MAP2K7

Summary

MAP2K7 (mitogen-activated protein kinase kinase 7, HGNC:6847) is a protein-coding gene on chromosome 19p13.2, encoding Dual specificity mitogen-activated protein kinase kinase 7 (O14733). Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway.

The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase specifically activates MAPK8/JNK1 and MAPK9/JNK2, and this kinase itself is phosphorylated and activated by MAP kinase kinase kinases including MAP3K1/MEKK1, MAP3K2/MEKK2,MAP3K3/MEKK5, and MAP4K2/GCK. This kinase is involved in the signal transduction mediating the cell responses to proinflammatory cytokines, and environmental stresses. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5609 — RefSeq curated summary.

At a glance

• Gene–disease (curated): schizophrenia (No Known Disease Relationship, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 75 total
• Druggable target: yes — 7 molecules with ChEMBL bioactivity
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• MANE Select transcript: NM_145185

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6847
Approved symbol	MAP2K7
Name	mitogen-activated protein kinase kinase 7
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	MKK7, Jnkk2, SAPKK4
Ensembl gene	ENSG00000076984
Ensembl biotype	protein_coding
OMIM	603014
Entrez	5609

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 5 retained_intron

ENST00000397979, ENST00000397981, ENST00000397983, ENST00000465324, ENST00000468058, ENST00000475022, ENST00000494348, ENST00000498118, ENST00000883420, ENST00000923690, ENST00000923691, ENST00000952594, ENST00000952595

RefSeq mRNA: 3 — MANE Select: NM_145185 NM_001297555, NM_001297556, NM_145185

CCDS: CCDS42491, CCDS74277, CCDS74278

Canonical transcript exons

ENST00000397979 — 11 exons

Exon	Start	End
ENSE00001296605	7912297	7914478
ENSE00001531069	7910260	7910373
ENSE00001531073	7910063	7910129
ENSE00001824378	7903877	7904068
ENSE00003479556	7911250	7911330
ENSE00003483468	7910453	7910572
ENSE00003489654	7911436	7911578
ENSE00003517500	7910980	7911159
ENSE00003588123	7910696	7910803
ENSE00003595901	7909755	7909896
ENSE00003616121	7912149	7912194

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 96.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.8501 / max 165.8349, expressed in 1812 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173615	21.9910	1812
173616	0.8591	612

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.25	gold quality
tendon of biceps brachii	UBERON:0008188	94.86	gold quality
gastrocnemius	UBERON:0001388	92.88	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.86	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.66	gold quality
nipple	UBERON:0002030	92.32	gold quality
cerebellar hemisphere	UBERON:0002245	92.29	gold quality
cerebellar cortex	UBERON:0002129	92.15	gold quality
hindlimb stylopod muscle	UBERON:0004252	92.07	gold quality
muscle of leg	UBERON:0001383	91.95	gold quality
cardia of stomach	UBERON:0001162	91.74	gold quality
body of tongue	UBERON:0011876	91.58	gold quality
body of uterus	UBERON:0009853	91.57	gold quality
granulocyte	CL:0000094	91.36	gold quality
mucosa of stomach	UBERON:0001199	91.32	gold quality
skin of leg	UBERON:0001511	91.32	gold quality
vena cava	UBERON:0004087	91.32	gold quality
left ovary	UBERON:0002119	91.31	gold quality
skin of abdomen	UBERON:0001416	91.24	gold quality
endocervix	UBERON:0000458	90.88	gold quality
ectocervix	UBERON:0012249	90.85	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.82	gold quality
subthalamic nucleus	UBERON:0001906	90.80	gold quality
lower esophagus	UBERON:0013473	90.80	gold quality
inferior vagus X ganglion	UBERON:0005363	90.76	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.64	gold quality
left uterine tube	UBERON:0001303	90.63	gold quality
adenohypophysis	UBERON:0002196	90.60	gold quality
medial globus pallidus	UBERON:0002477	90.58	gold quality
right uterine tube	UBERON:0001302	90.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN, NR2C2

miRNA regulators (miRDB)

66 targeting MAP2K7, 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-9-5P	100.00	72.28	2361
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721

Literature-anchored findings (GeneRIF, showing 40)

