENST00000858496, ENST00000928053

RefSeq mRNA: 2 — MANE Select: NM_002758 NM_001330450, NM_002758

CCDS: CCDS11686, CCDS82194

Canonical transcript exons

ENST00000590474 — 12 exons

Exon	Start	End
ENSE00001406278	69414697	69415000
ENSE00002780034	69541676	69553865
ENSE00003536946	69526570	69526709
ENSE00003550981	69536115	69536160
ENSE00003551163	69505780	69505846
ENSE00003554195	69520270	69520386
ENSE00003625227	69524901	69524978
ENSE00003625472	69519313	69519432
ENSE00003626341	69516855	69516903
ENSE00003652466	69521049	69521100
ENSE00003655398	69517500	69517613
ENSE00003692156	69523514	69523641

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 92.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.0166 / max 683.1810, expressed in 1278 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
162459	7.7357	1051
162464	1.8211	520
162460	0.6481	313
162463	0.4002	161
162462	0.1725	39
162461	0.0969	52
162465	0.0747	26
162466	0.0673	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	92.80	gold quality
mucosa of transverse colon	UBERON:0004991	92.29	gold quality
biceps brachii	UBERON:0001507	91.82	gold quality
vastus lateralis	UBERON:0001379	91.06	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	90.97	gold quality
quadriceps femoris	UBERON:0001377	90.62	gold quality
skeletal muscle tissue	UBERON:0001134	90.46	gold quality
gastrocnemius	UBERON:0001388	90.26	gold quality
muscle organ	UBERON:0001630	90.10	gold quality
triceps brachii	UBERON:0001509	89.99	gold quality
muscle of leg	UBERON:0001383	89.83	gold quality
deltoid	UBERON:0001476	89.40	gold quality
colonic mucosa	UBERON:0000317	88.78	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.52	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.15	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.14	gold quality
calcaneal tendon	UBERON:0003701	87.59	gold quality
body of tongue	UBERON:0011876	87.52	gold quality
monocyte	CL:0000576	87.13	gold quality
mononuclear cell	CL:0000842	86.77	gold quality
leukocyte	CL:0000738	86.65	gold quality
endometrium	UBERON:0001295	86.10	gold quality
tibialis anterior	UBERON:0001385	85.78	silver quality
muscle tissue	UBERON:0002385	84.54	gold quality
cortical plate	UBERON:0005343	84.08	gold quality
blood	UBERON:0000178	84.03	gold quality
transverse colon	UBERON:0001157	84.03	gold quality
buccal mucosa cell	CL:0002336	83.99	silver quality
bone marrow	UBERON:0002371	83.78	gold quality
colonic epithelium	UBERON:0000397	82.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.66

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, E2F1, JUN, ZHX2

miRNA regulators (miRDB)

82 targeting MAP2K6, 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-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-4694-3P	99.79	69.53	2640

Literature-anchored findings (GeneRIF, showing 40)

