MAPK14

Summary

MAPK14 (mitogen-activated protein kinase 14, HGNC:6876) is a protein-coding gene on chromosome 6p21.31, encoding Mitogen-activated protein kinase 14 (Q16539). Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway.

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress related transcription and cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.

Source: NCBI Gene 1432 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 50 total
• Druggable target: yes — 76 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_139012

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6876
Approved symbol	MAPK14
Name	mitogen-activated protein kinase 14
Location	6p21.31
Locus type	gene with protein product
Status	Approved
Aliases	p38alpha, PRKM14, p38, Mxi2, PRKM15
Ensembl gene	ENSG00000112062
Ensembl biotype	protein_coding
OMIM	600289
Entrez	1432

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 14 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000229794, ENST00000229795, ENST00000310795, ENST00000468133, ENST00000472333, ENST00000474429, ENST00000490379, ENST00000491957, ENST00000496250, ENST00000718318, ENST00000718319, ENST00000852146, ENST00000852147, ENST00000852148, ENST00000852149, ENST00000852150, ENST00000950877, ENST00000950878

RefSeq mRNA: 4 — MANE Select: NM_139012 NM_001315, NM_139012, NM_139013, NM_139014

CCDS: CCDS4815, CCDS4816, CCDS4817

Canonical transcript exons

ENST00000229794 — 12 exons

Exon	Start	End
ENSE00001884967	36108380	36111236
ENSE00003491453	36052699	36052828
ENSE00003500775	36102571	36102649
ENSE00003549575	36072873	36072984
ENSE00003551151	36076537	36076608
ENSE00003567782	36107455	36107628
ENSE00003568616	36073691	36073720
ENSE00003606188	36059289	36059347
ENSE00003642864	36074049	36074096
ENSE00003645527	36075848	36075962
ENSE00004034767	36027808	36028273
ENSE00004034768	36095987	36096066

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 96.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.0653 / max 788.3649, expressed in 1820 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67482	27.5431	1816
67481	2.4477	1386
67480	1.7145	1012
67479	1.4185	870
67483	0.7156	324
67484	0.2259	105

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	96.64	gold quality
blood	UBERON:0000178	96.53	gold quality
bone marrow	UBERON:0002371	96.01	gold quality
bone marrow cell	CL:0002092	95.87	gold quality
monocyte	CL:0000576	95.81	gold quality
trabecular bone tissue	UBERON:0002483	95.67	gold quality
mononuclear cell	CL:0000842	95.60	gold quality
leukocyte	CL:0000738	95.58	gold quality
bone element	UBERON:0001474	95.55	gold quality
calcaneal tendon	UBERON:0003701	93.66	gold quality
endothelial cell	CL:0000115	93.18	gold quality
granulocyte	CL:0000094	93.08	gold quality
stromal cell of endometrium	CL:0002255	92.98	gold quality
body of uterus	UBERON:0009853	92.71	gold quality
myometrium	UBERON:0001296	92.56	gold quality
smooth muscle tissue	UBERON:0001135	92.52	gold quality
rectum	UBERON:0001052	92.48	gold quality
tendon	UBERON:0000043	92.45	gold quality
esophagus squamous epithelium	UBERON:0006920	92.20	gold quality
decidua	UBERON:0002450	92.01	gold quality
triceps brachii	UBERON:0001509	91.88	gold quality
spleen	UBERON:0002106	91.85	gold quality
right lung	UBERON:0002167	91.78	gold quality
lower esophagus	UBERON:0013473	91.72	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.70	gold quality
vermiform appendix	UBERON:0001154	91.61	gold quality
skin of leg	UBERON:0001511	91.61	gold quality
mucosa of stomach	UBERON:0001199	91.50	gold quality
colonic epithelium	UBERON:0000397	91.49	gold quality
tonsil	UBERON:0002372	91.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.05

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
CCND1	Repression
COL1A1	Activation
DEFB131A	Activation
HBA1	Activation
HBB	Activation
IL12B	Activation
JUNB	Activation
LGALS9	Activation

Upstream regulators (CollecTRI, top): ATF1, CEBPB, CEBPD, DDIT3, ELF1, FOS, FOXM1, HBP1, HIF1A, HNRNPK, IRF6, JUN, LITAF, MEF2A, MYC, MYOD1, NEUROD1, NFE2L2, PARP1, RELA, ROCK1, SP1, SP3, SUPT20H, TBX2, TCF3, TP53, TXK, USF1, VDR, ZGLP1, ZHX2

miRNA regulators (miRDB)

120 targeting MAPK14, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4531	99.99	69.70	3181
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-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-124-3P	99.89	73.74	3043

Literature-anchored findings (GeneRIF, showing 40)

• PI3K promotes assembly of adherens junctions, which, in turn, control p38 MAPK activation and enterocyte differentiation. (PMID:11756422)
• p38 Map kinase pathway is a common effector for type I IFN and transforming growth factor beta signaling in human hematopoietic progenitors and plays a critical role in the induction of the suppressive effects of these cytokines on normal hematopoiesis (PMID:11773065)
• endotoxemia induced a phosphorylation and activation of p38 MAPK (PMID:11788789)
• mediates the cell death induced by PrP106-126 (PMID:11848686)
• TRAIL/Apo2L-induced apoptosis is mediated by ROS-activated p38 MAP kinase followed by caspase activation in HeLa cells. (PMID:11852102)
• allosteric binding site for a diaryl urea class of highly potent and selective inhibitors against human p38 MAP kinase (PMID:11896401)
• p38alpha MAP kinase is significantly activated in the inflamed colonic mucosa of Crohn’s disease patients and is linked to the induction of TNF-alpha secretion and signaling in this system. (PMID:11994493)
• involvement of P38 MAPK, AP-1 and NF-kappa B transcription factors in the IL-1 induction of MMPs in chondrocytes (PMID:12009331)
• Specificity of arachidonic acid-induced inhibition of growth and activation of c-jun kinases and p38 mitogen-activated protein kinase in hematopoietic cells (PMID:12051955)
• Activation of p38 mitogen-activated protein kinase and nuclear factor-kappaB in tumour necrosis factor-induced eotaxin release of human eosinophils. (PMID:12067303)
• UVB-mediated activation of p38 mitogen-activated protein kinase enhances resistance of normal human keratinocytes to apoptosis by stabilizing cytoplasmic p53. (PMID:12071847)
• Distinct roles for phosphoinositide 3-kinase, mitogen-activated protein kinase and p38 MAPK in mediating cell cycle progression of breast cancer cells. (PMID:12085235)
• P38 MAPK has a role in inducing IL-8 gene transcription via AP-1 activation in hVSMCs (PMID:12126643)
• activation of this stress-associated pathway has been reported for many stimuli, a unique translocation of p38 from the cytoplasm to the detergent-resistant fraction is a specific event during hapten-induced activation of antigen-presenting cells. (PMID:12164931)
• parthenolide inhibits LPS- but not TNF-alpha-induced maturation of human monocyte-derived dendritic cells by inhibition of the p38 mitogen-activated protein kinase pathway (PMID:12170268)
• both Ca(2+)-dependent and p38 kinase-mediated phosphorylation events, causes reassembly of the actin cytoskeleton and subsequent appearance of membrane blebs at the plasma membrane. (PMID:12183063)
• ITGB1 activated by ERK1/2, p38 MAPK after hypoxia (PMID:12200131)
• p38 MAPK has a role in STAT1 dependent trans activation independent of serine phosphorylation (PMID:12232043)
• As(2)O(3) is able to induce the apoptotic activity in K562 cells, and its apoptotic mechanism may be associated with the activation of p38. (PMID:12296996)
• there is a mechanically coupled transcriptional circuit that activates p38, tethers p38 to actin filaments, and promotes binding of p38 to Sp1 in the nucleus (PMID:12324467)
• p38 play a critical role in the UVA-induced expression of COX-2 in keratinocytes and may serve as a potential drug target in the chemoprevention of skin cancer. (PMID:12370831)
• p38 MAP Kinase suppresses the function of Mirk as a transcriptional activator only when cells are proliferating (PMID:12384504)
• p38 alpha is regulated by TauAlphaBeta1beta in physiological conditions (PMID:12429732)
• p38MAPK and caspase are required for zinc-induced apoptosis in human leukemia HL-60 cells (PMID:12473116)
• JNK-1 and p38 play a role in apoptosis induced by capsaicin in H-ras-transformed tumor cells (PMID:12478662)
• data suggest that thrombin induces p38 mitogen-activated protein kinase activation, which leads to NF-kappa B mobilization to the nucleus and causes the upregulation of E-selectin and subsequent leukocyte recruitment (PMID:12505871)
• p38 MAP kinase is involved in a positive feedback loop regulating macrophage signaling with MKK6 (PMID:12509443)
• p38 signaling is down-regulated in postinjury circulating neutrophils (PMID:12519482)
• p38 mitogen-activated protein kinase defines the common senescence-signaling pathway. (PMID:12581156)
• Lipopolysaccharide stimulates p38-dependent induction of antiviral genes , such as myxovirus resistance-1 (MX1) in neutrophils independently of paracrine factors. (PMID:12595530)
• upregulation of the p38 mitogen-activated protein kinase pathway might contribute to the loss of GLUT4 protein expression observed in adipose tissue from type 2 diabetic patients (PMID:12606502)
• activated p38 MAPK pathway may play a role in the pathogenesis of peritoneal fibrosis. (PMID:12631076)
• p38 MAPK activation is central to IL-10 production of cells from patients with schistosomiasis mansoni and the levels of phosphorylated p38 MAPK influences the amount of Il-10 produced in cells from intestinal and hepatosplenic patients (PMID:12654092)
• p38 and ERK1/2 have roles in coordinating cellular migration and proliferation in epithelial wound healing (PMID:12663671)
• This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 MAP KINASE activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer. (PMID:12698197)
• results indicate that epithelial TLR5 mediates p38 activation and subsequently regulates flagellin-induced IL-8 expression independently of NF-kappaB, probably by influencing IL-8 mRNA translation (PMID:12702497)
• These findings suggested that reduction of the p38 MAPK cascade may account, in part, for the resistance to apoptosis, leading to the unrestricted cell growth of human HCC. (PMID:12784337)
• Results suggest that tissue or plasma fibronectin may modulate the intestinal epithelial response to repetitive deformation through inhibted activation of p38 and jun kinases. (PMID:12810082)
• p38 has a role in apoptosis in human melanoma cells by modulating depolarization of mitochondrial membrane potential (PMID:12855667)
• p38 MAPK pathway predominantly regulates deadenylation, rather than decay of the mRNA body (PMID:12882963)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapk14a	ENSDARG00000000857
danio_rerio	mapk14b	ENSDARG00000028721
mus_musculus	Mapk14	ENSMUSG00000053436
rattus_norvegicus	Mapk14	ENSRNOG00000000513
drosophila_melanogaster	p38b	FBGN0024846
caenorhabditis_elegans		WBGENE00002187
caenorhabditis_elegans		WBGENE00002188
caenorhabditis_elegans		WBGENE00004055
caenorhabditis_elegans		WBGENE00004056
caenorhabditis_elegans	gskl-2	WBGENE00007977
caenorhabditis_elegans	Y106G6E.1	WBGENE00013705