• ML-1 activated a MAP kinase and an extracellular signal-regulated kinase (ERK)1/2 but not p38 or the c-Jun N-terminal kinase (JNK) (PMID:11891214)
• JNK, MKK-4, and MKK-7 form an active signaling complex in rheumatoid arthritis and this novel JNK signalsome is activated in response to IL-1 and migrates to the nucleus. (PMID:13130464)
• report the cloning of hMKK7gamma1, the human homolog of murine MKK7gamma1 (PMID:16442502)
• MKK7 contains three JNK-docking sites that interact to selectively bind JNK and contribute to JNK signal transmission and specificity (PMID:16533805)
• data indicate that only MKK-7 is required for JNK activation in fibroblast-like synoviocytes after cytokine stimulation (PMID:16802349)
• Association of Gadd45beta with MKK7 involves a network of interactions mediated by its putative helices alpha3 and alpha4 and loops 1 and 2 (PMID:17485467)
• p38 MAPK inhibitors SB202190 and SB203580 activated JNK via MLK-3/MKK7 pathway. (PMID:18222647)
• The results suggest the occurrence of a large complex containing at least an MKK7-Gadd45 beta:Gadd45 beta-MKK7 tetrameric unit whose complexity could be further increased by the dimeric nature of the isolated MKK7. (PMID:18343408)
• Disruption of signaling through MKK7 yields differential response in hypoxic colon cancer cells treated with oxaliplatin. (PMID:18436711)
• JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. (PMID:18713996)
• Filamin A is a scaffold protein whose function is to link MKK4 and MKK7 together and promote JNK1 activation. (PMID:20156194)
• Taxol induces apoptosis in chronic myelogenous leukemia cells by inducing intracellular oxidative stress and JNK activation pathway. (PMID:21074392)
• MKK7 works as a cytoplasmic anchoring protein for JNK1 in various cells, but exhibits aberrant nuclear entry in Jurkat cells; work suggests aberrant subcellular organization of JNK pathway may render certain tumor cells resistant to Fas-mediated apoptosis (PMID:21148294)
• WDR62 associates directly with the MKK7beta1 isoform independently of JNK binding, but fails to interact with MKK7alpha1. (PMID:21749326)
• 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)
• a novel function for the stress kinase MKK7 as a regulator of the circadian clock in mammalian cells at steady state. (PMID:22267733)
• Data show that HBx can induce HepG2 cell apoptosis via a novel active MLK3-MKK7-JNKs signaling module to upregulate FasL protein expression. (PMID:22509080)
• the results imply that reduced function of the MAP2K7-c-Jun N-terminal kinase (JNK) signalling cascade may underlie some of the neurochemical changes and core symptoms in schizophrenia. (PMID:22899651)
• Overexpressed RACK1 augments JNK activity and thereby promotes hepatocellular carcinoma growth through directly binding to MKK7 and enhancing MKK7 activity. (PMID:22903704)
• Data indicate that WDR62 dimerization is required for JNK2 and MKK7beta1 recruitment. (PMID:23341463)
• downregulation of MOR may activate JNK signal transduction pathway via regulating MKK7 phosphorylation level so as to inhibit the proliferation of hepatoma carcinoma cells and cause tumor growth retardation. (PMID:23900681)
• Gadd45B protects the liver through two entirely different processes: binding MKK7 to block damaging signal transduction or binding CAR to coactivate anabolic transcription. (Review) (PMID:24104474)
• MKK7 is a major functional target of miR-493, and its suppression thwarts liver metastasis of colon cancer cells. (PMID:24533778)
• Combination of AAG8 antagonist and very low concentration of a MEK inhibitor synergistically restricts the growth of drug-resistant cells. (PMID:24634165)
• BCR-ABL promotes PTEN downregulation through a MEK dependent pathway. (PMID:25343485)
• In conclusion, the expression of hepatitis B virus core protein sensitized hepatocytes to TNF-alpha-induced apoptosis by disrupting the interaction between MKK7 and RACK1. (PMID:25428880)
• The crystal structure of JNK1 in complex with the second docking site of MKK7, was determined, revealing two different binding modes of the docking motif correlating with observations from NMR exchange spectroscopy. (PMID:25737554)
• This review will focus on the science and clinical findings related to targeted therapies that inhibit BRAF or MEK as well as the immunotherapies that block the CTLA-4 or PD-1 pathways (PMID:25899612)
• we explored the effects of selumetinib in combination with gefitinib in a panel of TNBC cells, in order to evaluate whether the simultaneous blockade of the EGFR and the RAS/MEK/ERK pathway might increase the antitumor activity of selumetinib in TNBC. (PMID:25959272)
• combined pan-RAF and MEK inhibition can overcome intrinsic and acquired resistance to single-agent RAF/MEK inhibition, supporting dual pan-RAF and MEK inhibition as a novel therapeutic strategy for BRAF- and KRAS-mutant cancers (PMID:26351322)
• MKK7 undergoes neddylation in human breast cancer cells (PMID:26364603)
• a widespread role for the JNK-CELF2 axis in controlling splicing during T-cell activation, including a specific role in propagating JNK signaling. (PMID:26443849)
• our study suggested that black rice anthocyanins extract suppress metastasis in breast cancer cells by targeting the RAS/RAF/MAPK pathway (PMID:26649302)
• Crystal structures of the wild type and C218S mutant of MAP2K7 were determined. Cys218 plays a crucial role in configuring an auto-inhibition form of MAP2K7. (PMID:26987717)
• We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis (PMID:27028764)
• Therefore, EGF is suggested to induce E-cadherin down-regulation at the transcriptional level through the MEK/ERK pathway, which might result in, at least in part, the induction of cellular morphological changes and cell migration in LoVo cells. (PMID:27369075)
• In an Eastern Chinese population, carriers of MAP2K7 rs3679T variant genotypes had an increased risk of NSCLC. (PMID:27861856)
• the p.Glu116Lys rare variant in MAP2K7 predisposes its carriers to develop COPD, which would provide a useful genetic biomarker for COPD susceptibility in Chinese. (PMID:28120412)
• MEK activation cooperates with Cdkn2a and Pten inactivation to induce melanoma (PMID:28263969)
• In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study (PMID:28444112)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	map2k7	ENSDARG00000008279
mus_musculus	Map2k7	ENSMUSG00000002948
rattus_norvegicus	Map2k7	ENSRNOG00000001047
caenorhabditis_elegans		WBGENE00003185

Paralogs (8): MAP2K4 (ENSG00000065559), MAP3K4 (ENSG00000085511), MAP2K2 (ENSG00000126934), NEK1 (ENSG00000137601), MAP2K5 (ENSG00000137764), MAP2K1 (ENSG00000169032), MAP3K2 (ENSG00000169967), MAP3K3 (ENSG00000198909)

Protein

Protein identifiers

Dual specificity mitogen-activated protein kinase kinase 7 — O14733 (reviewed: O14733)

