MAP2K3

Summary

MAP2K3 (mitogen-activated protein kinase kinase 3, HGNC:6843) is a protein-coding gene on chromosome 17p11.2, encoding Dual specificity mitogen-activated protein kinase kinase 3 (P46734). Dual specificity kinase.

The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic and environmental stress, and participates in the MAP kinase-mediated signaling cascade. It phosphorylates and thus activates MAPK14/p38-MAPK. This kinase can be activated by insulin, and is necessary for the expression of glucose transporter. Expression of RAS oncogene is found to result in the accumulation of the active form of this kinase, which thus leads to the constitutive activation of MAPK14, and confers oncogenic transformation of primary cells. The inhibition of this kinase is involved in the pathogenesis of Yersina pseudotuberculosis. Multiple alternatively spliced transcript variants that encode distinct isoforms have been reported for this gene.

Source: NCBI Gene 5606 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 72 total
• Druggable target: yes — 16 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_145109

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6843
Approved symbol	MAP2K3
Name	mitogen-activated protein kinase kinase 3
Location	17p11.2
Locus type	gene with protein product
Status	Approved
Aliases	MEK3, MKK3, MAPKK3, SAPKK2
Ensembl gene	ENSG00000034152
Ensembl biotype	protein_coding
OMIM	602315
Entrez	5606

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 4 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000316920, ENST00000342679, ENST00000361818, ENST00000395491, ENST00000477540, ENST00000479129, ENST00000483928, ENST00000496046, ENST00000526076, ENST00000527123, ENST00000529517, ENST00000534743, ENST00000583508, ENST00000627447, ENST00000910861, ENST00000910862, ENST00000910863, ENST00000910864, ENST00000949557

RefSeq mRNA: 3 — MANE Select: NM_145109 NM_001316332, NM_002756, NM_145109

CCDS: CCDS11217, CCDS11218

Canonical transcript exons

ENST00000342679 — 12 exons

Exon	Start	End
ENSE00001902258	21314147	21315232
ENSE00003502027	21313492	21313537
ENSE00003511968	21284711	21284969
ENSE00003542129	21298413	21298479
ENSE00003544515	21300874	21300993
ENSE00003553037	21304426	21304553
ENSE00003555732	21302143	21302259
ENSE00003566030	21298878	21298926
ENSE00003619575	21312142	21312281
ENSE00003645682	21305051	21305128
ENSE00003656597	21300545	21300658
ENSE00003785478	21303183	21303234

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.41.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.0835 / max 1042.9663, expressed in 1811 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159903	43.2028	1809
159904	4.9527	1387
159902	1.2250	673
159905	0.5949	280
159907	0.5188	146
159910	0.3349	83
159908	0.1355	54
159909	0.1189	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	99.41	gold quality
vena cava	UBERON:0004087	98.66	gold quality
blood	UBERON:0000178	98.36	gold quality
body of tongue	UBERON:0011876	98.29	gold quality
saphenous vein	UBERON:0007318	98.14	gold quality
tongue	UBERON:0001723	97.76	gold quality
pharyngeal mucosa	UBERON:0000355	97.71	gold quality
pylorus	UBERON:0001166	97.62	gold quality
cervix squamous epithelium	UBERON:0006922	97.52	gold quality
cardia of stomach	UBERON:0001162	97.08	gold quality
superior surface of tongue	UBERON:0007371	97.08	gold quality
monocyte	CL:0000576	97.04	gold quality
mononuclear cell	CL:0000842	97.01	gold quality
leukocyte	CL:0000738	96.97	gold quality
pancreatic ductal cell	CL:0002079	96.86	gold quality
mucosa of urinary bladder	UBERON:0001259	96.70	gold quality
granulocyte	CL:0000094	96.68	gold quality
nipple	UBERON:0002030	96.52	gold quality
type B pancreatic cell	CL:0000169	96.50	gold quality
trabecular bone tissue	UBERON:0002483	96.47	gold quality
renal medulla	UBERON:0000362	96.40	gold quality
tongue squamous epithelium	UBERON:0006919	96.34	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.27	gold quality
trachea	UBERON:0003126	96.23	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.21	gold quality
oviduct epithelium	UBERON:0004804	96.20	gold quality
pericardium	UBERON:0002407	95.82	gold quality
bone marrow	UBERON:0002371	95.62	gold quality
gastrocnemius	UBERON:0001388	95.60	gold quality
right lobe of liver	UBERON:0001114	95.57	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	25.81
E-MTAB-9221	yes	17.62
E-HCAD-9	yes	5.99
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXC1, NFKB, NFYA, TP53, ZFP42

miRNA regulators (miRDB)