• active MKK6 in HepG2 cells enhanced basal activity or IL-6-induced transcriptional activation of a SOCS3 promoter (PMID:11727828)
• Results show that oncogenic ras provokes premature senescence by sequentially activating the MEK-ERK and MKK3/6-p38 pathways in normal, primary cells. (PMID:11971971)
• MKK6 is involved in a positive feedback loop regulating macrophage signaling with p38 MAP kinase (PMID:12509443)
• a specific requirement for p150(Glued)/dynein/functional microtubules in activation of MKK3/6 and p38 MAPKs in vivo. (PMID:15375157)
• role in cardioprotection (PMID:15492008)
• MAP kinase kinase3- and 6-dependent activation of the alpha-isoform of p38 MAP kinase is required for the cytoskeletal changes induced by neutrophil adherence and influences subsequent neutrophil migration toward endothelial cell junctions (PMID:15516490)
• PAK6 kinase activity was repressed by a p38 mitogen-activated protein (MAP) kinase antagonist and could be strongly stimulated by constitutively active MAP kinase kinase 6 (MKK6) (PMID:15550393)
• H-Ras-specific activation of Rac-MKK3/6-p38 pathway has a role in invasion and migration of breast epithelial cells (PMID:15677464)
• MKK6 promotes the development of cardiomyopathy by activation of a kinase cascade (PMID:15722372)
• MKK3 and MKK6 make individual contributions to p38 activation in fibroblast-like synoviocytes after cytokine stimulation (PMID:15778394)
• MEK6E activates p38 and results in phosphorylation of its downstream substrate, heat shock protein 27 (PMID:15790570)
• selectivity pocket compounds prevent MKK6-dependent activation of p38alpha in addition to inhibiting catalysis by activated p38alpha (PMID:16342939)
• findings show that Yersinia YopJ acted as an acetyltransferase, using acetyl-coenzyme A (CoA) to modify the critical serine and threonine residues in the activation loop of MAPKK6 and thereby blocking phosphorylation (PMID:16728640)
• Conditional induction of a dominant active form of MAPK kinase 6, a direct upstream kinase of p38, in Langerhans cells induces up-regulation of costimulatory molecules & enhances their T-cell stimulatory capacity. (PMID:16960152)
• Data suggest that sequence variations of ASK1 and MAP2K6 lead to partially sex-specific changes in the levels and/or phosphorylation states of p38 and p38-regulated proteins that might contribute to the observed delaying effects in the age of onset of HD. (PMID:18327563)
• as a mediator of SF- and Src-stimulated NF-kappaB activity. Finally, the Src/Rac1/MKK3/6/p38 and Src/TAK1/NF-kappaB-inducing kinase pathways exhibited cross-talk at the level of MKK3. (PMID:19047046)
• Gel filtration and small-angle X-ray scattering analysis confirm that the crystallographically observed ellipsoidal dimer is a feature of MEK6/DeltaN/DD and full-length unphosphorylated wild-type MEK6 in solution (PMID:19141286)
• Data provide evidence that p38 Map kinase pathway is activated leading to increased upregulation of mixed lineage kinase 3, MKK3/6, MSK1, and Mapkapk2, upon treatment of BCR/ABL expressing cells with dasatinib. (PMID:19672773)
• MKK6 p38 alpha signaling pathway regulates the expression of RAGE induced by mechanical stretch in A549 cells. (PMID:19846005)
• These results demonstrate that activin A induces erythroid differentiation of K562 cells through activation of MKK6-p38alpha/p38beta pathway and follistatin inhibits those effects. (PMID:20162623)
• Mechanism of oxidative stress-induced ASK1-catalyzed MKK6 phosphorylation.( (PMID:20364819)
• we demonstrated that MKK6 has a role for regulation of dendricity in melanocytes. (PMID:20869211)
• MKK6 and other MAP2Ks are a distinct class of cellular redox sensors (PMID:21078955)
• Results suggest that the p38alpha, MAPK, and MKK6 play prominent roles in IL-1beta and C/EBP-beta-mediated C3 gene expression in astrocytes. (PMID:21308746)
• Impaired cytokine production in natural killer (NK)T cells is demonstrated from MKK3-deficient6+/- mice. (PMID:21368234)
• activation by mechanical stretch induces HMGB1 and cytokine expression in A549 cells (PMID:21926646)
• Data suggest aberrant MAP2K protein (MKK3, MKK4, MKK6, and MKK7) expression indicates that altered cellular signal transduction mediated via JNK and p38 may be common in bladder cancer. (PMID:22154358)
• the balance between MKK6 and MKK3 mediates p38 MAPK associated resistance to cisplatin in NSCLC (PMID:22164285)
• crystal structure of human non-phosphorylated MAP2K6 (npMAP2K6) complexed with an ATP analogue was determined at 2.6 A resolution and represents an auto-inhibition state of MAP2K6 (PMID:22383536)
• The models confirmed the reaction order, revealed processivity in the phosphorylation of MEK6 by ASK1, and suggested that the order of phosphorylation is dictated by both binding and catalysis rates. (PMID:23744074)
• Serine phosphorylation of p66shc is carried out by active MKK6. beta-Amyloid-induced ROS production and apoptosis increased in the presence of MKK6 and p66shc, which directly associate. (PMID:24085465)
• uncover a new mechanism of deactivation of MKK6-p38 and substantiate a novel regulatory role of FBXO31 in stress response (PMID:24936062)
• Data show significant increase in the expression of MKK6 in Esophageal, Stomach, and Colon cancers as compared to controls. (PMID:25019214)
• Data indicate that mitogen-activated protein kinase kinase 6 (MKK6) levels were substantially higher in monocytes than in neutrophils. (PMID:25214442)
• MEK2 was essential for the phosphorylation of MKK3/MKK6 and p38 MAPK that directly impacted on cyclin D1 expression. (PMID:27181679)
• Data show that miR-625-3p induces oxaliplatin resistance by abrogating MAP2K6-p38-regulated apoptosis and cell cycle control networks. (PMID:27526785)
• acts as a repressor of UCP1 expression, suggesting that its inhibition promotes adipose tissue browning and increases organismal energy expenditure (PMID:29021624)
• The loss of MKK6 protein diminishes p38 activation, leading to further degradation of the remaining TRIM9 in glioblastoma cells. The disruption of the TRIM9s-MKK6 mutual stabilization loop ultimately leads to the inactivation of p38 signaling and promotes tumor progression. (PMID:29669288)
• Data suggest that mitogen-activated protein kinase kinase 6 (MAP2K6) might be an important regulator of leukemia inhibitory factor receptor (LIFR)-induced radioresistance in nasopharyngeal carcinoma cells (NPC). (PMID:30245131)
• Advanced glycation end products significantly activated ASK1, MKK3, and MKK6, which led to activation of p38 MAPK, resulting in upregulated fibrotic response in human coronary smooth muscle cells. (PMID:30305582)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	map2k6	ENSDARG00000099184
mus_musculus	Map2k6	ENSMUSG00000020623
rattus_norvegicus	Map2k6	ENSRNOG00000004437