Alternative names: JNK-activating kinase 2, MAPK/ERK kinase 7, Stress-activated protein kinase kinase 4, c-Jun N-terminal kinase kinase 2

All UniProt accessions (1): O14733

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. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K4/MKK4, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4/MKK4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The monophosphorylation of JNKs on the Thr residue is sufficient to increase JNK activity indicating that MAP2K7/MKK7 is important to trigger JNK activity, while the additional phosphorylation of the Tyr residue by MAP2K4/MKK4 ensures optimal JNK activation. Has a specific role in JNK signal transduction pathway activated by pro-inflammatory cytokines. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Part of a non-canonical MAPK signaling pathway, composed of the upstream MAP3K12 kinase and downstream MAP kinases MAPK1/ERK2 and MAPK3/ERK1, that enhances the AP-1-mediated transcription of APP in response to APOE.

Subunit / interactions. Interacts with isoform 1 of VRK2. Interacts (via its D domain) with its substrates MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. Interacts (via its DVD domain) with MAP3Ks activators like MAP3K5/ASK1 and MAP3K1/MEKK1. Interacts with MAPK8IP1/JIP1, MAPK8IP2/JIP2 and MAPK8IP3/JIP3 scaffold proteins. Interacts with RASSF7, the interaction promotes phosphorylation. Found in a complex with SH3RF1, RAC1, MAP3K11/MLK3, MAPK8IP1/JIP1 and MAPK8/JNK1. Found in a complex with SH3RF1, RAC2, MAP3K7/TAK1, MAPK8IP1/JIP1, MAPK8/JNK1 and MAPK9/JNK2.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Ubiquitous; with highest level of expression in skeletal muscle. Isoform 3 is found at low levels in placenta, fetal liver, and skeletal muscle.

Post-translational modifications. Activated by phosphorylation on Ser-271 and Thr-275 by MAP kinase kinase kinases (MAP3Ks).

Activity regulation. Activated by phosphorylation by specific MAP kinase kinase kinases such as MAP3K1/MEKK1, MAP3K3/MEKK3, MAP3K11/MLK3 and MAP3K12/DLK.

Domain organisation. The DVD domain (residues 377-400) 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 37-57) contains a conserved docking site and is required for the binding to MAPK substrates.

Miscellaneous. May be due to intron retention.

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

Isoforms (4)

UniProt ID	Names	Canonical?
O14733-1	1, A	yes
O14733-2	2, B
O14733-3	3, gamma1
O14733-4	4

RefSeq proteins (3): NP_001284484, NP_001284485, NP_660186* (*=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
IPR052468	Dual_spec_MAPK_kinase	Family

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 (64 total): helix 15, strand 12, sequence variant 6, sequence conflict 6, modified residue 4, turn 4, splice variant 3, region of interest 3, binding site 2, site 2, compositionally biased region 2, initiator methionine 1, chain 1, domain 1, coiled-coil region 1, active site 1

Structure

Experimental structures (PDB)

37 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5Y90	X-RAY DIFFRACTION	1.3
6YZ4	X-RAY DIFFRACTION	1.7
6YFZ	X-RAY DIFFRACTION	1.9
7OVI	X-RAY DIFFRACTION	1.95
6YG0	X-RAY DIFFRACTION	2
6YG2	X-RAY DIFFRACTION	2
6YG3	X-RAY DIFFRACTION	2.05
7OVK	X-RAY DIFFRACTION	2.05
7CBX	X-RAY DIFFRACTION	2.06
5B2L	X-RAY DIFFRACTION	2.1
6IB2	X-RAY DIFFRACTION	2.1
6QG7	X-RAY DIFFRACTION	2.1
6YG6	X-RAY DIFFRACTION	2.15
6QFL	X-RAY DIFFRACTION	2.2
6YG7	X-RAY DIFFRACTION	2.2
6YG1	X-RAY DIFFRACTION	2.22
9HZ0	X-RAY DIFFRACTION	2.25
5Z1D	X-RAY DIFFRACTION	2.28
5Z1E	X-RAY DIFFRACTION	2.3
6QFR	X-RAY DIFFRACTION	2.3
6QG4	X-RAY DIFFRACTION	2.3
6YG4	X-RAY DIFFRACTION	2.3
4UX9	X-RAY DIFFRACTION	2.34
7OVJ	X-RAY DIFFRACTION	2.35
6YG5	X-RAY DIFFRACTION	2.4
2DYL	X-RAY DIFFRACTION	2.45
6QHR	X-RAY DIFFRACTION	2.52
6IB0	X-RAY DIFFRACTION	2.6
6QFT	X-RAY DIFFRACTION	2.7
6QHO	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14733-F1	77.94	0.45

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 (3): 44–45 (cleavage; by anthrax lethal factor); 76–77 (cleavage; by anthrax lethal factor); 243 (proton acceptor)

Ligand- & substrate-binding residues (2): 126–134; 149

Post-translational modifications (4): 2, 271, 275, 411

Function

Pathways and Gene Ontology

Reactome pathways

34 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-5210891	Uptake and function of anthrax toxins
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1643685	Disease
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-2454202	Fc epsilon receptor (FCERI) signaling
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-5339562	Uptake and actions of bacterial toxins
R-HSA-5663205	Infectious disease
R-HSA-8953897	Cellular responses to stimuli
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling

MSigDB gene sets: 274 (showing top): GOBP_CHROMOSOME_ORGANIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, TGCGCANK_UNKNOWN, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_TELOMERE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, CACCAGC_MIR138, GOBP_CELLULAR_SENESCENCE