82 targeting MAP2K3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4645-5P	99.98	65.81	1284
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-4666A-3P	99.96	71.71	3434
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• role in activating Mirk protein kinase (PMID:11980910)
• interacts with phospholipase c-beta 2 (PMID:12054652)
• role in pathway that promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells (PMID:12377770)
• TAK1- and MKK3-mediated activation of p38 are facilitated by Smad7 (PMID:12589052)
• MKK3 is selectively activated by the new subfamily of Ste20-like kinases. (PMID:13679851)
• a specific requirement for p150(Glued)/dynein/functional microtubules in activation of MKK3/6 and p38 MAPKs in vivo. (PMID:15375157)
• 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)
• H-Ras-specific activation of Rac-MKK3/6-p38 pathway has a role in invasion and migration of breast epithelial cells (PMID:15677464)
• MKK3 and MKK6 make individual contributions to p38 activation in fibroblast-like synoviocytes after cytokine stimulation (PMID:15778394)
• p38 mediates EGF receptor activation after oxidant injury; Src activates MMK3, which, in turn, activates p38; and the EGF receptor signaling pathway plays a critical role in renal epithelial cell dedifferentiation (PMID:15797859)
• Bax is phosphorylated by stress-activated JNK and/or p38 kinase and phosphorylation of Bax leads to mitochondrial translocation prior to apoptosis (PMID:16709574)
• Mitogen-activated protein kinase (MAPK) kinase 3 (MKK3) is a key activator of p38 MAPK in glioma; MKK3 activation is strongly correlated with p38 activation in vitro and in vivo. (PMID:17406030)
• Cytokine activation of MAPK14 and apoptosis is opposed by ACTN4 targeting of protein phosphatase 2A for site-specific dephosphorylation of MEK3. (PMID:17438131)
• 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)
• Data provide evidence that p38 Map kinase (MAPK) 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)
• MAP2K3 is identified as a protein to promote senescence in human breast epithelial cells. (PMID:21137025)
• LFA-1-induced stabilization of ARE-containing mRNAs in T cells is dependent on HuR, and occurs through the Vav-1, Rac1/2, MKK3 and p38MAPK signaling cascade (PMID:21206905)
• The p38 MAPK pathway transgene is dispensable for the development of natural killer (NK)T cells; however, NKT cell cytokine production and NKT-mediated liver damage are highly dependent on activation of this pathway. (PMID:21368234)
• 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)
• miR-20a acts in a feedback loop to repress the expression of MKK3 and to negatively regulate the p38 pathway-mediated VEGF-induced endothelial cell migration and angiogenesis (PMID:22696064)
• study concludes MAP2K3 is a reproducible obesity locus that may affect body weight via complex mechanisms involving appetite regulation and hypothalamic inflammation (PMID:23825110)
• MicroRNA-21 promotes hepatocellular carcinoma HepG2 cell proliferation through repression of mitogen-activated protein kinase-kinase 3. (PMID:24112539)
• Our results suggest that asthma is associated with MKK3 over-expression in CD8+ cells; we have also demonstrated that MKK3 may be critical for airway neutrophilia (PMID:24480516)
• study detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls (PMID:24487387)
• MKK3 overexpression upregulated the cyclin-dependent kinase inhibitors, p16 INK4A and p15 INK4B in hepatocellular carcinoma cells was Bim1, was downregulated following MKK3 overexpression. (PMID:26573508)
• MEK2 was essential for the phosphorylation of MKK3/MKK6 and p38 MAPK that directly impacted on cyclin D1 expression. (PMID:27181679)
• The results revealed upregulation of MEK3, as well as phosphorylated MEK3 and phosphorylated p38 MAPK, in CMM patients. These results provide a “fingerprint” for mechanistic studies of CMM in the future and highlight the importance of MEK3-p38 MAPK activation in CMM. (PMID:27418173)
• The study identifies MKK3 as a negative regulator of mitochondrial function and inflammatory responses to cigarette smoke and suggests that MKK3 could be a therapeutic target. (PMID:27717867)
• High MKK3 expression is associated with lung cancer. (PMID:28628118)
• 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)
• Expression of human MKK3 in Drosophila is able to initiate JNK-mediated cell migration, cooperates with oncogenic Ras to trigger tumor invasion, and rescue loss-of-lic induced thorax closure defect. (PMID:30770795)
• it was demonstrated that upregulated miR21 expression and downregulated MKK3 expression suppressed cell proliferation and colony formation, promoted apoptosis, delayed the cell cycle, and inhibited cell migration and invasion. The present findings suggested that miR21 could inhibit the cell growth and metastasis of melanoma by negatively regulating MKK3. (PMID:31257538)
• MiR-214 represses the expression of MKK3 via directly binding its 3’UTR in cervical cancer cells.MKK3 role in the malignant phenotypes of cervical cancer cells. (PMID:31634561)
• MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer. (PMID:31695024)
• The MKK-Dependent Phosphorylation of p38alpha Is Augmented by Arginine Methylation on Arg49/Arg149 during Erythroid Differentiation. (PMID:32429593)
• Genome-wide RNA interference screening reveals a COPI-MAP2K3 pathway required for YAP regulation. (PMID:32747557)
• TIPE-mediated up-regulation of MMP-9 promotes colorectal cancer invasion and metastasis through MKK-3/p38/NF-kappaB pro-oncogenic signaling pathway. (PMID:32843639)
• The miR-19b-3p-MAP2K3-STAT3 feedback loop regulates cell proliferation and invasion in esophageal squamous cell carcinoma. (PMID:33660414)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Map2k3	ENSMUSG00000018932
rattus_norvegicus	Map2k3	ENSRNOG00000065992