Paralogs (19): MAPK9 (ENSG00000050748), MAPK6 (ENSG00000069956), MOK (ENSG00000080823), NLK (ENSG00000087095), SRPK1 (ENSG00000096063), MAPK1 (ENSG00000100030), MAPK3 (ENSG00000102882), MAPK8 (ENSG00000107643), MAPK10 (ENSG00000109339), MAK (ENSG00000111837), CILK1 (ENSG00000112144), SRPK2 (ENSG00000135250), MAPK4 (ENSG00000141639), MAPK13 (ENSG00000156711), MAPK7 (ENSG00000166484), MAPK15 (ENSG00000181085), SRPK3 (ENSG00000184343), MAPK11 (ENSG00000185386), MAPK12 (ENSG00000188130)

Protein

Protein identifiers

Mitogen-activated protein kinase 14 — Q16539 (reviewed: Q16539)

Alternative names: Cytokine suppressive anti-inflammatory drug-binding protein, MAP kinase MXI2, MAX-interacting protein 2, Mitogen-activated protein kinase p38 alpha, Stress-activated protein kinase 2a

All UniProt accessions (6): Q16539, B4E0K5, B5TY33, E7EX54, H7C4E2, L7RSM2

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 also interacts with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on ‘Ser-10’ (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at ‘Thr-113’. Phosphorylates NLRP1 downstream of MAP3K20/ZAK in response to UV-B irradiation and ribosome collisions, promoting activation of the NLRP1 inflammasome and pyroptosis. (Microbial infection) Activated by phosphorylation by M.tuberculosis EsxA in T-cells leading to inhibition of IFN-gamma production; phosphorylation is apparent within 15 minutes and is inhibited by kinase-specific inhibitors SB203580 and siRNA.

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 a kinase interaction motif within the protein tyrosine phosphatase, PTPRR. This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation. Interacts with SPAG9 and GADD45A. Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B. Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14 and may regulate its dephosphorylation. Interacts with DUSP2; this interaction does not lead to catalytic activation of DUSP2 and dephosphorylation of MAPK14.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Brain, heart, placenta, pancreas and skeletal muscle. Expressed to a lesser extent in lung, liver and kidney.

Post-translational modifications. Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. Dual phosphorylation can also be mediated by TAB1-mediated autophosphorylation. TCR engagement in T-cells also leads to Tyr-323 phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1, DUSP10 and DUSP16. PPM1D also mediates dephosphorylation and inactivation of MAPK14. Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity. Lys-53 and Lys-152 are deacetylated by HDAC3. Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway.

Activity regulation. Activated by cell stresses such as DNA damage, heat shock, osmotic shock, anisomycin and sodium arsenite, as well as pro-inflammatory stimuli such as bacterial lipopolysaccharide (LPS) and interleukin-1. Activation occurs through dual phosphorylation of Thr-180 and Tyr-182 by either of two dual specificity kinases, MAP2K3/MKK3 or MAP2K6/MKK6, and potentially also MAP2K4/MKK4, as well as by TAB1-mediated autophosphorylation. MAPK14 phosphorylated on both Thr-180 and Tyr-182 is 10-20-fold more active than MAPK14 phosphorylated only on Thr-180, whereas MAPK14 phosphorylated on Tyr-182 alone is inactive. whereas Thr-180 is necessary for catalysis, Tyr-182 may be required for auto-activation and substrate recognition. Phosphorylated at Tyr-323 by ZAP70 in an alternative activation pathway in response to TCR signaling in T-cells. This alternative pathway is inhibited by GADD45A. Inhibited by dual specificity phosphatases, such as DUSP1, DUSP10, and DUSP16. Specifically inhibited by the binding of pyridinyl-imidazole compounds, which are cytokine-suppressive anti-inflammatory drugs (CSAID). Isoform Mxi2 is 100-fold less sensitive to these agents than the other isoforms and is not inhibited by DUSP1. Isoform Exip is not activated by MAP2K6. SB203580 is an inhibitor of MAPK14.

Domain organisation. The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.

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

Isoforms (5)

UniProt ID	Names	Canonical?
Q16539-1	CSBP2	yes
Q16539-2	CSBP1
Q16539-3	Mxi2
Q16539-4	Exip, Exon skip
Q16539-5	5

RefSeq proteins (4): NP_001306, NP_620581, NP_620582, NP_620583 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR003527	MAP_kinase_CS	Conserved_site
IPR008352	MAPK_HOG-like	Family
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR038784	MAPK14	Family
IPR050117	MAPK	Family

Pfam: PF00069

Enzyme classification (BRENDA):

• EC 2.7.11.24 — mitogen-activated protein kinase (BRENDA: 48 organisms, 305 substrates, 720 inhibitors, 27 Km, 20 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.048–0.096	4
ATF2DELTA109	0.002–0.02	2
EGF RECEPTOR PEPTIDE	0.656–2.8	2
ERKSUB	0.127–1.2	2
MEK1ERK	0.0037–0.065	2
MEK2ERK	0.0056–0.03	2
ELKERK	0.0044	1
ERKMEK1	0.344	1
ERKMEK2	0.388	1
ERKSTE7	0.173	1
PROTEIN ATF2	0.0019	1
SCRAMMMEK2	0.096	1
STE7ERK	0.0006	1

Catalyzed reactions (Rhea), 2 shown:

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

UniProt features (80 total): helix 19, mutagenesis site 14, strand 13, modified residue 9, turn 9, splice variant 5, sequence variant 3, binding site 2, initiator methionine 1, chain 1, domain 1, short sequence motif 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