GO Biological Process (21): apoptotic process (GO:0006915), response to osmotic stress (GO:0006970), signal transduction (GO:0007165), JNK cascade (GO:0007254), response to heat (GO:0009408), response to UV (GO:0009411), response to wounding (GO:0009611), positive regulation of telomere maintenance (GO:0032206), response to tumor necrosis factor (GO:0034612), Fc-epsilon receptor signaling pathway (GO:0038095), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of JNK cascade (GO:0046330), stress-activated MAPK cascade (GO:0051403), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to lipopolysaccharide (GO:0071222), cellular response to interleukin-1 (GO:0071347), cellular senescence (GO:0090398), regulation of motor neuron apoptotic process (GO:2000671), protein phosphorylation (GO:0006468), stress-activated protein kinase signaling cascade (GO:0031098), positive regulation of MAPK cascade (GO:0043410)

GO Molecular Function (18): magnesium ion binding (GO:0000287), MAP kinase activity (GO:0004707), MAP kinase kinase activity (GO:0004708), protein tyrosine kinase activity (GO:0004713), ATP binding (GO:0005524), JUN kinase kinase activity (GO:0008545), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), protein phosphatase binding (GO:0019903), protein serine kinase activity (GO:0106310), molecular function activator activity (GO:0140677), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-11 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
Fc epsilon receptor (FCERI) signaling	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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	4
response to stress	3
protein kinase activity	3
cellular process	2
JNK cascade	2
positive regulation of MAPK cascade	2
cellular response to stress	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to abiotic stimulus	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
response to temperature stimulus	1
response to light stimulus	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
response to cytokine	1
Fc receptor signaling pathway	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of JNK cascade	1
stress-activated protein kinase signaling cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	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
response to interleukin-1	1
cellular response to cytokine stimulus	1
regulation of neuron apoptotic process	1
motor neuron apoptotic process	1
phosphorylation	1

Protein interactions and networks

STRING

1362 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP2K7	MAPK8IP1	Q9UQF2	981
MAP2K7	GADD45B	O75293	946
MAP2K7	MAPK8IP2	Q13387	940
MAP2K7	DUSP19	Q8WTR2	887
MAP2K7	JUN	P05412	875
MAP2K7	MAPK8IP3	Q9UPT6	848
MAP2K7	TIPRL	O75663	821
MAP2K7	WDR62	O43379	810
MAP2K7	BCL10	O95999	729
MAP2K7	MAP3K13	O43283	715
MAP2K7	MAP3K11	Q16584	683
MAP2K7	AKT1	P31749	657
MAP2K7	RACK1	P25388	635
MAP2K7	SPAG9	O60271	624
MAP2K7	CNKSR1	Q969H4	621

IntAct

110 interactions, top by confidence:

A	B	Type	Score
MAP2K7		psi-mi:“MI:0915”(physical association)	0.670
	MAP2K7	psi-mi:“MI:0407”(direct interaction)	0.670
MAP3K7	MAP2K7	psi-mi:“MI:0915”(physical association)	0.670
MAP2K7	MAP3K7	psi-mi:“MI:2364”(proximity)	0.670
MAP2K7		psi-mi:“MI:0407”(direct interaction)	0.670
MAP2K7	GADD45B	psi-mi:“MI:0407”(direct interaction)	0.650
GADD45B	MAP2K7	psi-mi:“MI:0407”(direct interaction)	0.650
GADD45B	MAP2K7	psi-mi:“MI:0915”(physical association)	0.650
MAPK8IP1	MAP2K7	psi-mi:“MI:0914”(association)	0.620
MAPK8IP1	MAP2K7	psi-mi:“MI:0915”(physical association)	0.620
MAP2K7	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.560
DLK1	TCAF2	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
TPCN2	AP3B1	psi-mi:“MI:0914”(association)	0.530
MAPK8	MAP2K7	psi-mi:“MI:0914”(association)	0.480
MAP2K7	MAPK8	psi-mi:“MI:2364”(proximity)	0.480
PIK3R1	MAP2K7	psi-mi:“MI:0914”(association)	0.460

BioGRID (262): MAP2K7 (Affinity Capture-MS), MAP2K7 (Affinity Capture-MS), MAP2K7 (Affinity Capture-MS), MAP2K7 (Affinity Capture-MS), MAP2K7 (Affinity Capture-MS), MAP2K7 (Affinity Capture-MS), ALDOA (Co-fractionation), GSK3B (Co-fractionation), HSPE1 (Co-fractionation), ILKAP (Co-fractionation), MAP2K4 (Affinity Capture-Western), MAPK8 (Affinity Capture-Western), MAP2K7 (Affinity Capture-MS), MAP2K7 (Affinity Capture-MS), MAP2K7 (Affinity Capture-MS)

ESM2 similar proteins: A0A1S4CGX4, A9RWC9, A9S5R3, A9SR33, O01775, O14047, O14733, O44408, O80396, P10506, P18652, P18654, P29678, P31938, P36506, P36507, P51812, Q01986, Q02750, Q03428, Q05116, Q08942, Q10664, Q13163, Q18846, Q1HG70, Q20347, Q21307, Q24324, Q4KSH7, Q4V3C8, Q5QN75, Q62862, Q63932, Q63980, Q7TPS0, Q8MXI4, Q91447, Q94A06, Q99JT2

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

40 interactions.