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), PAK5 (ENSG00000101349), STK24 (ENSG00000102572), STK3 (ENSG00000104375), MAP4K1 (ENSG00000104814), MAP3K8 (ENSG00000107968), MAP2K6 (ENSG00000108984), 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 3 — P46734 (reviewed: P46734)

Alternative names: MAPK/ERK kinase 3, Stress-activated protein kinase kinase 2

All UniProt accessions (8): E9PMA8, E9PRZ0, P46734, J3KRV4, J3QL77, J3QR49, Q6FI23, X6RB39

UniProt curated annotations — full annotation on UniProt →

Function. Dual specificity kinase. Is activated by cytokines and environmental stress in vivo. Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinase p38. Part of a signaling cascade that begins with the activation of the adrenergic receptor ADRA1B and leads to the activation of MAPK14.

Subunit / interactions. Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK. Binds to DYRK1B/MIRK and increases its kinase activity. Part of a complex with MAP3K3, RAC1 and CCM2. Interacts with ARRB1. (Microbial infection) Interacts with Yersinia YopJ.

Tissue specificity. Abundant expression is seen in the skeletal muscle. It is also widely expressed in other tissues.

Post-translational modifications. Autophosphorylated. Phosphorylation on Ser-218 and Thr-222 by MAP kinase kinase kinases positively regulates the kinase activity. Phosphorylated by TAOK2. (Microbial infection) Yersinia YopJ may acetylate Ser/Thr residues, preventing phosphorylation and activation, thus blocking the MAPK signaling pathway.

Disease relevance. Defects in MAP2K3 may be involved in colon cancer.

Activity regulation. Activated by dual phosphorylation on Ser-218 and Thr-222.

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

Isoforms (3)

UniProt ID	Names	Canonical?
P46734-1	3, 3b	yes
P46734-2	1
P46734-3	2, 3c

RefSeq proteins (3): NP_001303261, NP_002747, NP_659731* (*=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 (31 total): sequence variant 12, modified residue 5, mutagenesis site 4, splice variant 2, binding site 2, chain 1, domain 1, region of interest 1, compositionally biased region 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46734-F1	81.13	0.51

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): 190 (proton acceptor)

Ligand- & substrate-binding residues (2): 70–78; 93

Post-translational modifications (5): 218, 222, 1, 3, 15

Mutagenesis-validated functional residues (4):

Position	Phenotype
218	inactivation.
218	constitutive activation.
222	inactivation.
222	constitutive activation.