257 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2FST	X-RAY DIFFRACTION	1.45
3LFF	X-RAY DIFFRACTION	1.5
3OEF	X-RAY DIFFRACTION	1.6
3ZS5	X-RAY DIFFRACTION	1.6
4EHV	X-RAY DIFFRACTION	1.6
5WJJ	X-RAY DIFFRACTION	1.6
6SFI	X-RAY DIFFRACTION	1.6
9MHB	X-RAY DIFFRACTION	1.65
4GEO	X-RAY DIFFRACTION	1.66
6QYX	X-RAY DIFFRACTION	1.66
8YD9	X-RAY DIFFRACTION	1.66
2FSL	X-RAY DIFFRACTION	1.7
2QD9	X-RAY DIFFRACTION	1.7
3FMK	X-RAY DIFFRACTION	1.7
3K3I	X-RAY DIFFRACTION	1.7
3ROC	X-RAY DIFFRACTION	1.7
5XYY	X-RAY DIFFRACTION	1.7
6HWT	X-RAY DIFFRACTION	1.7
6HWV	X-RAY DIFFRACTION	1.7
6RFO	X-RAY DIFFRACTION	1.7
2RG6	X-RAY DIFFRACTION	1.72
6QDZ	X-RAY DIFFRACTION	1.73
6SFO	X-RAY DIFFRACTION	1.75
2GFS	X-RAY DIFFRACTION	1.75
1WBS	X-RAY DIFFRACTION	1.8
2NPQ	X-RAY DIFFRACTION	1.8
2ZAZ	X-RAY DIFFRACTION	1.8
3FL4	X-RAY DIFFRACTION	1.8
3FLY	X-RAY DIFFRACTION	1.8
3GC7	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16539-F1	89.91	0.75

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): 168 (proton acceptor)

Ligand- & substrate-binding residues (2): 30–38; 53

Post-translational modifications (9): 53, 152, 180, 182, 263, 323, 2, 2, 16

Mutagenesis-validated functional residues (14):

Position	Phenotype
34	lowered kinase activity.
53	loss of kinase activity.
54	impairs map2k6/mkk6-dependent autophosphorylation.
69	lowered kinase activity.
168	loss of kinase activity.
175	no effect on either the kinase activity or tyrosine phosphorylation.
176	emulation of the active state. increase in activity; when associated with s-327 or l-327.
177	loss of kinase activity.
180	loss of kinase activity.
182	loss of kinase activity.
320	lowered kinase activity.
327	emulation of the active state. increase in activity; when associated with a-176.
337	loss of kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

78 pathways

ID	Pathway
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-171007	p38MAPK events
R-HSA-198753	ERK/MAPK targets
R-HSA-2151209	Activation of PPARGC1A (PGC-1alpha) by phosphorylation
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-418592	ADP signalling through P2Y purinoceptor 1
R-HSA-432142	Platelet sensitization by LDL
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-450341	Activation of the AP-1 family of transcription factors
R-HSA-450604	KSRP (KHSRP) binds and destabilizes mRNA
R-HSA-525793	Myogenesis
R-HSA-5668599	RHO GTPases Activate NADPH Oxidases
R-HSA-6798695	Neutrophil degranulation
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-69601	Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A
R-HSA-9662834	CD163 mediating an anti-inflammatory response
R-HSA-9824585	Regulation of MITF-M-dependent genes involved in pigmentation
R-HSA-109582	Hemostasis
R-HSA-1266738	Developmental Biology
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1592230	Mitochondrial biogenesis
R-HSA-162582	Signal Transduction
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-166520	Signaling by NTRKs
R-HSA-167044	Signalling to RAS
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade

MSigDB gene sets: 858 (showing top): PID_BCR_5PATHWAY, GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_MYOTUBE_DIFFERENTIATION, GOBP_LIPID_MODIFICATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_RESPONSE_TO_IONIZING_RADIATION, BIOCARTA_FMLP_PATHWAY, GOBP_REGULATION_OF_FAT_CELL_DIFFERENTIATION, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE_TO_ANTIGENIC_STIMULUS, GOBP_MUSCLE_TISSUE_DEVELOPMENT

GO Biological Process (74): DNA damage checkpoint signaling (GO:0000077), MAPK cascade (GO:0000165), cell morphogenesis (GO:0000902), cartilage condensation (GO:0001502), angiogenesis (GO:0001525), osteoblast differentiation (GO:0001649), placenta development (GO:0001890), response to dietary excess (GO:0002021), chondrocyte differentiation (GO:0002062), negative regulation of inflammatory response to antigenic stimulus (GO:0002862), glucose metabolic process (GO:0006006), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), apoptotic process (GO:0006915), chemotaxis (GO:0006935), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), cell surface receptor protein serine/threonine kinase signaling pathway (GO:0007178), skeletal muscle tissue development (GO:0007519), positive regulation of gene expression (GO:0010628), positive regulation of myotube differentiation (GO:0010831), fatty acid oxidation (GO:0019395), platelet activation (GO:0030168), regulation of ossification (GO:0030278), osteoclast differentiation (GO:0030316), stress-activated protein kinase signaling cascade (GO:0031098), positive regulation of cyclase activity (GO:0031281), lipopolysaccharide-mediated signaling pathway (GO:0031663), response to muramyl dipeptide (GO:0032495), positive regulation of interleukin-12 production (GO:0032735), response to insulin (GO:0032868), tumor necrosis factor-mediated signaling pathway (GO:0033209), negative regulation of hippo signaling (GO:0035331), intracellular signal transduction (GO:0035556), cellular response to vascular endothelial growth factor stimulus (GO:0035924), response to muscle stretch (GO:0035994), p38MAPK cascade (GO:0038066), positive regulation of protein import into nucleus (GO:0042307), signal transduction in response to DNA damage (GO:0042770), positive regulation of erythrocyte differentiation (GO:0045648)

GO Molecular Function (14): protein serine/threonine kinase activity (GO:0004674), MAP kinase activity (GO:0004707), MAP kinase kinase activity (GO:0004708), ATP binding (GO:0005524), enzyme binding (GO:0019899), protein phosphatase binding (GO:0019903), mitogen-activated protein kinase p38 binding (GO:0048273), NFAT protein binding (GO:0051525), 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 (11): spindle pole (GO:0000922), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), nuclear speck (GO:0016607), secretory granule lumen (GO:0034774), glutamatergic synapse (GO:0098978), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
MAPK targets/ Nuclear events mediated by MAP kinases	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Signalling to RAS	1
Nuclear Events (kinase and transcription factor activation)	1
Mitochondrial biogenesis	1
Cellular Senescence	1
Signal amplification	1
Platelet homeostasis	1
Signaling by VEGF	1
MAP kinase activation	1
Regulation of mRNA stability by proteins that bind AU-rich elements	1
Developmental Biology	1
RHO GTPase Effectors	1
Innate Immune System	1
Regulation of TP53 Activity	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cartilage development	2
cell differentiation	2
protein kinase activity	2
MAPK cascade	2
intracellular membrane-bounded organelle	2
cytoplasm	2
DNA integrity checkpoint signaling	1
signal transduction in response to DNA damage	1
intracellular signaling cassette	1
anatomical structure morphogenesis	1
skeletal system morphogenesis	1
cell aggregation	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
ossification	1
animal organ development	1
response to nutrient levels	1
energy homeostasis	1
inflammatory response to antigenic stimulus	1
regulation of inflammatory response to antigenic stimulus	1
negative regulation of inflammatory response	1
negative regulation of immune response	1
hexose metabolic process	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
DNA-templated transcription	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to chemical	1
taxis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
enzyme-linked receptor protein signaling pathway	1
striated muscle tissue development	1

Protein interactions and networks

STRING

5952 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPK14	TAB1	Q15750	973
MAPK14	DUSP1	P28562	902
MAPK14	JUN	P05412	892
MAPK14	MAP2K3	P46734	864
MAPK14	NFKB1	P19838	855
MAPK14	DUSP10	Q9Y6W6	850
MAPK14	IL6	P05231	842
MAPK14	TNF	P01375	831
MAPK14	FOS	P01100	814
MAPK14	MYD88	P78397	792
MAPK14	KRAS	P01116	790
MAPK14	IL1B	P01584	780
MAPK14	IFNG	P01579	769
MAPK14	STAT1	P42224	769
MAPK14	RELA	Q04206	759

IntAct

213 interactions, top by confidence:

A	B	Type	Score
MAPK14	MAPKAPK2	psi-mi:“MI:0914”(association)	0.940
MAPK14	MAPKAPK2	psi-mi:“MI:0407”(direct interaction)	0.940
MAPKAPK2	MAPK14	psi-mi:“MI:0915”(physical association)	0.940
MAPKAPK2	MAPK14	psi-mi:“MI:2364”(proximity)	0.940
MAPK14	MAPKAPK3	psi-mi:“MI:0915”(physical association)	0.920
MAPK14	MAPKAPK3	psi-mi:“MI:2364”(proximity)	0.920
MAPK14	RPS6KA4	psi-mi:“MI:0914”(association)	0.870
MAPKAPK3	MAPK11	psi-mi:“MI:0914”(association)	0.870
MAPK14	RPS6KA4	psi-mi:“MI:0915”(physical association)	0.870
MED19	MED7	psi-mi:“MI:0914”(association)	0.840
DUSP4	MAPK1	psi-mi:“MI:0915”(physical association)	0.810
DUSP16	MAPK9	psi-mi:“MI:0914”(association)	0.800
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
MKNK2	MAPK14	psi-mi:“MI:2364”(proximity)	0.790
DUSP9	MAPK14	psi-mi:“MI:0915”(physical association)	0.780
MAPK14	DUSP9	psi-mi:“MI:0915”(physical association)	0.780
DUSP1	MAPK14	psi-mi:“MI:0915”(physical association)	0.770
DUSP1	MAPK14	psi-mi:“MI:2364”(proximity)	0.770
DUSP1	MAPK14	psi-mi:“MI:0203”(dephosphorylation reaction)	0.770
MAPK14	SUPT20H	psi-mi:“MI:0915”(physical association)	0.760
MAPKAPK2	MAPK11	psi-mi:“MI:0914”(association)	0.730

BioGRID (685): MAPKAPK2 (Biochemical Activity), MAPK14 (Affinity Capture-Western), ATF2 (Biochemical Activity), MAPK14 (Affinity Capture-Western), MAPK14 (Affinity Capture-Western), SUPT20H (Affinity Capture-Western), MAPK14 (Affinity Capture-Western), MAPKAPK2 (Affinity Capture-MS), MAPKAPK3 (Affinity Capture-MS), RPS6KA4 (Affinity Capture-MS), MAPK14 (Affinity Capture-Western), JUN (Biochemical Activity), SLX4IP (Affinity Capture-MS), CUL7 (Affinity Capture-MS), HOXB9 (Affinity Capture-MS)

ESM2 similar proteins: A0A194WDG1, A1CAF0, A1DES4, A2QN07, B0Y462, B0Y4X4, G4N374, O02812, O08911, O13352, O15264, O42376, O44408, O59854, O61443, O62618, P14681, P39745, P47811, P50750, P53778, P70618, Q00772, Q06060, Q0CIC7, Q16539, Q17446, Q1L5Z8, Q39026, Q3T0N5, Q40532, Q4WQR3, Q4WUN7, Q5J4W4, Q63538, Q750A9, Q84UI5, Q8MXI4, Q92398, Q95NE7

Diamond homologs: A0A194WDG1, A0A1S3Z5Y0, A1CPG7, A1D2C9, A2QRF6, A2XFC8, A5PKJ4, A9S9Q8, A9T142, B0XR80, B0Y4X4, B0Y8W7, C4YGK0, G4N0Z0, G4N374, O13352, O23236, O42781, O61443, O94737, P0C865, P0CP66, P0CP67, P0CP68, P0CP69, P14681, P16892, P21708, P26696, P27361, P27638, P28482, P36005, P39745, P40417, P42525, P43068, P46196, P47811, P47812

SIGNOR signaling

200 interactions.

A	Effect	B	Mechanism
AKT2	“down-regulates activity”	MAPK14
TRIM27	up-regulates	MAPK14
MAPK14	up-regulates	TP53	phosphorylation
DUSP16	down-regulates	MAPK14	dephosphorylation
MAPK14	up-regulates	SLC9A1	phosphorylation
“SB 203580”	down-regulates	MAPK14	“chemical inhibition”
PTPRR	down-regulates	MAPK14	dephosphorylation
MAPK14	up-regulates	PPARGC1A	phosphorylation
MAPK14	down-regulates	EIF4EBP1
FGF2	up-regulates	MAPK14
MAPK14	up-regulates	KRT8	phosphorylation
MAPK1	down-regulates	MAPK14
TAB1	“up-regulates activity”	MAPK14	binding
VX-745	down-regulates	MAPK14	“chemical inhibition”
MAPK14	“up-regulates activity”	MAPKAPK2	phosphorylation
STK39	up-regulates	MAPK14	binding
MAPK14	“down-regulates activity”	TAB1	phosphorylation
MAPK14	up-regulates	HBP1	phosphorylation
MAPK14	down-regulates	CASP3	phosphorylation
MAPK14	down-regulates	CASP8	phosphorylation
MAPK14	unknown	PXN	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 157 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
RAF-independent MAPK1/3 activation	7	40.0×	7e-09
MAPK targets/ Nuclear events mediated by MAP kinases	8	39.2×	5e-10
MAP kinase activation	12	33.4×	5e-13
activated TAK1 mediates p38 MAPK activation	7	31.3×	5e-08
ERK/MAPK targets	5	30.3×	1e-05
Nuclear Events (kinase and transcription factor activation)	9	28.1×	7e-10
Interleukin-17 signaling	12	27.4×	1e-12
Signalling to ERKs	5	27.1×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
p38MAPK cascade	6	37.2×	3e-06
stress-activated MAPK cascade	6	29.5×	9e-06
cellular senescence	7	14.5×	1e-04
regulation of signal transduction by p53 class mediator	5	13.4×	4e-03
ERK1 and ERK2 cascade	6	13.3×	9e-04
MAPK cascade	11	11.8×	2e-06
negative regulation of ERK1 and ERK2 cascade	6	9.1×	5e-03
protein phosphorylation	18	8.6×	5e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	24
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2315 predictions. Top by Δscore:

Variant	Effect	Δscore
6:36027841:G:GT	donor_gain	1.0000
6:36028269:GTGTG:G	donor_gain	1.0000
6:36052695:TTAGT:T	acceptor_loss	1.0000
6:36052696:TAGTG:T	acceptor_loss	1.0000
6:36052697:A:AG	acceptor_gain	1.0000
6:36052697:A:T	acceptor_loss	1.0000
6:36052697:AGT:A	acceptor_gain	1.0000
6:36052698:G:GG	acceptor_gain	1.0000
6:36052698:GT:G	acceptor_gain	1.0000
6:36052698:GTG:G	acceptor_gain	1.0000
6:36052698:GTGC:G	acceptor_gain	1.0000
6:36052698:GTGCT:G	acceptor_gain	1.0000
6:36052829:G:GG	donor_gain	1.0000
6:36059283:TTACA:T	acceptor_loss	1.0000
6:36059284:TACA:T	acceptor_loss	1.0000
6:36059285:ACAGG:A	acceptor_loss	1.0000
6:36059286:CAGGT:C	acceptor_loss	1.0000
6:36059287:A:AG	acceptor_gain	1.0000
6:36059288:G:C	acceptor_loss	1.0000
6:36059288:G:GG	acceptor_gain	1.0000
6:36059288:GGT:G	acceptor_gain	1.0000
6:36059343:GATGT:G	donor_gain	1.0000
6:36059344:ATGT:A	donor_gain	1.0000
6:36059346:GT:G	donor_gain	1.0000
6:36059348:G:GG	donor_gain	1.0000
6:36059349:TGAG:T	donor_loss	1.0000
6:36059350:GAGT:G	donor_loss	1.0000
6:36059351:AGTA:A	donor_loss	1.0000
6:36072978:TCTAA:T	donor_gain	1.0000
6:36072981:AAAG:A	donor_loss	1.0000

AlphaMissense

2380 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:36028209:T:A	W18R	1.000
6:36028209:T:C	W18R	1.000
6:36028254:G:C	G33R	1.000
6:36028255:G:A	G33D	1.000
6:36028263:G:C	G36R	1.000
6:36028264:G:A	G36D	1.000
6:36028264:G:T	G36V	1.000
6:36052734:C:A	A51E	1.000
6:36052739:A:G	K53E	1.000
6:36052741:G:C	K53N	1.000
6:36052741:G:T	K53N	1.000
6:36052791:G:C	R70T	1.000
6:36052791:G:T	R70I	1.000
6:36052792:A:C	R70S	1.000
6:36052792:A:T	R70S	1.000
6:36052806:T:C	L75P	1.000
6:36072980:T:C	L138P	1.000
6:36073719:G:C	R149T	1.000
6:36073719:G:T	R149M	1.000
6:36073720:G:C	R149S	1.000
6:36073720:G:T	R149S	1.000
6:36074049:G:C	D150H	1.000
6:36074050:A:C	D150A	1.000
6:36074050:A:G	D150G	1.000
6:36074050:A:T	D150V	1.000
6:36074051:C:A	D150E	1.000
6:36074051:C:G	D150E	1.000
6:36074053:T:C	L151P	1.000
6:36074066:T:A	N155K	1.000
6:36074066:T:G	N155K	1.000

dbSNP variants (sampled 300 via entrez): RS1000039628 (6:36080217 G>A), RS1000066509 (6:36121615 C>G), RS1000069643 (6:36041260 A>G), RS1000081547 (6:36033531 A>C,G), RS1000098838 (6:36093504 G>A), RS1000211771 (6:36029232 G>A,T), RS1000227135 (6:36115228 A>G), RS1000246885 (6:36062399 G>A,C), RS1000315292 (6:36115385 C>T), RS1000370357 (6:36119134 C>T), RS1000405435 (6:36100515 G>A), RS1000407711 (6:36069317 C>G), RS1000438918 (6:36066963 A>G), RS1000445826 (6:36112057 T>C), RS1000473084 (6:36086751 C>A)

Disease associations

OMIM: gene MIM:600289 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004724_1	Foot ulcer in diabetes and neuropathy	9.000000e-08
GCST004724_2	Foot ulcer in diabetes and neuropathy	3.000000e-08
GCST90013466_74	Height	4.000000e-09
GCST90013467_16	Height	9.000000e-08
GCST90020029_1555	Waist circumference adjusted for body mass index	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:1001459	diabetic foot
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (7): CHEMBL2094115 (PROTEIN FAMILY), CHEMBL260 (SINGLE PROTEIN), CHEMBL4106180 (PROTEIN FAMILY), CHEMBL5465522 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066552 (PROTEIN FAMILY), CHEMBL6066553 (PROTEIN FAMILY), CHEMBL6177902 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

76 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 900,664 (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
CHEMBL267495	NALFURAFINE	4	310
CHEMBL5416410	DASATINIB	4	655
CHEMBL941	IMATINIB	4	111,611
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL118	CELECOXIB	4	112,844
CHEMBL1276308	MIFEPRISTONE	4	30,535
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL24944	TRIBROMSALAN	4	2,453
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL290106	BITHIONOL	4	6,439
CHEMBL291338	3,3’,4’,5-TETRACHLOROSALICYLANILIDE	4	721
CHEMBL3301612	ENCORAFENIB	4	4,624
CHEMBL3348923	TOVORAFENIB	4	834
CHEMBL388590	BENZBROMARONE	4	8,245
CHEMBL411	DIETHYLSTILBESTROL	4	353,912
CHEMBL416146	ETORICOXIB	4
CHEMBL496	HEXACHLOROPHENE	4
CHEMBL506247	TANNIC ACID	4
CHEMBL547	ISOTRETINOIN	4
CHEMBL576982	QUIZARTINIB	4
CHEMBL584	NELFINAVIR	4
CHEMBL603	ZAFIRLUKAST	4
CHEMBL787	MONTELUKAST	4
CHEMBL939	GEFITINIB	4
CHEMBL1088750	ARRY-797	3

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3804454	MAPK14		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — p38 subfamily

Most potent curated ligand interactions (30 total), top 25:

Ligand	Action	Affinity	Parameter
PF-03715455	Binding	12.0	pKd
AZD7624	Inhibition	10.0	pIC50
compound 4e [PMID: 35546685]	Inhibition	10.0	pIC50
compound 12 [PMID: 22521646]	Inhibition	9.19	pIC50
pamapimod	Inhibition	8.89	pKd
PH-797804	Inhibition	8.54	pKi
VX-702	Inhibition	8.43	pKd
ARRY-371797	Inhibition	8.35	pIC50
ralimetinib	Inhibition	8.15	pIC50
TAK-715	Inhibition	8.15	pIC50
losmapimod	Inhibition	8.1	pKi
talmapimod	Inhibition	8.05	pIC50
SB203580	Inhibition	8.0	pKi
neflamapimod	Inhibition	8.0	pIC50
BMS-582949	Inhibition	7.89	pIC50
AZD6703	Inhibition	7.81	pIC50
SB220025	Inhibition	7.72	pIC50
doramapimod	Inhibition	7.7	pIC50
SB202190	Inhibition	7.52	pIC50
pexmetinib	Inhibition	7.46	pIC50
7-hydroxystaurosporine	Inhibition	7.02	pIC50
MW150	Inhibition	7.0	pKi
NDPPC	Inhibition	7.0	pIC50
SKF-86002	Inhibition	6.96	pIC50
PF-670462	Inhibition	6.72	pIC50

Binding affinities (BindingDB)