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), PAK5 (ENSG00000101349), STK24 (ENSG00000102572), STK3 (ENSG00000104375), MAP4K1 (ENSG00000104814), MAP3K8 (ENSG00000107968), NEK4 (ENSG00000114904), STK25 (ENSG00000115694), NRK (ENSG00000123572), PAK4 (ENSG00000130669), STK26 (ENSG00000134602), TAOK3 (ENSG00000135090), PAK6 (ENSG00000137843), MINK1 (ENSG00000141503), PAK1 (ENSG00000149269), TAOK2 (ENSG00000149930), TNIK (ENSG00000154310), TAOK1 (ENSG00000160551), MAP4K2 (ENSG00000168067), OXSR1 (ENSG00000172939), MAP3K19 (ENSG00000176601), PAK2 (ENSG00000180370), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Dual specificity mitogen-activated protein kinase kinase 6 — P52564 (reviewed: P52564)

Alternative names: MAPK/ERK kinase 6, Stress-activated protein kinase kinase 3

All UniProt accessions (5): P52564, A0A0A0MRF7, A8K3Y2, K7EIW3, K7ELM6

UniProt curated annotations — full annotation on UniProt →

Function. Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.

Subunit / interactions. Dimer. Interacts (via its D domain) with its substrates MAPK11, MAPK12, MAPK13 and MAPK14. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2. Interacts with DCTN1. Interacts with EIF2AK2/PKR. (Microbial infection) Interacts with Yersinia YopJ.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton.

Tissue specificity. Isoform 2 is only expressed in skeletal muscle. Isoform 1 is expressed in skeletal muscle, heart, and in lesser extent in liver or pancreas.

Post-translational modifications. Weakly autophosphorylated. Phosphorylated at Ser-207 and Thr-211 by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2. In response to genotoxic stress, MAP3K-phosphorylated MAP2K6 is ubiquitinated and degraded by the SCF(FBXO31) complex. (Microbial infection) Acetylation of Ser-207 and Thr-211 by Yersinia YopJ prevents phosphorylation and activation, thus blocking the MAPK signaling pathway.

Activity regulation. Activated by dual phosphorylation on Ser-207 and Thr-211 in response to a variety of cellular stresses, including UV radiation, osmotic shock, hypoxia, inflammatory cytokines, interferon gamma (IFNG), and less often by growth factors. MAP2K6/MKK6 is activated by the majority of M3Ks, such as MAP3K5/ASK1, MAP3K1/MEKK1, MAP3K2/MEKK2, MAP3K3/MEKK3, MAP3K4/MEKK4, MAP3K7/TAK1, MAP3K11/MLK3 and MAP3K17/TAOK2.

Domain organisation. The DVD domain (residues 311-334) contains a conserved docking site and is found in the mammalian MAP kinase kinases (MAP2Ks). The DVD sites bind to their specific upstream MAP kinase kinase kinases (MAP3Ks) and are essential for activation. The D domain (residues 4-19) contains a conserved docking site and is required for the binding to MAPK substrates.

Induction. Strongly activated by UV, anisomycin, and osmotic shock but not by phorbol esters, NGF or EGF.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P52564-1	1, MKK6b	yes
P52564-2	2, MKK6

RefSeq proteins (2): NP_001317379, NP_002749* (*=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
IPR017441	Protein_kinase_ATP_BS	Binding_site

Pfam: PF00069

Enzyme classification (BRENDA):

• 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)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
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), 3 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• 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 (47 total): helix 14, strand 8, turn 5, modified residue 4, mutagenesis site 4, region of interest 3, binding site 2, chain 1, domain 1, splice variant 1, sequence conflict 1, compositionally biased region 1, active site 1, site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
2Y8O	X-RAY DIFFRACTION	1.95
8PM3	X-RAY DIFFRACTION	2
3FME	X-RAY DIFFRACTION	2.26
3ENM	X-RAY DIFFRACTION	2.35
5ETF	X-RAY DIFFRACTION	2.4
8P7J	X-RAY DIFFRACTION	2.4
3VN9	X-RAY DIFFRACTION	2.6
9M1Z	X-RAY DIFFRACTION	3
8A8M	ELECTRON MICROSCOPY	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52564-F1	79.58	0.48

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): 179 (proton acceptor); 14–15 (cleavage; by anthrax lethal factor)

Ligand- & substrate-binding residues (2): 59–67; 82

Post-translational modifications (4): 207, 207, 211, 211

Mutagenesis-validated functional residues (4):

Position	Phenotype
207	decreased phosphorylation by map3k, leading to inactivation.
207	mimics phosphorylation. increased interaction with fbxo31. constitutive activation according to pubmed:8622669, but not
211	inactivation.
211	mimics phosphorylation. increased interaction with fbxo31.constitutive activation according to pubmed:8622669, but not t

Function

Pathways and Gene Ontology

Reactome pathways

44 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-525793	Myogenesis
R-HSA-6811555	PI5P Regulates TP53 Acetylation
R-HSA-9020702	Interleukin-1 signaling
R-HSA-9833482	PKR-mediated signaling
R-HSA-5210891	Uptake and function of anthrax toxins
R-HSA-1169410	Antimicrobial mechanism of IFN-stimulated genes
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-3700989	Transcriptional Regulation by TP53