A	Effect	B	Mechanism
MAP3K13	up-regulates	MAP2K7	phosphorylation
MAP3K5	up-regulates	MAP2K7	phosphorylation
MAP2K7	“down-regulates activity”	FADD	phosphorylation
MAP2K7	up-regulates	MAPK10	phosphorylation
MAP2K7	“down-regulates activity”	IRS1	phosphorylation
MAP3K20	“up-regulates activity”	MAP2K7	phosphorylation
FLNA	“up-regulates activity”	MAP2K7	binding
MAP2K7	“up-regulates activity”	MAPK13	phosphorylation
MAP3K7	“up-regulates activity”	MAP2K7	phosphorylation
MAP3K1	“up-regulates activity”	MAP2K7	phosphorylation
MAP3K5	“up-regulates activity”	MAP2K7	phosphorylation
MAP3K2	“up-regulates activity”	MAP2K7	phosphorylation
MAP3K12	“up-regulates activity”	MAP2K7	phosphorylation
RIPK2	“up-regulates activity”	MAP2K7	phosphorylation
MAP2K7	up-regulates	MAPK8	phosphorylation
MAP3K1	up-regulates	MAP2K7	phosphorylation
MAPK8IP2	up-regulates	MAP2K7	binding
MAP2K7	up-regulates	MAPK9	phosphorylation
MAPK8IP1	up-regulates	MAP2K7	binding
MAPK8IP3	up-regulates	MAP2K7	binding
TAOK2	up-regulates	MAP2K7	binding
MAP2K7	“up-regulates activity”	JNK	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 95 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
Programmed Cell Death	5	13.8×	2e-03
Diseases of signal transduction by growth factor receptors and second messengers	6	6.4×	1e-02
SARS-CoV Infections	6	6.3×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
JNK cascade	5	18.6×	2e-03
regulation of autophagy	5	16.5×	2e-03
MAPK cascade	6	12.6×	2e-03
cellular response to insulin stimulus	5	11.7×	7e-03
response to endoplasmic reticulum stress	5	11.4×	7e-03
positive regulation of JNK cascade	5	11.2×	7e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	4
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

1232 predictions. Top by Δscore:

Variant	Effect	Δscore
19:7904064:GCCCA:G	donor_gain	1.0000
19:7904065:CCCAG:C	donor_loss	1.0000
19:7904066:CCAG:C	donor_loss	1.0000
19:7904067:CAGTA:C	donor_loss	1.0000
19:7904068:AGT:A	donor_loss	1.0000
19:7904069:G:GG	donor_gain	1.0000
19:7909894:GAG:G	donor_gain	1.0000
19:7909894:GAGGT:G	donor_loss	1.0000
19:7909895:AGGT:A	donor_loss	1.0000
19:7909896:GGTG:G	donor_loss	1.0000
19:7909897:G:GA	donor_loss	1.0000
19:7909898:T:A	donor_loss	1.0000
19:7910256:CCAG:C	acceptor_loss	1.0000
19:7910257:CAG:C	acceptor_loss	1.0000
19:7910258:A:AG	acceptor_gain	1.0000
19:7910258:AGC:A	acceptor_gain	1.0000
19:7910259:G:GT	acceptor_gain	1.0000
19:7910259:GC:G	acceptor_gain	1.0000
19:7910259:GCG:G	acceptor_gain	1.0000
19:7910259:GCGC:G	acceptor_gain	1.0000
19:7910259:GCGCT:G	acceptor_gain	1.0000
19:7910369:T:G	donor_gain	1.0000
19:7910369:TTAAG:T	donor_loss	1.0000
19:7910371:AAGG:A	donor_loss	1.0000
19:7910372:AGGT:A	donor_loss	1.0000
19:7910374:G:GA	donor_loss	1.0000
19:7910375:T:G	donor_loss	1.0000
19:7910442:T:TA	acceptor_gain	1.0000
19:7910446:T:TA	acceptor_gain	1.0000
19:7910447:GTGCA:G	acceptor_loss	1.0000

AlphaMissense

2763 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:7910083:T:C	L96P	1.000
19:7910113:T:C	L106P	1.000
19:7910285:T:C	L120P	1.000
19:7910305:G:C	G127R	1.000
19:7910311:G:C	G129R	1.000
19:7910311:G:T	G129C	1.000
19:7910312:G:A	G129D	1.000
19:7910312:G:T	G129V	1.000
19:7910320:G:C	G132R	1.000
19:7910321:G:A	G132D	1.000
19:7910321:G:T	G132V	1.000
19:7910327:T:A	V134E	1.000
19:7910366:C:A	A147D	1.000
19:7910369:T:A	V148D	1.000
19:7910371:A:C	K149Q	1.000
19:7910371:A:G	K149E	1.000
19:7910372:A:C	K149T	1.000
19:7910372:A:T	K149M	1.000
19:7910373:G:C	K149N	1.000
19:7910373:G:T	K149N	1.000
19:7910457:T:A	M151K	1.000
19:7910457:T:C	M151T	1.000
19:7910457:T:G	M151R	1.000
19:7910489:C:A	R162S	1.000
19:7910490:G:C	R162P	1.000
19:7910496:T:C	L164P	1.000
19:7910500:G:A	M165I	1.000
19:7910500:G:C	M165I	1.000
19:7910500:G:T	M165I	1.000
19:7910501:G:C	D166H	1.000

dbSNP variants (sampled 300 via entrez): RS1000082187 (19:7913169 C>G,T), RS1000158066 (19:7913408 T>C), RS1000202521 (19:7905362 G>A), RS1000457870 (19:7909122 C>G), RS1000805709 (19:7906040 C>T), RS1001084460 (19:7914141 G>T), RS1001117499 (19:7912644 G>A,T), RS1001121127 (19:7904134 G>A,C), RS1001392655 (19:7910684 C>G,T), RS1001713213 (19:7907346 C>G), RS1001741480 (19:7908729 C>A,T), RS1001771176 (19:7908500 T>G), RS1001807898 (19:7906930 A>G), RS1001995837 (19:7911609 G>C), RS1002042147 (19:7904608 C>T)