875 measured of 1068 human assays (1074 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
3-(3,3-dimethyl-2-oxo-1H-indol-6-yl)-4-methyl-N-(1,2-oxazol-3-yl)benzamide	IC50	0.04 nM	US-8772288: Substituted spiro[cycloalkyl-1,3′-indo]-2′(1′H)-one derivatives and their use as P38 mitogen-activated kinase inhibitors
3-({5-cyano-6-[(2,2-dimethylpropyl)(methyl)amino]-2-(methylamino)pyrimidin-4-yl}amino)-N-methoxy-4-methylbenzamide	KI	0.047 nM
3-({2-amino-5-cyano-6-[(2,2-dimethylpropyl)(methyl)amino]pyrimidin-4-yl}amino)-N-methoxy-4-methylbenzamide	KI	0.05 nM
3-({5-cyano-6-[(2,2-dimethylpropyl)(methyl)amino]-2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl}amino)-N-methoxy-4-methylbenzamide	KI	0.057 nM
3-{[2-amino-5-cyano-6-(propan-2-ylamino)pyrimidin-4-yl]amino}-4-methyl-N-(1,2-oxazol-3-yl)benzamide	KI	0.057 nM
4-methyl-N-(1,2-oxazol-3-yl)-3-(2-oxospiro[1H-indole-3,4’-oxane]-6-yl)benzamide	IC50	0.06 nM	US-8772288: Substituted spiro[cycloalkyl-1,3′-indo]-2′(1′H)-one derivatives and their use as P38 mitogen-activated kinase inhibitors
BIRB-796 Analog 33	KD	0.09 nM
3-({5-cyano-6-[(2,2-dimethylpropyl)(methyl)amino]pyrimidin-4-yl}amino)-N-methoxy-4-methylbenzamide	KI	0.15 nM
3-{[2-amino-5-cyano-6-(cyclopentylamino)pyrimidin-4-yl]amino}-N-isoxazol-3-yl-4-methylbenzamide	KI	0.16 nM
2-(2,4-difluorophenoxy)-5-(2-methylphenyl)pyrido[2,3-d]pyridazine	IC50	0.2 nM	US-8772481: Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
4-methyl-N-(1,2-oxazol-3-yl)-3-(2-oxospiro[1H-indole-3,1’-cyclopentane]-6-yl)benzamide	IC50	0.2 nM	US-8772288: Substituted spiro[cycloalkyl-1,3′-indo]-2′(1′H)-one derivatives and their use as P38 mitogen-activated kinase inhibitors
N,5-bis(2,4-difluorophenyl)pyrido[2,3-d]pyridazin-2-amine	IC50	0.3 nM	US-8772481: Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
3-[2-(2,4-difluorophenoxy)pyrido[2,3-d]pyridazin-5-yl]-4-methylbenzamide	IC50	0.3 nM	US-8772481: Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
4-(4-fluorophenyl)-5-[3-(2-methoxyphenyl)-[1,2,4]triazolo[3,4-a]pyridin-6-yl]-1,3-oxazole	IC50	0.4 nM
5-[3-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-a]pyridin-6-yl]-4-(4-fluorophenyl)-1,3-oxazole	IC50	0.4 nM
CHEMBL142697	IC50	0.4 nM
3-({5-cyano-6-[(1-methylethyl)amino]pyrimidin-4-yl}amino)-N-isoxazol-3-yl-4-methylbenzamide	KI	0.41 nM
3-{[5-cyano-6-(cyclopentylamino)pyrimidin-4-yl]amino}-N-methoxy-4-methylbenzamide	KI	0.42 nM
N-(2,4-difluorophenyl)-5-(2-methylphenyl)pyrido[2,3-d]pyridazin-2-amine	IC50	0.5 nM	US-8772481: Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
N-(2,4-difluorophenyl)-5-(2-methyl-4-methylsulfonylphenyl)pyrido[2,3-d]pyridazin-2-amine	IC50	0.5 nM	US-8772481: Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
BIRB-796 Analog 30	KD	0.5 nM
5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-(8-isopropyl-8-aza-bicyclo[3.2.1]octan-3-yl)quinolin-2(1H)-one	IC50	0.51 nM
3-({5-cyano-6-[(1-methylethyl)amino]pyrimidin-4-yl}amino)-N-methoxy-4-methylbenzamide	KI	0.61 nM
2-(2,4-difluorophenoxy)-5-(2-methyl-4-methylsulfonylphenyl)pyrido[2,3-d]pyridazine	IC50	0.7 nM	US-8772481: Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
4-(2,4-difluorophenyl)-5-[3-(1-methylcyclopropyl)-[1,2,4]triazolo[3,4-a]pyridin-6-yl]-1,3-oxazole	IC50	0.7 nM
N-cyclopropyl-3-(1’-hydroxy-1’-methyl-2-oxospiro[1H-indole-3,4’-cyclohexane]-6-yl)-4-methylbenzamide	IC50	0.8 nM	US-8772288: Substituted spiro[cycloalkyl-1,3′-indo]-2′(1′H)-one derivatives and their use as P38 mitogen-activated kinase inhibitors
N-cyclopropyl-4-methyl-3-(2-oxospiro[1H-pyrrolo[3,2-c]pyridine-3,1’-cyclopentane]-6-yl)benzamide	IC50	0.8 nM	US-8772288: Substituted spiro[cycloalkyl-1,3′-indo]-2′(1′H)-one derivatives and their use as P38 mitogen-activated kinase inhibitors
N-(4-fluorophenyl)-5-(2-methyl-4-methylsulfonylphenyl)pyrido[2,3-d]pyridazin-2-amine	IC50	0.9 nM	US-8772481: Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
2-(4-fluorophenoxy)-5-(2-methylphenyl)pyrido[2,3-d]pyridazine	IC50	0.9 nM	US-8772481: Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
6-[4-(4-Fluoro-phenyl)-oxazol-5-yl]-1-isopropyl-1H-benzotriazole	IC50	0.9 nM
3-{[5-cyano-6-(propylamino)pyrimidin-4-yl]amino}-N-methoxy-4-methylbenzamide	KI	0.97 nM
N-cyclopropyl-4-methyl-3-(4’-morpholin-4-yl-2-oxospiro[1H-indole-3,1’-cyclohexane]-6-yl)benzamide	IC50	1 nM	US-8772288: Substituted spiro[cycloalkyl-1,3′-indo]-2′(1′H)-one derivatives and their use as P38 mitogen-activated kinase inhibitors
BIRB-796 Analog 4	KD	1 nM
3-(2-aminoquinazolin-6-yl)-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide	IC50	1 nM
(2S)-1-({4-[3-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}amino)propan-2-ol	IC50	1 nM
(2R)-1-({4-[3-(4-fluorophenyl)-1H-pyrrolo[3,2-b]pyridin-2-yl]pyridin-2-yl}amino)propan-2-ol	IC50	1 nM
tert-butyl (2S)-2-[2-[4-[2-amino-3-(2,4-difluorobenzoyl)-6-oxo-1-pyridinyl]-3,5-difluorophenyl]ethylamino]propanoate	IC50	1 nM	US-9388136: Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof
cyclopentyl (2S)-4-amino-2-[3-[4-[2-amino-3-(2,4-difluorobenzoyl)-6-oxo-1-pyridinyl]-3,5-difluorophenoxy]propylamino]butanoate	IC50	1 nM	US-9388136: Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof
tert-butyl (2S)-2-[2-[4-[2-amino-3-(2,4-difluorobenzoyl)-6-oxo-1-pyridinyl]-3,5-difluorophenyl]ethylamino]-4-methylpentanoate	IC50	1 nM	US-9388136: Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof
cyclopentyl (2S)-2-[2-[4-[2-amino-3-(2,4-difluorobenzoyl)-6-oxo-1-pyridinyl]-3,5-difluorophenyl]ethylamino]-4-methylpentanoate	IC50	1 nM	US-9388136: Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof
cyclopentyl (2S)-2-[2-[4-[2-amino-3-(4-fluorobenzoyl)-6-oxo-1-pyridinyl]-3,5-difluorophenyl]ethylamino]-4-methylpentanoate	IC50	1 nM	US-9388136: Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof
cyclopentyl (2S)-2-[2-[4-[2-amino-3-(2,4-difluorobenzoyl)-6-oxo-1-pyridinyl]-3,5-difluorophenyl]ethylamino]-2-phenylacetate	IC50	1 nM	US-9388136: Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof
tert-butyl (2S)-2-[2-[4-[2-amino-3-(2,4-difluorobenzoyl)-6-oxo-1-pyridinyl]-3,5-difluorophenyl]ethylamino]-2-phenylacetate	IC50	1 nM	US-9388136: Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof
cyclopentyl (2S)-2-[2-[4-[2-amino-3-(2,4-difluorobenzoyl)-6-oxo-1-pyridinyl]-3,5-difluorophenyl]ethylamino]-3-[(2-methylpropan-2-yl)oxy]propanoate	IC50	1 nM	US-9388136: Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof
tert-butyl (2S)-2-[2-[4-[2-amino-3-(2,4-difluorobenzoyl)-6-oxo-1-pyridinyl]-3,5-difluorophenyl]ethylamino]-3-[(2-methylpropan-2-yl)oxy]propanoate	IC50	1 nM	US-9388136: Tert-butyl N-[2-{4-[6-amino-5-(2,4-difluorobenzoyl)-2-oxopyridin-1(2H)-yl]-3,5-difluorophenyl}ethyl]-L-alaninate or a salt, hydrate or solvate thereof
N-cyclopropyl-3-fluoro-4-methyl-5-(1’-methylsulfonyl-2-oxospiro[1H-indole-3,4’-piperidine]-6-yl)benzamide	IC50	1 nM	US-8772288: Substituted spiro[cycloalkyl-1,3′-indo]-2′(1′H)-one derivatives and their use as P38 mitogen-activated kinase inhibitors
N-(2,4-difluorophenyl)-5-(5-methyl-1H-pyrazol-4-yl)pyrido[2,3-d]pyridazin-2-amine	IC50	1.1 nM	US-8772481: Aza- and diaza-phthalazine compounds as P38 map kinase modulators and methods of use thereof
4-(2,4-difluorophenyl)-5-[3-(1-methylcyclobutyl)-[1,2,4]triazolo[3,4-a]pyridin-6-yl]-1,3-oxazole	IC50	1.1 nM
5-{3-tert-butyl-[1,2,4]triazolo[3,4-a]pyridin-6-yl}-4-(2,4-difluorophenyl)-1,3-oxazole	IC50	1.1 nM

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.52	IC50	0.03	nM	CHEMBL5186216
10.40	IC50	0.04	nM	CHEMBL3640006
10.34	Kd	0.046	nM	DORAMAPIMOD
10.33	Ki	0.047	nM	CHEMBL194813
10.30	Ki	0.05	nM	CHEMBL363643
10.30	IC50	0.05	nM	CHEMBL5172781
10.30	IC50	0.05	nM	CHEMBL5174953
10.30	Kd	0.05	nM	CHEMBL1088796
10.24	Ki	0.057	nM	CHEMBL196741
10.24	Ki	0.057	nM	CHEMBL197206
10.22	IC50	0.06	nM	CHEMBL1825148
10.22	IC50	0.06	nM	CHEMBL5180443
10.22	IC50	0.06	nM	CHEMBL1911339
10.10	IC50	0.08	nM	CHEMBL199679
10.10	IC50	0.08	nM	CHEMBL5206397
10.10	IC50	0.08	nM	CHEMBL1825149
10.05	Kd	0.09	nM	CHEMBL318810
10.05	IC50	0.09	nM	CHEMBL1825148
10.01	Kd	0.098	nM	DORAMAPIMOD
10.01	Kd	0.097	nM	CHEMBL318810
10.01	Ki	0.097	nM	DORAMAPIMOD
10.01	Kd	0.097	nM	DORAMAPIMOD
10.00	Kd	0.1	nM	DORAMAPIMOD
10.00	IC50	0.1	nM	CHEMBL328614
10.00	IC50	0.1	nM	CHEMBL97227
10.00	IC50	0.1	nM	CHEMBL327959
10.00	IC50	0.1	nM	CHEMBL199680
10.00	IC50	0.1	nM	CHEMBL4060815
10.00	IC50	0.1	nM	DORAMAPIMOD
10.00	Kd	0.1	nM	CHEMBL318810
10.00	IC50	0.1	nM	CHEMBL303144
10.00	IC50	0.1	nM	CHEMBL5173417
10.00	IC50	0.1	nM	CHEMBL5200224
10.00	IC50	0.1	nM	CHEMBL5202475
9.98	Kd	0.104	nM	CHEMBL143134
9.96	IC50	0.11	nM	CHEMBL305178
9.92	IC50	0.12	nM	CHEMBL270004
9.91	Kd	0.123	nM	DORAMAPIMOD
9.90	Ki	0.1259	nM	CHEMBL1991678
9.89	IC50	0.13	nM	CHEMBL327746
9.89	IC50	0.13	nM	CHEMBL1916528
9.85	IC50	0.14	nM	CHEMBL199679
9.82	Ki	0.15	nM	CHEMBL195532
9.82	IC50	0.15	nM	CHEMBL545353
9.80	Ki	0.16	nM	CHEMBL197351
9.80	IC50	0.16	nM	CHEMBL269792
9.80	Kd	0.16	nM	DORAMAPIMOD
9.80	IC50	0.16	nM	CHEMBL1911338
9.74	Kd	0.18	nM	CHEMBL1092013
9.72	IC50	0.19	nM	CHEMBL303144