MSigDB gene sets: 398 (showing top): BIOCARTA_FMLP_PATHWAY, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_FGF3, REACTOME_INNATE_IMMUNE_SYSTEM, TGCGCANK_UNKNOWN, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, REACTOME_NOD1_2_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, MODULE_255, FISCHER_G1_S_CELL_CYCLE, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_SIGNALING_PATHWAY, PID_IL1_PATHWAY, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE

GO Biological Process (22): MAPK cascade (GO:0000165), osteoblast differentiation (GO:0001649), apoptotic process (GO:0006915), signal transduction (GO:0007165), stress-activated protein kinase signaling cascade (GO:0031098), nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway (GO:0035872), p38MAPK cascade (GO:0038066), signal transduction in response to DNA damage (GO:0042770), positive regulation of MAPK cascade (GO:0043410), stress-activated MAPK cascade (GO:0051403), regulation of cell cycle (GO:0051726), cardiac muscle contraction (GO:0060048), bone development (GO:0060348), cellular senescence (GO:0090398), negative regulation of cold-induced thermogenesis (GO:0120163), regulation of signal transduction by p53 class mediator (GO:1901796), protein phosphorylation (GO:0006468), protein maturation (GO:0051604), pyroptotic inflammatory response (GO:0070269), cellular response to UV-B (GO:0071493), regulation of intracellular signal transduction (GO:1902531), NLRP1 inflammasome complex assembly (GO:1904784)

GO Molecular Function (12): protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase activity (GO:0004708), protein tyrosine kinase activity (GO:0004713), ATP binding (GO:0005524), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Toll-like Receptor Cascades	6
Toll Like Receptor 4 (TLR4) Cascade	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Cellular Senescence	1
MAP kinase activation	1
Developmental Biology	1
Regulation of TP53 Activity through Acetylation	1
Interleukin-1 family signaling	1
Antimicrobial mechanism of IFN-stimulated genes	1
Uptake and actions of bacterial toxins	1
Interferon Signaling	1
Immune System	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Toll Like Receptor 2 (TLR2) Cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	4
protein kinase activity	3
cellular anatomical structure	3
cellular process	2
regulation of cellular process	2
cellular response to stress	2
intracellular signal transduction	2
intracellular signaling cassette	1
ossification	1
cell differentiation	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
signaling	1
cellular response to stimulus	1
cytoplasmic pattern recognition receptor signaling pathway	1
DNA damage response	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
stress-activated protein kinase signaling cascade	1
cell cycle	1
striated muscle contraction	1
heart contraction	1
skeletal system development	1
animal organ development	1
negative regulation of multicellular organismal process	1
cold-induced thermogenesis	1
regulation of cold-induced thermogenesis	1
signal transduction by p53 class mediator	1
regulation of intracellular signal transduction	1
phosphorylation	1
protein modification process	1
gene expression	1
protein metabolic process	1
inflammatory response	1
response to UV-B	1
cellular response to UV	1
protein serine/threonine/tyrosine kinase activity	1
adenyl ribonucleotide binding	1

Protein interactions and networks

STRING

1128 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP2K6	TRAF6	Q9Y4K3	659
MAP2K6	GLYR1	Q49A26	643
MAP2K6	ABCA10	Q8WWZ4	642
MAP2K6	MAP3K5	Q99683	605
MAP2K6	CHUK	O15111	600
MAP2K6	ABCA5	Q8WWZ7	595
MAP2K6	ABCA6	Q8N139	594
MAP2K6	MAPK8IP1	Q9UQF2	586
MAP2K6	JUN	P05412	578
MAP2K6	KCNJ16	Q9NPI9	576
MAP2K6	MAP3K7	O43318	562
MAP2K6	PPM1L	Q5SGD2	552
MAP2K6	CDC42	P21181	548
MAP2K6	PPP5C	P53041	547
MAP2K6	SLCO6A1	Q86UG4	547

IntAct

42 interactions, top by confidence:

A	B	Type	Score
MAPK14	OBSL1	psi-mi:“MI:0914”(association)	0.790
CDCA4	PPP2R1A	psi-mi:“MI:0914”(association)	0.790
NFE2L2	MAP2K6	psi-mi:“MI:0915”(physical association)	0.630
MAP2K6	MAP2K3	psi-mi:“MI:0914”(association)	0.610
MAP2K6	MAP2K3	psi-mi:“MI:2364”(proximity)	0.610
MAP2K6	PICK1	psi-mi:“MI:0915”(physical association)	0.560
MAP2K6	WFS1	psi-mi:“MI:0915”(physical association)	0.560
MAP2K6	MAPK14	psi-mi:“MI:0915”(physical association)	0.560
MAP2K6	MAP3K4	psi-mi:“MI:0915”(physical association)	0.520
GADD45A	MAP2K6	psi-mi:“MI:0915”(physical association)	0.520
MAP2K6	MAP3K4	psi-mi:“MI:2364”(proximity)	0.520
MAP2K6	GADD45A	psi-mi:“MI:2364”(proximity)	0.520
LRRK2	MAP2K6	psi-mi:“MI:0915”(physical association)	0.460
MAP2K6	LRRK2	psi-mi:“MI:0915”(physical association)	0.460
MAP2K6	LRRK2	psi-mi:“MI:0403”(colocalization)	0.460
PKN1	MAP2K6	psi-mi:“MI:0915”(physical association)	0.400
MAPK14	MAP2K6	psi-mi:“MI:0915”(physical association)	0.400
MLH1	MAP2K6	psi-mi:“MI:0915”(physical association)	0.370
GADD45B	MAP2K6	psi-mi:“MI:0915”(physical association)	0.370
GADD45G	MAP2K6	psi-mi:“MI:0915”(physical association)	0.370
PAK6	CNOT1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (126): MAPK1 (Biochemical Activity), MAP2K6 (Biochemical Activity), MAP2K3 (Affinity Capture-MS), ZG16B (Affinity Capture-MS), MAP2K6 (Co-localization), MAP3K4 (Co-localization), GADD45A (Co-localization), TAOK2 (Co-localization), RELA (Co-localization), GNB2L1 (Affinity Capture-Western), MAP2K6 (Affinity Capture-Western), MAP2K6 (Affinity Capture-Western), MAP2K6 (Biochemical Activity), MAP2K6 (Biochemical Activity), MAP2K6 (Biochemical Activity)

ESM2 similar proteins: A0A5B9GBF0, A1CPG7, A1D2C9, A1IVT7, A2BD05, A2QRF6, B0XR80, D3ZBE5, G1XJZ4, G5EDF7, G5EFM9, M1T7M3, O09110, O75716, O88697, P0CP69, P21708, P26696, P27361, P28482, P45985, P46196, P46734, P47809, P52564, P57760, P59895, P70236, Q0D0P5, Q0U4L8, Q1DUU8, Q1KTF2, Q2WFL5, Q4PC06, Q4W6D3, Q4WSF6, Q52PH6, Q56R42, Q5E9X2, Q63844

Diamond homologs: A0A194VNL2, A0A1S4CGX4, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8XJW8, A9RWC9, A9S5R3, A9SR33, B0LT89, B0XPE4, G4N6Z6, G4NEB8, G5EDF7, H2L099, O00506, O09110, O14047, O14733, O54748, O61122, O61125, O80396, O80397, P06784, P08018, P10506, P29678, P31938, P32490, P32491, P33886, P36506, P36507, P45985, P46734

SIGNOR signaling

32 interactions.

A	Effect	B	Mechanism
MAP2K6	up-regulates	MAPK13	phosphorylation
TAOK2	“up-regulates activity”	MAP2K6	phosphorylation
MAP3K7	“up-regulates activity”	MAP2K6	phosphorylation
MAP2K6	up-regulates	PAK6	phosphorylation
MAP2K6	up-regulates	MAPK12	phosphorylation
MAP2K6	“up-regulates activity”	MAPK14	phosphorylation
MAP2K6	“up-regulates activity”	MAP2K6	phosphorylation
MAP2K6	“up-regulates activity”	p38
MAP2K6	“up-regulates activity”	MAPK13	phosphorylation
EIF2AK2	“up-regulates activity”	MAP2K6	phosphorylation
MAP2K6	up-regulates	CRK	phosphorylation
MAP3K5	“up-regulates activity”	MAP2K6	phosphorylation
MAP2K6	up-regulates	MAPK10	phosphorylation
MAP2K6	up-regulates	MAPK9	phosphorylation
MAP3K4	“up-regulates activity”	MAP2K6	phosphorylation
MAP2K6	up-regulates	MAPK11	phosphorylation
MAP3K1	up-regulates	MAP2K6	phosphorylation
MAP3K3	up-regulates	MAP2K6
TAOK2	“up-regulates activity”	MAP2K6	binding
MAP2K6	“up-regulates activity”	STAT4	phosphorylation
MAP2K6	“up-regulates activity”	HSF4	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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
Cellular responses to stimuli	5	7.2×	7e-03
Innate Immune System	6	7.0×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
intracellular signal transduction	8	11.7×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

2324 predictions. Top by Δscore:

Variant	Effect	Δscore
17:69504145:G:GT	donor_gain	1.0000
17:69505777:T:G	acceptor_gain	1.0000
17:69505778:A:AG	acceptor_gain	1.0000
17:69505778:A:C	acceptor_loss	1.0000
17:69505779:G:A	acceptor_loss	1.0000
17:69505779:G:GG	acceptor_gain	1.0000
17:69505779:GGCAA:G	acceptor_gain	1.0000
17:69505847:G:GG	donor_gain	1.0000
17:69516845:T:G	acceptor_gain	1.0000
17:69516853:A:AG	acceptor_gain	1.0000
17:69516854:G:GG	acceptor_gain	1.0000
17:69516901:CAGGT:C	donor_loss	1.0000
17:69516902:AGGTA:A	donor_loss	1.0000
17:69516904:GTA:G	donor_loss	1.0000
17:69516905:T:G	donor_loss	1.0000
17:69517497:CA:C	acceptor_loss	1.0000
17:69517498:A:AG	acceptor_gain	1.0000
17:69517499:G:GA	acceptor_gain	1.0000
17:69517499:GA:G	acceptor_gain	1.0000
17:69517499:GAA:G	acceptor_gain	1.0000
17:69517499:GAAC:G	acceptor_gain	1.0000
17:69517499:GAACT:G	acceptor_gain	1.0000
17:69517609:TGAAG:T	donor_loss	1.0000
17:69517612:AGG:A	donor_loss	1.0000
17:69517614:GTAGA:G	donor_loss	1.0000
17:69517615:T:A	donor_loss	1.0000
17:69519301:A:AG	acceptor_gain	1.0000
17:69519302:T:G	acceptor_gain	1.0000
17:69519307:A:AG	acceptor_gain	1.0000
17:69519308:T:G	acceptor_gain	1.0000

AlphaMissense

2202 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:69517525:T:C	L53P	1.000
17:69517545:G:A	G60R	1.000
17:69517545:G:C	G60R	1.000
17:69517546:G:A	G60E	1.000
17:69517551:G:C	G62R	1.000
17:69517552:G:A	G62D	1.000
17:69517560:G:A	G65R	1.000
17:69517560:G:C	G65R	1.000
17:69517560:G:T	G65W	1.000
17:69517561:G:A	G65E	1.000
17:69517606:C:A	A80E	1.000
17:69517611:A:C	K82Q	1.000
17:69517611:A:G	K82E	1.000
17:69517613:G:C	K82N	1.000
17:69517613:G:T	K82N	1.000
17:69519404:T:A	V113D	1.000
17:69521089:T:A	V175D	1.000
17:69521094:C:G	H177D	1.000
17:69521098:G:C	R178T	1.000
17:69521098:G:T	R178I	1.000
17:69521099:A:C	R178S	1.000
17:69521099:A:T	R178S	1.000
17:69521100:G:C	D179H	1.000
17:69523514:A:C	D179A	1.000
17:69523514:A:G	D179G	1.000
17:69523514:A:T	D179V	1.000
17:69523515:C:A	D179E	1.000
17:69523515:C:G	D179E	1.000
17:69523517:T:A	V180D	1.000
17:69523519:A:G	K181E	1.000

dbSNP variants (sampled 300 via entrez): RS1000003479 (17:69548619 G>A), RS1000046976 (17:69510122 A>G), RS1000049655 (17:69417778 A>G), RS1000058064 (17:69536673 T>G), RS1000061544 (17:69456258 C>T), RS1000092565 (17:69462508 C>T), RS1000099528 (17:69461528 T>G), RS1000136245 (17:69485978 AC>A), RS1000139693 (17:69504907 C>T), RS1000157383 (17:69422748 A>G), RS1000158293 (17:69460921 A>T), RS1000191848 (17:69492409 T>C,G), RS1000192264 (17:69466920 C>G,T), RS1000243238 (17:69534690 C>G,T), RS1000246491 (17:69498536 T>G)

Disease associations

OMIM: gene MIM:601254 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001510_2	Response to TNF-alpha inhibitors in rheumatoid arthritis	3.000000e-06
GCST002366_2	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 1 peripheral neuropathy)	3.000000e-06
GCST003074_19	Cerebral amyloid deposition in APOEe4 non-carriers (PET imaging)	6.000000e-07
GCST008155_43	Waist-hip ratio	3.000000e-06
GCST009462_68	Optic disc size	3.000000e-08
GCST90000025_616	Appendicular lean mass	1.000000e-21
GCST90020024_786	A body shape index	2.000000e-08
GCST90020024_787	A body shape index	3.000000e-08

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004653	response to TNF antagonist
EFO:0000180	HIV-1 infection
EFO:0007707	cerebral amyloid deposition measurement
EFO:0004343	waist-hip ratio
EFO:0004980	appendicular lean mass
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2171 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

16 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 145,838 (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
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL456	ETHACRYNIC ACID	4	20,004
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL535	SUNITINIB	4	79,020
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1721885	SU-014813	2	363
CHEMBL475251	R-406	2	762
CHEMBL495727	AT-9283	2	1,376
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL574737	UCN-01	2	2,217
CHEMBL1084546	PF-00562271	1	399
CHEMBL1908397	KW-2449	1	622
CHEMBL3545083	RGB-286638	1	551

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11651488	Toxicity	3	sorafenib	Diarrhea
rs12948059	Toxicity	3	sorafenib	Drug Toxicity

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11651488	MAP2K6	3	3.00	1	sorafenib
rs12948059	MAP2K6	3	2.50	1	sorafenib

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — STE7 family

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

Ligand	Action	Affinity	Parameter
staurosporine	Inhibition	9.0	pIC50

Binding affinities (BindingDB)