Function

Pathways and Gene Ontology

Reactome pathways

28 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-5210891	Uptake and function of anthrax toxins
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-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-448424	Interleukin-17 signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-450294	MAP kinase activation
R-HSA-8953897	Cellular responses to stimuli
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation
R-HSA-975155	MyD88 dependent cascade initiated on endosome
R-HSA-975871	MyD88 cascade initiated on plasma membrane

MSigDB gene sets: 457 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, BIOCARTA_FMLP_PATHWAY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELLULAR_RESPONSE_TO_LIPID, ENK_UV_RESPONSE_KERATINOCYTE_UP, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, MODULE_45, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP

GO Biological Process (25): MAPK cascade (GO:0000165), regulation of cytokine production (GO:0001817), response to ischemia (GO:0002931), inflammatory response (GO:0006954), signal transduction (GO:0007165), heart development (GO:0007507), stress-activated protein kinase signaling cascade (GO:0031098), negative regulation of hippo signaling (GO:0035331), cellular response to vascular endothelial growth factor stimulus (GO:0035924), p38MAPK cascade (GO:0038066), positive regulation of MAPK cascade (GO:0043410), positive regulation of blood vessel endothelial cell migration (GO:0043536), positive regulation of protein kinase activity (GO:0045860), positive regulation of DNA-templated transcription (GO:0045893), cardiac muscle contraction (GO:0060048), cellular response to lipopolysaccharide (GO:0071222), cellular response to sorbitol (GO:0072709), cellular senescence (GO:0090398), protein phosphorylation (GO:0006468), intracellular signal transduction (GO:0035556), 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 (11): 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), 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 (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Toll-like Receptor Cascades	7
Immune System	2
Toll Like Receptor 4 (TLR4) Cascade	2
Toll Like Receptor 2 (TLR2) Cascade	2
Cellular Senescence	1
MAP kinase activation	1
Uptake and actions of bacterial toxins	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
Innate Immune System	1
Cellular responses to stimuli	1
Cellular responses to stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	4
cellular anatomical structure	4
MAPK cascade	3
cellular process	2
cellular response to stress	2
intracellular anatomical structure	2
intracellular signaling cassette	1
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
response to stress	1
defense response	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
animal organ development	1
circulatory system development	1
intracellular signal transduction	1
hippo signaling	1
regulation of hippo signaling	1
negative regulation of intracellular signal transduction	1
cellular response to growth factor stimulus	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
positive regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
regulation of blood vessel endothelial cell migration	1
positive regulation of protein phosphorylation	1
positive regulation of kinase activity	1
regulation of protein kinase activity	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
striated muscle contraction	1
heart contraction	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1

Protein interactions and networks

STRING

1846 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP2K3	CCM2	Q9BSQ5	975
MAP2K3	PKN1	Q16512	952
MAP2K3	MAP3K20	Q9NYL2	938
MAP2K3	MAPK14	Q16539	864
MAP2K3	MAPK8IP2	Q13387	861
MAP2K3	AKT1	P31749	830
MAP2K3	JUN	P05412	787
MAP2K3	TAB1	Q15750	786
MAP2K3	SMAD7	O15105	742
MAP2K3	TRAF3	Q13114	722
MAP2K3	TP53	P04637	640
MAP2K3	CREB1	P16220	629
MAP2K3	TAOK2	Q9UL54	628
MAP2K3	CDC42	P21181	610
MAP2K3	MAP3K5	Q99683	602

IntAct

95 interactions, top by confidence:

A	B	Type	Score
MAPK14	RPS6KA4	psi-mi:“MI:0914”(association)	0.870
MAPK14	MAP2K3	psi-mi:“MI:0914”(association)	0.800
MAPK14	MAP2K3	psi-mi:“MI:0915”(physical association)	0.800
MAPK14	OBSL1	psi-mi:“MI:0914”(association)	0.790
MAP3K5	MAP2K3	psi-mi:“MI:0915”(physical association)	0.760
MAP2K3	MAP3K5	psi-mi:“MI:0915”(physical association)	0.760
MAP3K5	MAP2K3	psi-mi:“MI:0914”(association)	0.760
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
MAP2K6	MAP2K3	psi-mi:“MI:0914”(association)	0.610
MAP2K6	MAP2K3	psi-mi:“MI:2364”(proximity)	0.610
LRRK2	MAP2K3	psi-mi:“MI:0915”(physical association)	0.590
MAP2K3	LRRK2	psi-mi:“MI:0915”(physical association)	0.590
DYRK1B	MAP2K3	psi-mi:“MI:0915”(physical association)	0.540
MAP2K3	DYRK1B	psi-mi:“MI:0217”(phosphorylation reaction)	0.540
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
APLNR	SLC33A1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
MAP2K3	TINF2	psi-mi:“MI:0915”(physical association)	0.510
lef	MAP2K3	psi-mi:“MI:0570”(protein cleavage)	0.440
MAP2K3	PKN1	psi-mi:“MI:0915”(physical association)	0.400
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
MAPK14	MAP2K3	psi-mi:“MI:0915”(physical association)	0.400
MAP2K3	E7	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (322): MAP2K3 (Affinity Capture-MS), MAP2K3 (Affinity Capture-MS), MAP2K3 (Affinity Capture-MS), MAP2K6 (Co-localization), MAP3K4 (Co-localization), TAOK2 (Co-localization), MAP2K3 (Affinity Capture-MS), MAP2K3 (Affinity Capture-MS), MAP2K3 (Affinity Capture-MS), MAP2K3 (Affinity Capture-MS), MAPK14 (FRET), MAP2K3 (Affinity Capture-MS), MAP2K3 (Affinity Capture-MS), MAP2K3 (Affinity Capture-MS), MAP2K3 (Affinity Capture-MS)

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, B0XPE4, C4YLK8, E1BK52, F1NBT0, G4N6Z6, G4NEB8, G5EDF7, O00506, O09110, O14733, O54748, O80396, O94804, O95819, P06784, P08018, P0CY25, P10506, P29678, P31938, P32490, P32491, P33886, P36506, P36507, P45985, P46734

SIGNOR signaling

21 interactions.

A	Effect	B	Mechanism
TAOK2	“up-regulates activity”	MAP2K3	phosphorylation
MAP3K5	“up-regulates activity”	MAP2K3	phosphorylation
MAP3K7	“up-regulates activity”	MAP2K3	phosphorylation
MAP2K3	“up-regulates activity”	MAPK14	phosphorylation
MAP2K3	“up-regulates activity”	MAPK13	phosphorylation
LRRK2	“up-regulates activity”	MAP2K3	phosphorylation
MAP3K11	“up-regulates activity”	MAP2K3	phosphorylation
MAP3K3	“up-regulates activity”	MAP2K3	phosphorylation
MAP3K4	“up-regulates activity”	MAP2K3	phosphorylation
TAOK1	“up-regulates activity”	MAP2K3	phosphorylation
MAP2K3	up-regulates	MAPK12	phosphorylation
MAP2K3	up-regulates	DYRK1B	phosphorylation
MAP2K3	“up-regulates activity”	p38	phosphorylation
TAOK2	“up-regulates activity”	MAP2K3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 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.

GO biological processes:

GO term	Partners	Fold	FDR
MAPK cascade	6	10.4×	5e-03
protein phosphorylation	9	7.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	15
Benign	20

Top pathogenic / likely-pathogenic (0)

SpliceAI

2522 predictions. Top by Δscore:

Variant	Effect	Δscore
17:21298477:CACGT:C	donor_loss	1.0000
17:21298479:CG:C	donor_loss	1.0000
17:21298480:G:GG	donor_gain	1.0000
17:21298480:GT:G	donor_loss	1.0000
17:21298481:T:A	donor_loss	1.0000
17:21298877:GACC:G	acceptor_gain	1.0000
17:21298925:GA:G	donor_gain	1.0000
17:21298927:G:GG	donor_gain	1.0000
17:21300540:TCAA:T	acceptor_loss	1.0000
17:21300542:A:AG	acceptor_gain	1.0000
17:21300542:AAG:A	acceptor_loss	1.0000
17:21300543:A:AT	acceptor_loss	1.0000
17:21300543:A:G	acceptor_gain	1.0000
17:21300544:G:GT	acceptor_gain	1.0000
17:21300544:GA:G	acceptor_gain	1.0000
17:21300544:GAA:G	acceptor_gain	1.0000
17:21300544:GAAC:G	acceptor_gain	1.0000
17:21300544:GAACT:G	acceptor_gain	1.0000
17:21300659:G:GG	donor_gain	1.0000
17:21300660:T:A	donor_loss	1.0000
17:21300872:A:AG	acceptor_gain	1.0000
17:21300872:AGC:A	acceptor_gain	1.0000
17:21300872:AGCG:A	acceptor_gain	1.0000
17:21300873:G:GT	acceptor_gain	1.0000
17:21300873:GC:G	acceptor_gain	1.0000
17:21300873:GCG:G	acceptor_gain	1.0000
17:21300873:GCGG:G	acceptor_gain	1.0000
17:21300873:GCGGA:G	acceptor_gain	1.0000
17:21300989:GAGAG:G	donor_gain	1.0000
17:21300990:AGAGG:A	donor_loss	1.0000