Disease associations

OMIM: gene MIM:603014 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
schizophrenia	No Known Disease Relationship	Unknown

Mondo (2): neuroblastoma (MONDO:0005072), schizophrenia (MONDO:0005090)

Orphanet (1): Neuroblastoma (Orphanet:635)

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST009379_230	Type 2 diabetes	8.000000e-13
GCST009391_1839	Metabolite levels	9.000000e-06
GCST010118_70	Type 2 diabetes	1.000000e-09
GCST010242_353	HDL cholesterol levels	8.000000e-11
GCST90000025_674	Appendicular lean mass	1.000000e-19
GCST90002391_103	Mean corpuscular hemoglobin concentration	3.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0010412	triacylglycerol 50:5 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004980	appendicular lean mass
EFO:0004528	mean corpuscular hemoglobin concentration

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009447	Neuroblastoma	C04.557.465.625.600.590.650.550; C04.557.470.670.590.650.550; C04.557.580.625.600.590.650.550

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3530 (SINGLE PROTEIN), CHEMBL4523678 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

7 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 105,813 (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
CHEMBL180022	NERATINIB	4	9,404
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL554	LAPATINIB	4	69,326
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL603469	LESTAURTINIB	3
CHEMBL295316	PLUMBAGIN	1	6,294
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 (3 total), top 3:

Ligand	Action	Affinity	Parameter
compound 1k [PMID: 35912476]	Inhibition	8.4	pIC50
compound 11 [PMID: 26431428]	Inhibition	5.3	pIC50
cobimetinib	Negative	5.0	pIC50

Binding affinities (BindingDB)

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

Ligand	Measure	Value
PF-06651600	IC50	606 nM

ChEMBL bioactivities

99 potent at pChembl≥5 of 105 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.22	IC50	0.6	nM	CHEMBL4764965
8.72	IC50	1.9	nM	CHEMBL3329977
8.52	IC50	3	nM	CHEMBL5174214
8.40	IC50	4	nM	CHEMBL5195838
8.30	IC50	5	nM	CHEMBL4749823
8.22	IC50	6	nM	CHEMBL3901151
8.19	IC50	6.5	nM	CHEMBL4764965
8.00	IC50	10	nM	CHEMBL5284723
7.85	IC50	14	nM	CHEMBL4787266
7.57	Kd	27	nM	AST-487
7.52	IC50	30	nM	CHEMBL4071151
7.52	IC50	30	nM	CHEMBL5169325
7.52	Kd	30	nM	STAUROSPORINE
7.38	IC50	42	nM	CHEMBL5283781
7.22	IC50	60	nM	CHEMBL5271442
7.18	IC50	66	nM	CHEMBL5267499
7.13	IC50	74	nM	CHEMBL5279577
7.10	Kd	80	nM	LESTAURTINIB
7.02	IC50	96	nM	CHEMBL4866649
6.96	IC50	110	nM	CHEMBL5271266
6.96	IC50	110	nM	CHEMBL5267684
6.96	Kd	110	nM	CANERTINIB
6.72	IC50	188.6	nM	CHEMBL4095253
6.64	Kd	230	nM	CHEMBL100206
6.64	IC50	230	nM	CHEMBL100206
6.58	EC50	265	nM	CHEMBL5195838
6.58	IC50	260	nM	AST-487
6.58	IC50	260	nM	CHEMBL5282673
6.58	IC50	260	nM	CHEMBL5277855
6.57	IC50	270	nM	CHEMBL5271906
6.53	Kd	293	nM	CHEMBL4465866
6.52	IC50	300	nM	CHEMBL1077979
6.52	IC50	300	nM	CHEMBL5272546
6.44	IC50	360	nM	CHEMBL5271334
6.44	IC50	360	nM	CHEMBL5271519
6.42	EC50	380	nM	CHEMBL5174214
6.39	IC50	410	nM	CHEMBL5273066
6.38	IC50	420	nM	CHEMBL5273762
6.28	Kd	530	nM	NERATINIB
6.27	IC50	540	nM	CHEMBL4879048
6.24	IC50	571	nM	STAUROSPORINE
6.10	IC50	800	nM	CHEMBL5266940
6.08	IC50	840	nM	CHEMBL4872723
6.07	IC50	860	nM	CHEMBL507249
6.05	IC50	900	nM	CHEMBL5287907
6.04	IC50	920	nM	CHEMBL4865159
6.03	IC50	930	nM	CHEMBL5278028
6.00	IC50	1000	nM	CHEMBL3715933
6.00	IC50	1000	nM	CHEMBL3715441
6.00	IC50	1000	nM	CHEMBL3717892