9 measured of 12 human assays (12 total across all organisms); most potent 9 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
3,8-Dihydroxy-11-oxo-1-(2-oxo-heptyl)-6-pentyl-11H-dibenzo[b,e][1,4]dioxepine-7-carboxylic acid	EC50	4020 nM
1,4,10-Trihydroxy-5-hydroxymethyl-8-methyl-3,7-dioxo-1,3-dihydro-7H-benzo[e]furo[3’’’’,4’’’’:3,4]benzo[b][1,4]dioxepine-11-carbaldehyde	IC50	85000 nM
1,4-Dihydroxy-10-methoxy-5,8-dimethyl-3,7-dioxo-1,3-dihydro-7H-benzo[e]furo[3’,4’:3,4]benzo[b][1,4]dioxepine-11-carbaldehyde	IC50	85000 nM
4-Formyl-3-hydroxy-8-methoxy-1,9-dimethyl-11-oxo-11H-dibenzo[b,e][1,4]dioxepine-6-carboxylic acid	IC50	85000 nM

ChEMBL bioactivities

50 potent at pChembl≥5 of 55 total, top 45 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.84	IC50	1.44	nM	STAUROSPORINE
8.47	Kd	3.4	nM	STAUROSPORINE
8.32	IC50	4.75	nM	STAUROSPORINE
8.08	IC50	8.34	nM	STAUROSPORINE
7.80	Kd	16	nM	CHEMBL4576489
7.55	Kd	28	nM	CHEMBL4465866
7.43	Kd	36.84	nM	CHEMBL3752910
7.43	ED50	36.84	nM	CHEMBL3752910
7.36	Kd	44	nM	LESTAURTINIB
7.06	Kd	87	nM	LESTAURTINIB
7.06	Kd	88	nM	K-252A
6.54	IC50	290	nM	CHEMBL4568087
6.51	Kd	310	nM	CHEMBL2425628
6.41	IC50	388.2	nM	CHEMBL2012519
6.32	Kd	480	nM	R-406
6.10	Kd	792	nM	UCN-01
6.09	Kd	820	nM	KW-2449
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
6.00	Kd	1000	nM	JNJ-7706621
5.89	Kd	1300	nM	BOSUTINIB
5.77	Kd	1708	nM	CHEMBL5653589
5.77	ED50	1708	nM	CHEMBL5653589
5.72	Kd	1895	nM	GILTERITINIB
5.71	Kd	1952	nM	RGB-286638
5.71	Kd	1934	nM	PF-00562271
5.70	Kd	2000	nM	TAE-684
5.58	Kd	2600	nM	TOZASERTIB
5.50	Kd	3200	nM	CHEMBL1908395
5.48	IC50	3300	nM	CHEMBL4552628
5.45	Kd	3545	nM	AT-9283
5.41	Kd	3900	nM	RUBOXISTAURIN
5.39	Kd	4100	nM	PAZOPANIB
5.39	Kd	4100	nM	CHEMBL386051
5.35	IC50	4500	nM	ETHACRYNIC ACID
5.34	Kd	4559	nM	CHEMBL3688339
5.28	Kd	5200	nM	SUNITINIB
5.26	Kd	5500	nM	CHEMBL5794154
5.26	Kd	5500	nM	CHEMBL6036508
5.26	Kd	5500	nM	SU-014813
5.21	IC50	6200	nM	CHEMBL456689
5.19	Kd	6500	nM	MIDOSTAURIN
5.00	IC50	1e+04	nM	CHEMBL1788116
5.00	IC50	1e+04	nM	CHEMBL3884319

PubChem BioAssay actives

44 with measured affinity, of 1215 total; 34 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	126765: Inhibition of Mitogen activated protein kinase kinase 6	ic50	0.0010	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-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]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526299: Binding affinity to recombinant human full length N-terminal GST-tagged MAP2K6 expressed in baculovirus expression system using p38alpha (9 to 352 residues) as substrate incubated for 1 hr by TR-FRET assay	kd	0.0160	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-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]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526299: Binding affinity to recombinant human full length N-terminal GST-tagged MAP2K6 expressed in baculovirus expression system using p38alpha (9 to 352 residues) as substrate incubated for 1 hr by TR-FRET assay	kd	0.0280	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148688: Binding affinity to human MAP2K6 incubated for 45 mins by Kinobead based pull down assay	kd	0.0368	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	507616: Binding affinity to MEK6	kd	0.0440	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	1425043: 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	0.0880	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637099: Inhibition of full-length recombinant human His-tagged MAP2K6 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.2900	uM
(4-hydroxypiperidin-1-yl)-[4-[[4-[4-(3-methylsulfonylpropoxy)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]methanone	769506: Binding affinity to MEK6 (unknown origin)	kd	0.3100	uM
(4S,6Z,9S,10S)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,15,17-tetraene-2,8-dione	1431754: Inhibition of human MKK6 using p38a as substrate in presence of [gamma-33P]-ATP by scintillation counting method	ic50	0.3882	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	624895: Binding constant for MEK6 kinase domain	kd	0.4800	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	1425043: 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	0.7920	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624895: Binding constant for MEK6 kinase domain	kd	0.8200	uM
4-phenyl-9H-pyrimido[4,5-b]indole-6-carboxamide	1863529: Inhibition of MKK6 (unknown origin)	ic50	1.0000	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435911: Binding constant for MEK6 kinase domain	kd	1.0000	uM
Bosutinib	624895: Binding constant for MEK6 kinase domain	kd	1.3000	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148688: Binding affinity to human MAP2K6 incubated for 45 mins by Kinobead based pull down assay	kd	1.7076	uM
Gilteritinib	1425043: 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	1.8950	uM
N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]methyl]-2-pyridinyl]methanesulfonamide	1425043: 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	1.9340	uM
1-[3-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]phenyl]-4-oxo-1H-indeno[2,1-d]pyrazol-5-yl]-3-morpholin-4-ylurea	1425043: 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	1.9520	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	624895: Binding constant for MEK6 kinase domain	kd	2.0000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	435911: Binding constant for MEK6 kinase domain	kd	2.6000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624895: Binding constant for MEK6 kinase domain	kd	3.2000	uM
N-[(1R,6R)-6-amino-2,2-difluorocyclohexyl]-4-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-5-methylthiophene-2-carboxamide	1637099: Inhibition of full-length recombinant human His-tagged MAP2K6 expressed in baculovirus expression system by Z’-LYTE assay	ic50	3.3000	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1425043: 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	3.5450	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	624895: Binding constant for MEK6 kinase domain	kd	3.9000	uM
Pazopanib	435911: Binding constant for MEK6 kinase domain	kd	4.1000	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624895: Binding constant for MEK6 kinase domain	kd	4.1000	uM
Ethacrynic Acid	1720282: Inhibition of MEK6 (unknown origin)	ic50	4.5000	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425043: 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	4.5590	uM
Sunitinib	624895: Binding constant for MEK6 kinase domain	kd	5.2000	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	435911: Binding constant for MEK6 kinase domain	kd	5.5000	uM
Midostaurin	624895: Binding constant for MEK6 kinase domain	kd	6.5000	uM
(2Z)-2-(3H-1,3-benzothiazol-2-ylidene)-2-[2-(2-pyridin-3-ylethylamino)pyrimidin-4-yl]acetonitrile;bis(2,2,2-trifluoroacetic acid)	241695: Inhibition of Mitogen activated protein kinase 6; Range is 5-10	ic50	10.0000	uM
2-anilino-7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one	1336073: Inhibition of human recombinant full length His-tagged MAP2K6 expressed in baculovirus expression system	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	8
sodium arsenite	affects reaction, increases activity, affects cotreatment, decreases expression, increases abundance (+1 more)	5
Benzo(a)pyrene	affects expression, decreases expression	5
Cyclosporine	affects cotreatment, decreases expression, increases expression	5
Aflatoxin B1	affects expression, decreases expression, increases methylation	5
Cadmium Chloride	decreases reaction, increases phosphorylation, increases abundance, increases expression, affects cotreatment (+1 more)	4
trichostatin A	affects cotreatment, decreases expression, increases expression	3
Arsenic	increases abundance, affects methylation, decreases expression, affects cotreatment	3
Copper	decreases expression, affects binding	3
Estradiol	increases expression, affects cotreatment, decreases expression	3
methylmercuric chloride	decreases expression	2
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation, decreases expression	2
sulforaphane	decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Arsenic Trioxide	decreases expression, increases activity, increases phosphorylation	2
Fulvestrant	affects cotreatment, decreases methylation, decreases expression, increases reaction	2
Acetaminophen	decreases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance	2
Chenodeoxycholic Acid	affects cotreatment, decreases expression, increases expression	2
Cisplatin	increases expression, increases reaction, affects response to substance	2
Deoxycholic Acid	affects cotreatment, decreases expression, increases expression	2
Diethylhexyl Phthalate	decreases expression, increases abundance, increases methylation	2
Glycochenodeoxycholic Acid	affects cotreatment, decreases expression, increases expression	2
Glycocholic Acid	increases expression, affects cotreatment, decreases expression	2
Glycodeoxycholic Acid	affects cotreatment, decreases expression, increases expression	2
Methotrexate	affects response to substance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Quercetin	decreases expression, increases expression	2
Silicon Dioxide	decreases expression	2
Tretinoin	decreases expression, increases expression	2

ChEMBL screening assays

355 unique, capped per target: 354 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004493	Binding	Binding affinity to human recombinant MAP2K6 expressed in Escherichia coli assessed as thermal shift by differential scanning fluorimetry	Discovery of a potent and selective inhibitor for human carbonyl reductase 1 from propionate scanning applied to the macrolide zearalenone. — Bioorg Med Chem
CHEMBL734028	Functional	Inhibition of MKK-6, Mitogen activated protein kinase kinase 6 (Not tested)	Potent and selective inhibitors of platelet-derived growth factor receptor phosphorylation. 1. Synthesis, structure-activity relationship, and biological effects of a new class of quinazoline derivatives. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D7U6	Ubigene A-549 MAP2K6 KO	Cancer cell line	Male
CVCL_D9J6	Ubigene HEK293 MAP2K6 KO	Transformed cell line	Female
CVCL_E0H5	Ubigene HeLa MAP2K6 KO	Cancer cell line	Female
CVCL_SW48	HAP1 MAP2K6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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