AlphaMissense

2299 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:21300590:G:C	G71R	1.000
17:21300596:G:A	G73R	1.000
17:21300596:G:C	G73R	1.000
17:21300597:G:A	G73E	1.000
17:21300605:G:A	G76R	1.000
17:21300605:G:C	G76R	1.000
17:21300605:G:T	G76W	1.000
17:21300606:G:A	G76E	1.000
17:21300651:C:A	A91D	1.000
17:21300656:A:G	K93E	1.000
17:21300658:G:C	K93N	1.000
17:21300658:G:T	K93N	1.000
17:21300875:G:C	R94P	1.000
17:21300926:T:C	L111P	1.000
17:21300965:T:A	V124D	1.000
17:21300976:G:T	G128W	1.000
17:21300977:G:A	G128E	1.000
17:21303196:T:C	L177P	1.000
17:21303205:T:C	L180P	1.000
17:21303228:C:G	H188D	1.000
17:21303232:G:C	R189T	1.000
17:21303232:G:T	R189I	1.000
17:21303233:A:C	R189S	1.000
17:21303233:A:T	R189S	1.000
17:21303234:G:C	D190H	1.000
17:21304426:A:C	D190A	1.000
17:21304426:A:G	D190G	1.000
17:21304426:A:T	D190V	1.000
17:21304427:T:A	D190E	1.000
17:21304427:T:G	D190E	1.000

dbSNP variants (sampled 300 via entrez): RS1000064651 (17:21292650 C>A,T), RS1000180896 (17:21293322 C>G,T), RS1000264659 (17:21296677 C>T), RS1000612817 (17:21282741 C>T), RS1000648578 (17:21315563 C>G,T), RS1000990129 (17:21300823 G>C,T), RS1001042592 (17:21301101 G>A,T), RS1001192628 (17:21310409 T>C), RS1001359331 (17:21287801 C>G), RS1001439000 (17:21315053 C>G), RS1001534149 (17:21290368 G>C), RS1001661657 (17:21284417 G>C), RS1001890083 (17:21314819 C>G,T), RS1001951271 (17:21310885 C>T), RS1001962630 (17:21310677 G>A)

Disease associations

OMIM: gene MIM:602315 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004904_123	Body mass index	2.000000e-10
GCST005951_14	Body mass index	5.000000e-10
GCST90000047_221	Age at first sexual intercourse	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2109 (SINGLE PROTEIN), CHEMBL4888452 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

16 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 179,089 (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
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL3426621	RIPASUDIL	3	870
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL230011	TG100-115	2	1,504
CHEMBL475251	R-406	2	762
CHEMBL101309	AVASIMIBE	2	10,153
CHEMBL1908397	KW-2449	1	622
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 — STE7 family

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
(R)-STU104	Binding	7.15	pKi
MEK inhibitor I	Inhibition	6.0	pIC50

Binding affinities (BindingDB)

4 measured of 4 human assays (4 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
PKC-412	KD	190 nM
SCH772984	IC50	580 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM

ChEMBL bioactivities

45 potent at pChembl≥5 of 49 total, top 41 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.60	IC50	2.54	nM	STAUROSPORINE
8.43	Kd	3.694	nM	CHEMBL3752910
8.43	ED50	3.694	nM	CHEMBL3752910
8.40	IC50	4	nM	CHEMBL3746157
8.40	IC50	4	nM	CHEMBL3747095
8.30	Kd	5	nM	STAUROSPORINE
8.30	Kd	5	nM	LESTAURTINIB
8.27	IC50	5.42	nM	STAUROSPORINE
7.76	IC50	17.2	nM	STAUROSPORINE
7.52	IC50	30	nM	CHEMBL3747443
7.15	Kd	71	nM	CHEMBL5178905
7.04	Kd	92	nM	CHEMBL1241674
7.00	Kd	100	nM	R-406
6.92	Kd	120	nM	LESTAURTINIB
6.82	IC50	150	nM	CHEMBL3746484
6.82	Kd	150	nM	KW-2449
6.77	Kd	170	nM	TAE-684
6.44	Kd	360	nM	CHEMBL1908395
6.33	Kd	470	nM	RUXOLITINIB
6.00	Kd	1000	nM	CHEMBL464552
5.92	Kd	1200	nM	CHEMBL379218
5.92	Kd	1200	nM	ALVOCIDIB
5.83	Kd	1480	nM	Cerdulatinib Hydrochloride
5.82	Kd	1500	nM	JNJ-7706621
5.77	Kd	1700	nM	SUNITINIB
5.70	Kd	2000	nM	CHEMBL449216
5.68	Kd	2100	nM	NINTEDANIB
5.66	Kd	2200	nM	SU-014813
5.66	Kd	2200	nM	AST-487
5.58	Kd	2600	nM	BOSUTINIB
5.51	Kd	3079	nM	RIPASUDIL
5.48	Kd	3300	nM	CRIZOTINIB
5.46	Kd	3500	nM	FEDRATINIB
5.42	IC50	3800	nM	CHEMBL2336409
5.38	IC50	4200	nM	CHEMBL3745744
5.28	Kd	5300	nM	MIDOSTAURIN
5.28	Kd	5200	nM	CHEMBL386051
5.26	Kd	5500	nM	CHEMBL6036508
5.18	Kd	6600	nM	TG100-115
5.07	IC50	8460	nM	CHEMBL2336409
5.01	IC50	9670	nM	CHEMBL2336409

PubChem BioAssay actives

44 with measured affinity, of 593 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	1715280: Inhibition of human MEK3 using p38alpha as substrate by [gamma-33P]-ATP assay	ic50	0.0025	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148686: Binding affinity to human MAP2K3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0037	uM
1-(1,2-thiazol-5-yl)imidazo[1,5-a]pyridine-3-carboxamide	1268992: Inhibition of MKK3 (unknown origin) using [gamma-33P]-ATP after 20 mins by radiometric assay	ic50	0.0040	uM
3-(methylamino)-6-pyridin-4-ylpyridine-2-carboxamide	1268992: Inhibition of MKK3 (unknown origin) using [gamma-33P]-ATP after 20 mins by radiometric assay	ic50	0.0040	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	507614: Binding affinity to MEK3	kd	0.0050	uM
3-amino-6-pyridin-4-ylpyridine-2-carboxamide	1268992: Inhibition of MKK3 (unknown origin) using [gamma-33P]-ATP after 20 mins by radiometric assay	ic50	0.0300	uM
(3R)-4,6-dimethoxy-3-(4-methoxyphenyl)-2,3-dihydroinden-1-one	1909094: Binding affinity to CM5 chip immobilized human MKK3 (20 to 347 residues) expressed in Escherichia coli BL21 (DE3) assessed as dissociation constants, KD by surface plasmon resonance analysis	kd	0.0710	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624894: Binding constant for MEK3 kinase domain	kd	0.0920	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	624894: Binding constant for MEK3 kinase domain	kd	0.1000	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624894: Binding constant for MEK3 kinase domain	kd	0.1500	uM
1-pyridin-4-ylimidazo[1,5-a]pyridine-3-carboxamide	1268992: Inhibition of MKK3 (unknown origin) using [gamma-33P]-ATP after 20 mins by radiometric assay	ic50	0.1500	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	624894: Binding constant for MEK3 kinase domain	kd	0.1700	uM
(3S)-1-[2-oxo-2-[4-(4-pyrimidin-2-ylphenyl)piperazin-1-yl]ethyl]-N-(3-pyridin-4-yl-1H-indazol-5-yl)pyrrolidine-3-carboxamide	1800457: Selectivity screening from Article 10.1038/nchembio.1629: “A unique inhibitor binding site in ER K1/2 is associated with slow binding kinetics”	ic50	0.3040	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624894: Binding constant for MEK3 kinase domain	kd	0.3600	uM
Ruxolitinib	624894: Binding constant for MEK3 kinase domain	kd	0.4700	uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	624894: Binding constant for MEK3 kinase domain	kd	1.0000	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	624894: Binding constant for MEK3 kinase domain	kd	1.2000	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	624894: Binding constant for MEK3 kinase domain	kd	1.2000	uM
4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide;hydrochloride	1425040: 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	1.4800	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	436022: Binding constant for full-length MEK3	kd	1.5000	uM
Sunitinib	624894: Binding constant for MEK3 kinase domain	kd	1.7000	uM
4-aminocinnoline-3-carboxamide	1268993: Binding affinity to MKK3 (unknown origin) by surface plasmon resonance assay	kd	2.0000	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624894: Binding constant for MEK3 kinase domain	kd	2.1000	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	624894: Binding constant for MEK3 kinase domain	kd	2.2000	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624894: Binding constant for MEK3 kinase domain	kd	2.2000	uM
Bosutinib	624894: Binding constant for MEK3 kinase domain	kd	2.6000	uM
4-fluoro-5-[[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl]isoquinoline	1425040: 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	3.0790	uM
Crizotinib	624894: Binding constant for MEK3 kinase domain	kd	3.3000	uM
Fedratinib	624894: Binding constant for MEK3 kinase domain	kd	3.5000	uM
N-[4-[(2-amino-6-methylpyrimidin-4-yl)amino]phenyl]-4-(quinolin-4-ylamino)benzamide	1777419: Disruption of interaction between human recombinant GST-tagged MKK3 (1 to 210 residues)/VF-tagged MYC expressed in HEK293T cells measured after 2 hrs by TR-FRET assay	ic50	3.8000	uM
3-amino-6-phenylpyridine-2-carboxamide	1268992: Inhibition of MKK3 (unknown origin) using [gamma-33P]-ATP after 20 mins by radiometric assay	ic50	4.2000	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624894: Binding constant for MEK3 kinase domain	kd	5.2000	uM
Midostaurin	436022: Binding constant for full-length MEK3	kd	5.3000	uM
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol	624894: Binding constant for MEK3 kinase domain	kd	6.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, affects cotreatment, decreases expression	4
Valproic Acid	affects cotreatment, increases expression, decreases methylation	4
Cadmium Chloride	increases expression, decreases reaction, increases phosphorylation, increases abundance	4
Arsenic Trioxide	decreases reaction, increases activity, increases phosphorylation, increases expression	3
Lipopolysaccharides	increases expression, decreases reaction, affects expression, affects response to substance	3
bisphenol A	decreases expression, affects cotreatment	2
Arsenic	decreases expression, increases abundance, increases expression, affects cotreatment	2
Cisplatin	affects cotreatment, decreases expression, increases response to substance	2
Copper	increases expression, decreases expression, affects binding	2
Dexamethasone	increases expression, affects cotreatment, decreases expression	2
Estradiol	decreases expression, increases expression	2
Methotrexate	decreases expression, increases expression	2
Silicon Dioxide	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
Okadaic Acid	increases expression	2
tert-Butylhydroperoxide	increases expression, increases phosphorylation	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
tributyltin	decreases expression	1
beta-lapachone	increases expression	1
afimoxifene	decreases response to substance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
nonylphenol	increases expression	1
manganese chloride	decreases methylation	1
deacylcortivazol	increases expression	1
aflatoxin B2	increases methylation	1

ChEMBL screening assays

222 unique, capped per target: 220 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1047445	Binding	Inhibition of MEK3 assessed as enzyme activity at 1 uM relative to untreated control	Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. — J Med Chem
CHEMBL712094	Functional	Inhibitory potency against MAP kinase kinase 3 (MKK3)	Beyond U0126. Dianion chemistry leading to the rapid synthesis of a series of potent MEK inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

9 cell lines: 8 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7Y4	Abcam Raji MAP2K3 KO	Cancer cell line	Male
CVCL_B9YU	Abcam THP-1 MAP2K3 KO	Cancer cell line	Male
CVCL_C7AK	Abcam PC-3 MAP2K3 KO	Cancer cell line	Male
CVCL_D7U4	Ubigene A-549 MAP2K3 KO	Cancer cell line	Male
CVCL_D8PU	Ubigene HCT 116 MAP2K3 KO	Cancer cell line	Male
CVCL_D9J4	Ubigene HEK293 MAP2K3 KO	Transformed cell line	Female
CVCL_E0H3	Ubigene HeLa MAP2K3 KO	Cancer cell line	Female
CVCL_SW42	HAP1 MAP2K3 (-) 1	Cancer cell line	Male
CVCL_SW43	HAP1 MAP2K3 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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