PubChem BioAssay actives

80 with measured affinity, of 868 total; 50 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
3-(1H-indazol-3-yl)-5-(prop-2-enoylamino)-N-prop-2-ynylbenzamide	1870679: Inhibition of N-terminal 6XHis-tagged recombinant MKK7 (117 to 423 residues) (unknown origin) expressed in Escherichia coli BL21-DE3 preincubated for 2 hrs in presence of ATP measured after 17 hrs	ic50	0.0006	uM
3-[(1,4-dioxonaphthalen-2-yl)amino]benzoic acid	1720294: Inhibition of MEK7 (unknown origin)	ic50	0.0019	uM
1-[(3R)-3-[4-amino-3-[1-[2-(4-chlorophenyl)-2,2-difluoroethyl]triazol-4-yl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one	1870679: Inhibition of N-terminal 6XHis-tagged recombinant MKK7 (117 to 423 residues) (unknown origin) expressed in Escherichia coli BL21-DE3 preincubated for 2 hrs in presence of ATP measured after 17 hrs	ic50	0.0030	uM
1-[(3R)-3-[4-amino-3-[1-(2,2-difluoro-2-phenylethyl)triazol-4-yl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one	1870679: Inhibition of N-terminal 6XHis-tagged recombinant MKK7 (117 to 423 residues) (unknown origin) expressed in Escherichia coli BL21-DE3 preincubated for 2 hrs in presence of ATP measured after 17 hrs	ic50	0.0040	uM
N-[3-(6-methyl-1H-indazol-3-yl)phenyl]prop-2-enamide	1697384: Inhibition of MAP2K7 (unknown origin) using JNK peptide KFMMTPYVVTR incubated for 30 mins measured by multimode reader based ADP-glo assay	ic50	0.0050	uM
N-[3-(1H-indazol-3-yl)phenyl]prop-2-enamide	1720294: Inhibition of MEK7 (unknown origin)	ic50	0.0060	uM
N-[3-[6-(benzylamino)pyrimidin-4-yl]oxyphenyl]-2-chloroacetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.0100	uM
N-[3-(6-nitro-1H-indazol-3-yl)phenyl]prop-2-enamide	1720294: Inhibition of MEK7 (unknown origin)	ic50	0.0140	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624722: Binding constant for MKK7 kinase domain	kd	0.0270	uM
1-[(3R)-3-(4-amino-3-ethynylpyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl]prop-2-en-1-one	1870679: Inhibition of N-terminal 6XHis-tagged recombinant MKK7 (117 to 423 residues) (unknown origin) expressed in Escherichia coli BL21-DE3 preincubated for 2 hrs in presence of ATP measured after 17 hrs	ic50	0.0300	uM
3-(1H-indazol-3-yl)-N-[[1-[(1R,2R)-2-methoxycyclohexyl]triazol-4-yl]methyl]-5-(prop-2-enoylamino)benzamide	1870679: Inhibition of N-terminal 6XHis-tagged recombinant MKK7 (117 to 423 residues) (unknown origin) expressed in Escherichia coli BL21-DE3 preincubated for 2 hrs in presence of ATP measured after 17 hrs	ic50	0.0300	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	624722: Binding constant for MKK7 kinase domain	kd	0.0300	uM
2-chloro-N-[3-[6-[(3,4-difluorophenyl)methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.0420	uM
2-chloro-N-[3-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.0600	uM
2-chloro-N-[3-[6-[2-(4-chlorophenyl)ethylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.0660	uM
2-chloro-N-[3-[6-[(3,5-difluorophenyl)methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.0740	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	624722: Binding constant for MKK7 kinase domain	kd	0.0800	uM
4-[[3-(6-fluoro-1H-indazol-3-yl)phenyl]sulfonylamino]benzamide	1780568: Inhibition of human recombinant full length N-terminal GST tagged MEK7 expressed in Sf21 cells using JNK1 as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.0960	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	624722: Binding constant for MKK7 kinase domain	kd	0.1100	uM
N-[3-[6-[benzyl(methyl)amino]pyrimidin-4-yl]oxyphenyl]-2-chloroacetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.1100	uM
2-chloro-N-[3-[6-[(2,3,6-trifluorophenyl)methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.1100	uM
5-(1,3-benzodioxol-5-yl)-7-[[(2R)-1-ethenylsulfonylpyrrolidin-2-yl]methyl]pyrrolo[2,3-d]pyrimidin-4-amine	1488750: Inhibition of recombinant human N-terminal GST-tagged MKK7beta (2 to end residues) expressed in Escherichia coli preincubated for 5 mins followed by substrate addition after 30 to 60 mins in presence of ATP by fluorescence assay	ic50	0.1886	uM
3-(1,4-dioxonaphthalen-2-yl)sulfanylpropanoic acid	1517764: Binding affinity to MKK7 (unknown origin) expressed in HEK293 cells assessed as dissociation constant by kinomescan method	kd	0.2300	uM
2-chloro-N-[3-[6-[2-(1H-indol-3-yl)ethylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.2600	uM
2-chloro-N-[3-[6-[(3,4-dimethoxyphenyl)methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.2600	uM
2-chloro-N-[3-[6-(cyclopentylamino)pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.2700	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	1526139: Binding affinity to recombinant human full-length N-terminal GST-tagged MAP2K7 (1 to 419 residues) expressed in baculovirus expression system using JNK2 as substrate incubated for 1 hr by TR-FRET assay	kd	0.2930	uM
2-chloro-N-[3-[6-[(4-methoxyphenyl)methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.3000	uM
(4S,6Z,9S,10S,12E)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	719899: Inhibition of MEK7	ic50	0.3000	uM
2-chloro-N-[3-[6-[(4-methylphenyl)methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.3600	uM
2-chloro-N-[3-[6-[(2,4-difluorophenyl)methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.3600	uM
2-chloro-N-[3-[6-[[4-(trifluoromethyl)phenyl]methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.4100	uM