PubChem BioAssay actives

3447 with measured affinity, of 6100 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
1-[3-tert-butyl-1-(3-chloro-4-hydroxyphenyl)pyrazol-5-yl]-3-[[2-[[3-[2-(2-hydroxyethylsulfanyl)phenyl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]sulfanyl]phenyl]methyl]urea	639694: Binding affinity to human p38alpha MAPK by surface plasmon resonance method	kd	<0.0001	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	127252: Dissociation constant at Tref against human Mitogen-activated protein kinase p38 alpha	kd	<0.0001	uM
3-[[5-cyano-6-[2,2-dimethylpropyl(methyl)amino]-2-(4-methyl-1,4-diazepan-1-yl)pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	1797497: Enzyme Inhibition Assay from Article 10.1021/jm0503594: “5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.”	ki	0.0001	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-pyridin-4-ylethoxy)naphthalen-1-yl]urea	127252: Dissociation constant at Tref against human Mitogen-activated protein kinase p38 alpha	kd	0.0001	uM
3-[[5-cyano-6-[2,2-dimethylpropyl(methyl)amino]pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	1797497: Enzyme Inhibition Assay from Article 10.1021/jm0503594: “5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.”	ki	0.0001	uM
3-[[2-amino-5-cyano-6-[2,2-dimethylpropyl(methyl)amino]pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	1797497: Enzyme Inhibition Assay from Article 10.1021/jm0503594: “5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.”	ki	0.0001	uM
7-(1-tert-butylpiperidin-4-yl)-1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)quinolin-2-one	258380: Inhibition of P38 alpha MAPK	ic50	0.0001	uM
3-[[2-amino-5-cyano-6-(propan-2-ylamino)pyrimidin-4-yl]amino]-4-methyl-N-(1,2-oxazol-3-yl)benzamide	1797497: Enzyme Inhibition Assay from Article 10.1021/jm0503594: “5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.”	ki	0.0001	uM
N-cyclopropyl-3-[1-(2-fluorophenyl)phthalazin-6-yl]-4-methylbenzamide	476149: Binding affinity to p38alpha by scintillation proximity assay	kd	0.0001	uM
13-[2,4-difluoro-5-[(3-fluorobenzoyl)amino]anilino]-N-methyl-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0001	uM
5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-7-piperidin-4-yl-3,4-dihydroquinazolin-2-one	127254: Inhibitory activity against mitogen-activated protein kinase p38 alpha	ic50	0.0001	uM
7-(1-tert-butylpiperidin-4-yl)-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)quinolin-2-one	258380: Inhibition of P38 alpha MAPK	ic50	0.0001	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-piperidin-4-yloxy-3,4-dihydroquinazolin-2-one	127254: Inhibitory activity against mitogen-activated protein kinase p38 alpha	ic50	0.0002	uM
6-(2,4-difluorophenoxy)-8-methyl-2-(oxan-4-ylamino)pyrido[2,3-d]pyrimidin-7-one	592305: Inhibition of p38alpha	kd	0.0002	uM
3-[[2-amino-5-cyano-6-(cyclopentylamino)pyrimidin-4-yl]amino]-4-methyl-N-(1,2-oxazol-3-yl)benzamide	1797497: Enzyme Inhibition Assay from Article 10.1021/jm0503594: “5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.”	ki	0.0002	uM
13-[2,4-difluoro-5-[(3-methoxybenzoyl)amino]anilino]-N-methyl-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0002	uM
13-(5-benzamido-2,4-difluoroanilino)-N-(2,3-dihydroxypropyl)-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0002	uM
13-[5-[(4-chlorobenzoyl)amino]-2,4-difluoroanilino]-N-methyl-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0002	uM
13-[2,4-difluoro-5-[[4-(trifluoromethyl)benzoyl]amino]anilino]-N-methyl-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0002	uM
4-methyl-N-(1,2-oxazol-3-yl)-3-[(1-phenylpyrazolo[3,4-d]pyrimidin-4-yl)amino]benzamide	327699: Inhibition of human recombinant p38alpha-mediated myelin basic protein phosphorylation	ki	0.0002	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(piperidin-4-ylamino)-1,6-naphthyridin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0002	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(1-propan-2-ylpiperidin-4-yl)quinolin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0002	uM
1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-7-piperidin-4-yl-3,4-dihydroquinazolin-2-one	127254: Inhibitory activity against mitogen-activated protein kinase p38 alpha	ic50	0.0002	uM
1-(2,6-dichlorophenyl)-5-(2,4-difluorophenyl)-7-(1-propan-2-ylpiperidin-4-yl)-3,4-dihydroquinazolin-2-one	268899: Inhibition of p38alpha	ic50	0.0002	uM
N-[5-(cyclopropylcarbamoyl)-2-methylphenyl]-5-[4-(morpholine-4-carbonyl)phenyl]thiophene-2-carboxamide	758213: Inhibition of human p38alpha expressed in Escherichia coli using MBP as substrate preincubated for 10 mins prior to substrate addition measured after 45 mins by microbeta scintillation counting analysis	ic50	0.0002	uM
13-(3-benzamido-4-fluoroanilino)-N-(2-hydroxyethyl)-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0003	uM
13-(5-benzamido-4-fluoro-2-methylanilino)-N-[(2R)-2,3-dihydroxypropyl]-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451482: Inhibition of P38 alpha MAPK in human whole blood assessed as reduction in TNF-alpha release after 10 mins by ELISA	ic50	0.0003	uM
13-(3-benzamido-4-fluoroanilino)-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0003	uM
13-[5-[(3-chlorobenzoyl)amino]-2,4-difluoroanilino]-N-methyl-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0003	uM
1-[3-tert-butyl-1-[3-[(4-methylpiperazin-1-yl)methyl]phenyl]pyrazol-5-yl]-3-[(1S,4R)-4-[[3-[(2S)-2-methylcyclohexyl]-[1,2,4]triazolo[4,3-a]pyridin-6-yl]oxy]-1,2,3,4-tetrahydronaphthalen-1-yl]urea	1910477: Inhibition of human recombinant full length GST-tagged p38alpha expressed in Escherichia coli preincubated for 2 hrs followed by ATP addition and measured after 1 hr by Alpha screen assay	ic50	0.0003	uM
7-(1-tert-butylpiperidin-4-yl)-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)quinolin-2-one	258380: Inhibition of P38 alpha MAPK	ic50	0.0003	uM
7-(1-tert-butylpiperidin-4-yl)-5-(2-chloro-4-fluorophenyl)-1-(2,6-difluorophenyl)quinolin-2-one	258380: Inhibition of P38 alpha MAPK	ic50	0.0003	uM
6-(2-chlorophenyl)-8-methyl-2-(oxan-4-ylamino)pyrido[2,3-d]pyrimidin-7-one	592305: Inhibition of p38alpha	kd	0.0003	uM
4-(2-chlorophenyl)-8-(2,6-difluorophenyl)-7-oxido-2-piperidin-4-yl-1,7-naphthyridin-7-ium	630192: Inhibition of human p38alpha MAP kinase after 1 hr by FRET analysis	ic50	0.0003	uM
4-(2,4-difluorophenyl)-8-(2,6-difluorophenyl)-7-oxido-N-piperidin-4-yl-1,7-naphthyridin-7-ium-2-amine	630192: Inhibition of human p38alpha MAP kinase after 1 hr by FRET analysis	ic50	0.0003	uM
N-cyclopropyl-3-[1-(2,6-difluorophenyl)-7-methyl-6-oxopyrazolo[5,4-b]pyridin-5-yl]-4-methylbenzamide	476149: Binding affinity to p38alpha by scintillation proximity assay	kd	0.0003	uM
N-cyclopropyl-3-[1-(2,4-difluorophenyl)-7-methyl-6-oxopyrazolo[5,4-b]pyridin-5-yl]-4-methylbenzamide	1540359: Binding affinity to P38alpha MAPK (unknown origin) assessed as dissociation constant	kd	0.0003	uM
N-cyclopropyl-4-methyl-3-[3-[2-[2-[2-(methylamino)ethoxy]phenyl]propan-2-ylamino]-2-oxopyrazin-1-yl]benzamide	1721543: Inhibition of p38alpha MAPK (unknown origin)	ic50	0.0003	uM
6-(4-fluorophenyl)-7-[2-[[(1S)-1-phenylethyl]amino]pyrimidin-4-yl]-2,3-dihydro-1H-pyrazolo[1,2-a]pyrazol-5-one	215246: Inhibition of LPS-stimulated p38-related TNF-alpha production in human peripheral blood mononuclear cells (PBMC)	ic50	0.0004	uM
N-benzyl-4-[5-(methoxycarbamoyl)-2-methylanilino]-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide	312134: Inhibition of p38alpha	ic50	0.0004	uM
N-[(1R)-1-phenylethyl]-4-[2-piperidin-4-yl-4-[3-(trifluoromethyl)phenyl]-1H-imidazol-5-yl]pyrimidin-2-amine	92862: Inhibition of LPS-induced release of Tumor necrosis factor-alpha (TNF-alpha) from human whole blood	ic50	0.0004	uM
3-[[5-cyano-6-(cyclopentylamino)pyrimidin-4-yl]amino]-N-methoxy-4-methylbenzamide	1797497: Enzyme Inhibition Assay from Article 10.1021/jm0503594: “5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.”	ki	0.0004	uM
3-[[5-cyano-6-(propan-2-ylamino)pyrimidin-4-yl]amino]-4-methyl-N-(1,2-oxazol-3-yl)benzamide	1797497: Enzyme Inhibition Assay from Article 10.1021/jm0503594: “5-Cyanopyrimidine derivatives as a novel class of potent, selective, and orally active inhibitors of p38alpha MAP kinase.”	ki	0.0004	uM
methyl 3-[4-fluoro-2-methyl-5-(thiophene-3-carbonylamino)anilino]-11-oxo-6H-benzo[c][1]benzoxepine-9-carboxylate	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0004	uM
13-[2,4-difluoro-5-[(4-fluorobenzoyl)amino]anilino]-N-methyl-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0004	uM
13-(5-benzamido-2,4-difluoroanilino)-N-(2-morpholin-4-ylethyl)-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0004	uM
N-[5-[(14-carbamoyl-2-oxo-6-tricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaenyl)amino]-2,4-difluorophenyl]thiophene-2-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0004	uM
13-[2,4-difluoro-5-[(4-methoxybenzoyl)amino]anilino]-N-methyl-2-oxotricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene-5-carboxamide	1451480: Inhibition of P38 alpha MAPK (unknown origin) by ELISA	ic50	0.0004	uM
5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-[(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino]-3,4-dihydroquinazolin-2-one	127092: Inhibition of p38 MAP kinase	ic50	0.0004	uM
7-(1-tert-butylpiperidin-4-yl)-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2-one	258380: Inhibition of P38 alpha MAPK	ic50	0.0004	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
SB 203580	decreases reaction, increases phosphorylation, increases expression, decreases expression, increases activity (+2 more)	22
Cadmium Chloride	increases activity, increases reaction, increases degradation, increases ubiquitination, decreases reaction (+4 more)	15
Arsenic Trioxide	affects localization, decreases response to substance, affects cotreatment, decreases reaction, increases phosphorylation (+2 more)	10
Acetylcysteine	affects cotreatment, decreases reaction, increases activity, increases phosphorylation, increases reaction	9
Lipopolysaccharides	decreases reaction, increases phosphorylation, increases reaction, decreases activity	7
Doxorubicin	affects activity, affects expression, decreases expression, increases reaction, decreases phosphorylation (+3 more)	6
Rotenone	decreases reaction, increases phosphorylation, decreases expression, increases activity	5
Tetradecanoylphorbol Acetate	decreases reaction, increases activity, increases phosphorylation, increases reaction	5
Acrolein	increases phosphorylation, decreases reaction	4
Cadmium	increases abundance, increases expression, decreases expression, increases phosphorylation, decreases reaction	4
Cannabidiol	decreases phosphorylation, decreases expression	4
Estradiol	decreases reaction, increases activity, affects cotreatment, increases expression	4
Hydrogen Peroxide	decreases reaction, increases activity, increases phosphorylation, increases expression, increases reaction (+1 more)	4
Tretinoin	decreases expression, increases activity, increases degradation, increases phosphorylation, increases expression	4
Asbestos, Crocidolite	decreases phosphorylation, decreases activity, increases activity, decreases reaction, increases reaction (+3 more)	4
deoxynivalenol	affects cotreatment, increases expression, increases activity, increases phosphorylation	3
arsenite	increases ubiquitination, affects binding, affects reaction, increases reaction, increases phosphorylation (+2 more)	3
sodium arsenite	increases activity, increases phosphorylation	3
epigallocatechin gallate	increases activity, increases expression, decreases expression, affects cotreatment	3
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	decreases activity, decreases reaction, increases phosphorylation	3
U 0126	decreases reaction, increases phosphorylation, decreases activity	3
Benzo(a)pyrene	affects expression, increases expression, increases phosphorylation	3
Curcumin	decreases reaction, increases expression, affects cotreatment, increases phosphorylation, affects reaction	3
Dexamethasone	decreases reaction, increases activity, increases phosphorylation, increases reaction	3
Glucose	affects cotreatment, decreases expression, increases secretion, decreases reaction, increases activity (+3 more)	3
tert-Butylhydroperoxide	decreases expression, increases expression, increases methylation	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
trichostatin A	decreases reaction, increases phosphorylation, affects expression	2
ochratoxin A	increases expression, affects binding, decreases reaction, increases reaction, decreases expression (+1 more)	2
dracorhodin	increases phosphorylation, decreases reaction	2

ChEMBL screening assays

2041 unique, capped per target: 1969 binding, 66 functional, 5 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004015	Binding	Inhibition of human p38 MAPK	Hepatitis C virus NS5A is a direct substrate of casein kinase I-alpha, a cellular kinase identified by inhibitor affinity chromatography using specific NS5A hyperphosphorylation inhibitors. — J Biol Chem
CHEMBL4181658	ADMET	Inhibition of P38 (unknown origin)	Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors. — Bioorg Med Chem Lett
CHEMBL697600	Functional	Inhibition of LPS-induced p38-related TNF alpha release from human monocytes	Pyrroles and other heterocycles as inhibitors of p38 kinase. — Bioorg Med Chem Lett

Cellosaurus cell lines

13 cell lines: 7 cancer cell line, 2 spontaneously immortalized cell line, 2 somatic stem cell, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_6754	RKOP	Spontaneously immortalized cell line	Female
CVCL_6755	EKOP	Spontaneously immortalized cell line	Female
CVCL_AS78	HLSC SH3	Somatic stem cell	Sex unspecified
CVCL_AS79	HLSC SH2	Somatic stem cell	Sex unspecified
CVCL_B3AP	Abcam HEK293T MAPK14 KO	Transformed cell line	Female
CVCL_B8K5	Abcam HCT 116 MAPK14 KO	Cancer cell line	Male
CVCL_B8YM	Abcam MCF-7 MAPK14 KO	Cancer cell line	Female
CVCL_B9MD	Abcam A-549 MAPK14 KO	Cancer cell line	Male
CVCL_D7UK	Ubigene A-549 MAPK14 KO	Cancer cell line	Male
CVCL_D9JP	Ubigene HEK293 MAPK14 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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