N-[3-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]prop-2-enamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.4200	uM
Neratinib	624722: Binding constant for MKK7 kinase domain	kd	0.5300	uM
4-(6-fluoro-1H-indazol-3-yl)benzenesulfonamide	1780568: Inhibition of human recombinant full length N-terminal GST tagged MEK7 expressed in Sf21 cells using JNK1 as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.5400	uM
2-chloro-N-[3-[6-[(2-methoxyphenyl)methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.8000	uM
3-(6-fluoro-1H-indazol-3-yl)-N-phenylbenzenesulfonamide	1780568: Inhibition of human recombinant full length N-terminal GST tagged MEK7 expressed in Sf21 cells using JNK1 as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.8400	uM
4-[4-[2-(cyclopentylamino)pyrimidin-4-yl]-1H-pyrazol-5-yl]cyclohexan-1-ol	353703: Inhibition of MKK7beta	ic50	0.8600	uM
2-chloro-N-[3-(6-morpholin-4-ylpyrimidin-4-yl)oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.9000	uM
3-(6-fluoro-1H-indazol-3-yl)-N-(4-methylsulfonylphenyl)benzenesulfonamide	1780568: Inhibition of human recombinant full length N-terminal GST tagged MEK7 expressed in Sf21 cells using JNK1 as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	0.9200	uM
2-chloro-N-[3-[6-[2-(4-methoxyphenyl)ethylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	0.9300	uM
1-[(3R)-3-[4-amino-3-[1-(4-chloro-2-hydroxyphenyl)triazol-4-yl]pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one	1870680: Inhibition of N-terminal 6XHis-tagged recombinant MKK7 (117 to 423 residues) in human U2OS assessed as reduction in c-Jun phosphorylation level incubated for 80 mins by Western blot analysis	ec50	1.0930	uM
N-[3-[6-[2-(1,3-benzodioxol-5-yl)ethylamino]pyrimidin-4-yl]oxyphenyl]-2-chloroacetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	1.1000	uM
2,3-bis(2-hydroxyethylsulfanyl)naphthalene-1,4-dione	1517764: Binding affinity to MKK7 (unknown origin) expressed in HEK293 cells assessed as dissociation constant by kinomescan method	kd	1.1000	uM
2-chloro-N-[3-[6-[2-(4-fluorophenyl)ethylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	1.2000	uM
2-chloro-N-[3-[6-[[2-(trifluoromethyl)phenyl]methylamino]pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	1.2000	uM
2-chloro-N-[3-[6-(2-phenylethyl)pyrimidin-4-yl]oxyphenyl]acetamide	1956477: Inhibition of human recombinant full-length MEK7 using JNK1 as substrate incubated for 30 mins followed by ATP addition measured after 1 hr by ADP Glo luminescent assay	ic50	1.2000	uM
N-[3-(6-fluoro-1H-indazol-3-yl)phenyl]pyridine-3-sulfonamide	1780568: Inhibition of human recombinant full length N-terminal GST tagged MEK7 expressed in Sf21 cells using JNK1 as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	1.3000	uM
N-(4-acetylphenyl)-3-(6-fluoro-1H-indazol-3-yl)benzenesulfonamide	1780568: Inhibition of human recombinant full length N-terminal GST tagged MEK7 expressed in Sf21 cells using JNK1 as substrate pre-incubated for 30 mins followed by addition of ATP and measured after 150 mins by ADP-Glo kinase assay	ic50	1.3000	uM
2-(1,4-dioxonaphthalen-2-yl)sulfanylacetic acid	1517764: Binding affinity to MKK7 (unknown origin) expressed in HEK293 cells assessed as dissociation constant by kinomescan method	kd	1.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, increases expression, affects cotreatment, decreases expression, increases abundance	5
diallyl trisulfide	affects expression, affects reaction, increases degradation, increases phosphorylation	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Plant Extracts	affects cotreatment, increases expression, decreases expression	2
Valproic Acid	increases methylation, decreases expression	2
bisphenol F	decreases methylation	1
moringin	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
stachydrine	decreases reaction, increases phosphorylation, affects reaction	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
trichostatin A	affects expression	1
afimoxifene	decreases response to substance	1
butyraldehyde	decreases expression	1
bufalin	decreases expression	1
potassium chromate(VI)	decreases reaction, increases phosphorylation	1
diallyl disulfide	affects expression	1
cupric chloride	increases expression	1
andrographolide	decreases reaction, increases phosphorylation	1
allyl sulfide	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases phosphorylation	1
deguelin	decreases expression	1
obeticholic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1

ChEMBL screening assays

217 unique, capped per target: 217 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1041385	Binding	Inhibition of MKK7 at 2 uM	Structure-guided design of potent and selective pyrimidylpyrrole inhibitors of extracellular signal-regulated kinase (ERK) using conformational control. — J Med Chem

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 2 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A5QT	WAe001-A-54	Embryonic stem cell	Male
CVCL_A5QU	WAe001-A-55	Embryonic stem cell	Male
CVCL_B1GB	Abcam A-549 MAP2K7 KO 1	Cancer cell line	Male
CVCL_B2NV	Abcam A-549 MAP2K7 KO 2	Cancer cell line	Male
CVCL_D7U7	Ubigene A-549 MAP2K7 KO	Cancer cell line	Male
CVCL_D9J7	Ubigene HEK293 MAP2K7 KO	Transformed cell line	Female
CVCL_SW49	HAP1 MAP2K7 (-) 1	Cancer cell line	Male
CVCL_SW50	HAP1 MAP2K7 (-) 2	Cancer cell line	Male
CVCL_SW51	HAP1 MAP2K7 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety