MAPK6

Summary

MAPK6 (mitogen-activated protein kinase 6, HGNC:6879) is a protein-coding gene on chromosome 15q21.2, encoding Mitogen-activated protein kinase 6 (Q16659). Atypical MAPK protein.

The protein encoded by this gene is a member of the Ser/Thr protein kinase family, and is most closely related to mitogen-activated protein kinases (MAP kinases). MAP kinases also known as extracellular signal-regulated kinases (ERKs), are activated through protein phosphorylation cascades and act as integration points for multiple biochemical signals. This kinase is localized in the nucleus, and has been reported to be activated in fibroblasts upon treatment with serum or phorbol esters.

Source: NCBI Gene 5597 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 84 total
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002748

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6879
Approved symbol	MAPK6
Name	mitogen-activated protein kinase 6
Location	15q21.2
Locus type	gene with protein product
Status	Approved
Aliases	ERK3, p97MAPK, HsT17250
Ensembl gene	ENSG00000069956
Ensembl biotype	protein_coding
OMIM	602904
Entrez	5597

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 7 protein_coding_CDS_not_defined

ENST00000261845, ENST00000558063, ENST00000558100, ENST00000558841, ENST00000558891, ENST00000560254, ENST00000560774, ENST00000560802, ENST00000680066, ENST00000680652, ENST00000680777, ENST00000681888, ENST00000691380, ENST00000895516, ENST00000955405, ENST00000955406

RefSeq mRNA: 1 — MANE Select: NM_002748 NM_002748

CCDS: CCDS10147

Canonical transcript exons

ENST00000261845 — 6 exons

Exon	Start	End
ENSE00000688875	52058633	52058797
ENSE00000688876	52061299	52061500
ENSE00000884734	52063902	52067375
ENSE00000931423	52049993	52050137
ENSE00000942191	52045830	52047015
ENSE00002542065	52019219	52019376

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.5916 / max 1045.3779, expressed in 1823 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146699	41.3818	1821
146703	3.7289	1272
146704	2.3696	664
146700	1.9456	555
146707	0.5187	241
207521	0.2108	60
146709	0.1649	56
146705	0.1072	43
146698	0.0823	37
146708	0.0818	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	98.32	gold quality
gingiva	UBERON:0001828	98.12	gold quality
gingival epithelium	UBERON:0001949	98.08	gold quality
ileal mucosa	UBERON:0000331	97.69	gold quality
hair follicle	UBERON:0002073	97.52	gold quality
middle temporal gyrus	UBERON:0002771	97.31	gold quality
cervix epithelium	UBERON:0004801	97.31	gold quality
pons	UBERON:0000988	97.22	gold quality
squamous epithelium	UBERON:0006914	97.19	gold quality
upper leg skin	UBERON:0004262	97.12	gold quality
body of tongue	UBERON:0011876	97.10	gold quality
pharyngeal mucosa	UBERON:0000355	96.99	gold quality
esophagus squamous epithelium	UBERON:0006920	96.97	gold quality
biceps brachii	UBERON:0001507	96.96	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.91	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.69	gold quality
mucosa of urinary bladder	UBERON:0001259	96.60	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.50	gold quality
jejunal mucosa	UBERON:0000399	96.43	gold quality
colonic mucosa	UBERON:0000317	96.42	gold quality
deltoid	UBERON:0001476	96.34	gold quality
oral cavity	UBERON:0000167	96.33	gold quality
tongue	UBERON:0001723	96.30	gold quality
skin of hip	UBERON:0001554	96.29	gold quality
superior vestibular nucleus	UBERON:0007227	96.26	gold quality
postcentral gyrus	UBERON:0002581	96.20	gold quality
cauda epididymis	UBERON:0004360	96.18	gold quality
epithelium of esophagus	UBERON:0001976	96.17	gold quality
tongue squamous epithelium	UBERON:0006919	96.16	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.14	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.57
E-CURD-46	yes	5.34
E-MTAB-6058	no	500.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2

miRNA regulators (miRDB)

218 targeting MAPK6, 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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371A-3P	99.99	66.77	91
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478

Literature-anchored findings (GeneRIF, showing 26)

• ERK3 biological activity is regulated by its cellular abundance through the control of protein stability (PMID:12808096)
• Data show that extracellular signal-regulated kinase 3 (ERK3) is conjugated to ubiquitin via its free NH(2) terminus, and that N-terminal tags stabilize expression of p21 but not that of substrates ubiquitinated on internal lysine residues. (PMID:15226418)
• These findings further expand distinct roles of cyclin D3 and suggest the potential activity of ERK3 in cell proliferation. (PMID:16360641)
• Extracellular signal-regulated kinase-3 (ERK3/MAPK6) is highly expressed in response to BRAF signaling. (PMID:16964379)
• Cdc14A forms a stable complex with atypical mitogen-activated protein kinase Erk3 in human cells independent of its intrinsic phosphatase activity but mediated by its regulatory C-terminal domain. (PMID:18235225)
• identify the Erk3 protein as a novel class I Pak substrate and further suggest a role for Pak kinase activity in atypical MAPK signaling. (PMID:21317288)
• A previously unknown role for ERK3 in promoting lung cancer cell invasiveness by phosphorylating SRC-3 and regulating SRC-3 proinvasive activity by site-specific phosphorylation. (PMID:22505454)
• ERK3 regulates endothelial cell migration, proliferation and tube formation by upregulating SRC-3/SP-1-mediated VEGFR2 expression. (PMID:24585635)
• MAPK6 could rescue the cell growth induced by miR499a and HBV (PMID:25340781)
• Study revealed a post-translational regulation of TDP2 activity and discovered a new role of ERK3 in increasing cancer cells’ DNA damage response and chemoresistance to Top2 inhibitors. (PMID:26701725)
• Metformin sensitizes arsenic trioxide to suppress intrahepatic cholangiocarcinoma via the regulation of AMPK/p38 MAPK-ERK3/mTORC1 pathways. ERK3 is a newfound potential prognostic predictor and a tumor suppressor in ICC. (PMID:28241849)
• NEAT1/hsa-mir-98-5p/MAPK6 is involved in the development and progress in non-small-cell lung cancer. (PMID:29095526)
• MicroRNA-138 knockdown promotes proliferation and inhibits apoptosis of laryngeal carcinoma cells via inhibiting MAPK6 expression. (PMID:30229830)
• MiR-144-3p: a novel tumor suppressor targeting MAPK6 in cervical cancer. (PMID:31016619)
• ERK3/MAPK6 controls IL-8 production and chemotaxis. (PMID:32314963)
• ERK3/MAPK6 is required for KRAS-mediated NSCLC tumorigenesis. (PMID:33070159)
• Crystal Structure and Inhibitor Identifications Reveal Targeting Opportunity for the Atypical MAPK Kinase ERK3. (PMID:33114754)
• let7f5p attenuates inflammatory injury in in vitro pneumonia models by targeting MAPK6. (PMID:33300070)
• CircRNA_100395 protects breast carcinoma deterioration by targeting MAPK6. (PMID:33336740)
• miR6535p suppresses the growth and migration of breast cancer cells by targeting MAPK6. (PMID:33495824)
• ERK3 is transcriptionally upregulated by Np63alpha and mediates the role of Np63alpha in suppressing cell migration in non-melanoma skin cancers. (PMID:33579235)
• LncRNA LINC00649 recruits TAF15 and enhances MAPK6 expression to promote the development of lung squamous cell carcinoma via activating MAPK signaling pathway. (PMID:35228660)
• miR-128-3p inhibits the inflammation by targeting MAPK6 in penicillin-induced astrocytes. (PMID:36250437)
• ERK3/MAPK6 dictates CDC42/RAC1 activity and ARP2/3-dependent actin polymerization. (PMID:37057894)
• Increased methylation of ZNF671 suppresses tumor progression by promoting MAPK6 transcription in laryngeal carcinoma. (PMID:37215982)
• The circ_0003928/miR-31-5p/MAPK6 cascade affects high glucose-induced inflammatory response, fibrosis and oxidative stress in HK-2 cells. (PMID:38964515)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapk6	ENSDARG00000032103
mus_musculus	Mapk6	ENSMUSG00000042688
rattus_norvegicus	Mapk6	ENSRNOG00000009381
drosophila_melanogaster	CG8565	FBGN0030697
drosophila_melanogaster	SRPK	FBGN0286813
caenorhabditis_elegans		WBGENE00002187
caenorhabditis_elegans		WBGENE00002188
caenorhabditis_elegans		WBGENE00004055
caenorhabditis_elegans		WBGENE00004056
caenorhabditis_elegans		WBGENE00004980
caenorhabditis_elegans	gskl-2	WBGENE00007977
caenorhabditis_elegans	Y106G6E.1	WBGENE00013705

Paralogs (19): MAPK9 (ENSG00000050748), MOK (ENSG00000080823), NLK (ENSG00000087095), SRPK1 (ENSG00000096063), MAPK1 (ENSG00000100030), MAPK3 (ENSG00000102882), MAPK8 (ENSG00000107643), MAPK10 (ENSG00000109339), MAK (ENSG00000111837), MAPK14 (ENSG00000112062), 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 6 — Q16659 (reviewed: Q16659)

Alternative names: Extracellular signal-regulated kinase 3, MAP kinase isoform p97

All UniProt accessions (1): Q16659

UniProt curated annotations — full annotation on UniProt →

Function. Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6. May promote entry in the cell cycle.

Subunit / interactions. Heterodimer with ERK4/MAPK4. Interacts with (via FRIEDE motif) MAPKAPK5. Interacts with UBE3A; this interaction may be indirect and mediated by HERC2, possibly via HERC2 interaction with NEURL4.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highest expression in the skeletal muscle, followed by the brain. Also found in heart, placenta, lung, liver, pancreas, kidney and skin fibroblasts.

Post-translational modifications. Phosphorylated at Ser-189 by PAK1, PAK2 and PAK3 resulting in catalytic activation. Phosphorylated by MAPKAPK5 at other sites. Ubiquitination at Met-1 leads to degradation by the proteasome pathway.

Activity regulation. Activated by phosphorylation at Ser-189.

Domain organisation. In contrast to classical MAPKs, the TXY motif within the activation loop is replaced by the SEG motif, whose phosphorylation activates the MAP kinases.

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

RefSeq proteins (1): NP_002739* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR008350	MAPK_ERK3/4	Family
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
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 (54 total): helix 16, strand 14, modified residue 7, turn 4, sequence conflict 2, short sequence motif 2, binding site 2, chain 1, domain 1, cross-link 1, sequence variant 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7AQB	X-RAY DIFFRACTION	2.25
6YLC	X-RAY DIFFRACTION	2.43
6YKY	X-RAY DIFFRACTION	2.52
6YLL	X-RAY DIFFRACTION	2.89

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16659-F1	58.61	0.26

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): 152 (proton acceptor)

Ligand- & substrate-binding residues (2): 26–34; 49

Post-translational modifications (8): 386, 452, 556, 558, 665, 684, 1, 189

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-162582	Signal Transduction
R-HSA-5683057	MAPK family signaling cascades

MSigDB gene sets: 398 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_DENDRITE_DEVELOPMENT, CREL_01, E2F4DP1_01, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_DENDRITIC_SPINE_DEVELOPMENT, TATTATA_MIR374, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_NEUROGENESIS, GOLDRATH_ANTIGEN_RESPONSE, AGTCTTA_MIR499, E2F1DP1_01, CHIBA_RESPONSE_TO_TSA_DN, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN

GO Biological Process (5): protein phosphorylation (GO:0006468), signal transduction (GO:0007165), intracellular signal transduction (GO:0035556), positive regulation of dendritic spine development (GO:0060999), MAPK cascade (GO:0000165)

GO Molecular Function (11): protein serine/threonine kinase activity (GO:0004674), MAP kinase activity (GO:0004707), ATP binding (GO:0005524), protein kinase binding (GO:0019901), protein heterodimerization activity (GO:0046982), 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 (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), septin cytoskeleton (GO:0032156), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
MAPK family signaling cascades	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular anatomical structure	2
protein kinase activity	2
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
positive regulation of developmental process	1
dendritic spine development	1
regulation of dendritic spine development	1
intracellular signaling cassette	1
MAPK cascade	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
cytoskeleton	1
cellular_component	1

Protein interactions and networks

STRING

3359 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPK6	MAPKAPK5	Q8IW41	800
MAPK6	NEURL4	Q96JN8	729
MAPK6	UBE3A	P78355	724
MAPK6	SH2D1A	O60880	590
MAPK6	VAV1	P15498	549
MAPK6	CD244	Q9BZW8	549
MAPK6	C5AR2	Q9P296	549
MAPK6	SEPTIN7	Q16181	536
MAPK6	HIF1AN	Q9NWT6	529
MAPK6	EPM2A	O95278	518
MAPK6	HSPA4	P34932	512
MAPK6	HERC2	O95714	507
MAPK6	DUSP1	P28562	499
MAPK6	GYS1	P13807	497
MAPK6	KLRD1	Q13241	496
MAPK6	NHLRC1	Q6VVB1	496

IntAct

237 interactions, top by confidence:

A	B	Type	Score
MAPK6	MAPKAPK5	psi-mi:“MI:0915”(physical association)	0.920
MAPKAPK5	MAPK6	psi-mi:“MI:0915”(physical association)	0.920
MAPKAPK5	MAPK6	psi-mi:“MI:0914”(association)	0.920
MAPK6	HERC2	psi-mi:“MI:0914”(association)	0.840
MAPK6	MAPKAPK5	psi-mi:“MI:0915”(physical association)	0.740
MAPK6	EGLN3	psi-mi:“MI:0915”(physical association)	0.680
EGLN3	MAPK6	psi-mi:“MI:0915”(physical association)	0.680
APOA1	MAPK6	psi-mi:“MI:0915”(physical association)	0.660
BRAF	MEN1	psi-mi:“MI:0914”(association)	0.600
MAPK6	ANKRD2	psi-mi:“MI:0915”(physical association)	0.560
MAPK6	EIF3C	psi-mi:“MI:0915”(physical association)	0.550
PLK1	MAPK6	psi-mi:“MI:0915”(physical association)	0.550
BRAF	MAPK6	psi-mi:“MI:2364”(proximity)	0.540
MAPK6	BRAF	psi-mi:“MI:0915”(physical association)	0.540
NEURL4	APBB1	psi-mi:“MI:0914”(association)	0.530
MAPK6	ECI2	psi-mi:“MI:0914”(association)	0.530
vif	HDAC3	psi-mi:“MI:0914”(association)	0.500
vif	MAPK6	psi-mi:“MI:0915”(physical association)	0.500
	TK2	psi-mi:“MI:0915”(physical association)	0.400
KDSR	MAPK6	psi-mi:“MI:0915”(physical association)	0.370
MAPK6	JUNB	psi-mi:“MI:0915”(physical association)	0.370
SLC20A1	MAPK6	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (545): MAPKAPK5 (Two-hybrid), MAPK6 (Affinity Capture-Western), MAPK6 (Biochemical Activity), MAPKAPK5 (Affinity Capture-MS), APOA1 (Affinity Capture-MS), ZNF7 (Affinity Capture-MS), SERPINA1 (Affinity Capture-MS), FGB (Affinity Capture-MS), HP (Affinity Capture-MS), HBB (Affinity Capture-MS), FGG (Affinity Capture-MS), FGA (Affinity Capture-MS), NEURL4 (Affinity Capture-MS), HERC2 (Affinity Capture-MS), HBA2 (Affinity Capture-MS)

ESM2 similar proteins: A2YMV6, A5D791, B1WAS2, F4JBP3, O22040, O22042, P27704, P41279, P50526, Q07174, Q0D598, Q16659, Q2V338, Q40541, Q5F3W3, Q5R7U1, Q5XHI9, Q61532, Q63562, Q65X23, Q6EU49, Q6GPE9, Q6I576, Q6NPP4, Q6NQ79, Q6VZ17, Q75LH6, Q8GSA7, Q8LST2, Q8RXE5, Q8S8Y8, Q8S8Y9, Q944Q0, Q9C9U5, Q9CAV6, Q9FPR3, Q9FY74, Q9FYG2, Q9FZ36, Q9LJD8

Diamond homologs: A0A075F7E9, A0A509AMC3, A8XSC1, A9S9Q8, C6KTB8, D0Z5N4, G1XJZ4, O02812, O14132, O43948, O65238, P27704, P31152, P42525, P46551, P47811, P47812, P52304, P54665, P70618, Q09892, Q16539, Q16659, Q25AG2, Q38775, Q40531, Q4PKS0, Q4PNJ1, Q55F45, Q5AP97, Q5F3W3, Q5I6M2, Q5R7U1, Q61532, Q63184, Q63454, Q6P5G0, Q75JN1, Q7FAZ0, Q7FAZ3

SIGNOR signaling

31 interactions.

A	Effect	B	Mechanism
CDC14A	down-regulates	MAPK6	dephosphorylation
CDC14B	down-regulates	MAPK6	dephosphorylation
CDK1	up-regulates	MAPK6	phosphorylation
MAPK6	up-regulates	NCOA3	phosphorylation
CyclinB/CDK1	up-regulates	MAPK6	phosphorylation
CDC14B	“down-regulates quantity by destabilization”	MAPK6	dephosphorylation
CDC14A	“down-regulates quantity by destabilization”	MAPK6	dephosphorylation
DUSP2	“down-regulates activity”	MAPK6	dephosphorylation
MAPK6	“up-regulates activity”	TDP2	phosphorylation
MAPK6	“up-regulates activity”	MAPKAPK5	phosphorylation
MAPK6	up-regulates	MAPK6	phosphorylation
MAPK6	“up-regulates activity”	KALRN	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 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
Vesicle-mediated transport	15	4.0×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein stabilization	12	5.0×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2515 predictions. Top by Δscore:

Variant	Effect	Δscore
15:51953124:GTTA:G	donor_loss	1.0000
15:51953125:TTA:T	donor_loss	1.0000
15:51953126:TA:T	donor_loss	1.0000
15:51953127:A:AT	donor_loss	1.0000
15:51953128:CCTG:C	donor_loss	1.0000
15:51953260:CATG:C	acceptor_gain	1.0000
15:51953262:TG:T	acceptor_gain	1.0000
15:51953264:C:CC	acceptor_gain	1.0000
15:51959893:CCTTA:C	donor_loss	1.0000
15:51959894:CTTA:C	donor_loss	1.0000
15:51959895:TTA:T	donor_loss	1.0000
15:51959896:TA:T	donor_loss	1.0000
15:51959897:A:AT	donor_loss	1.0000
15:51959983:T:TA	donor_gain	1.0000
15:51960629:A:AC	donor_gain	1.0000
15:51960630:C:CC	donor_gain	1.0000
15:51960630:CTGA:C	donor_gain	1.0000
15:51960633:A:AC	donor_gain	1.0000
15:51960634:C:CC	donor_gain	1.0000
15:51960637:A:AC	donor_gain	1.0000
15:51960638:C:CC	donor_gain	1.0000
15:51960638:CAA:C	donor_gain	1.0000
15:51960648:T:TA	donor_gain	1.0000
15:51960730:TTAT:T	acceptor_gain	1.0000
15:51960733:TC:T	acceptor_loss	1.0000
15:51960734:C:CC	acceptor_gain	1.0000
15:51960734:CTTCA:C	acceptor_loss	1.0000
15:51960735:T:A	acceptor_loss	1.0000
15:51960737:CAA:C	acceptor_gain	1.0000
15:51960739:A:AC	acceptor_gain	1.0000

AlphaMissense

4837 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:52046500:T:C	F14L	1.000
15:52046502:T:A	F14L	1.000
15:52046502:T:G	F14L	1.000
15:52046569:G:C	A37P	1.000
15:52046570:C:A	A37D	1.000
15:52046599:G:C	A47P	1.000
15:52046600:C:A	A47D	1.000
15:52046605:A:G	K49E	1.000
15:52046607:G:C	K49N	1.000
15:52046607:G:T	K49N	1.000
15:52046644:G:C	A62P	1.000
15:52046650:C:A	R64S	1.000
15:52046651:G:C	R64P	1.000
15:52046654:A:T	E65V	1.000
15:52046675:T:C	L72P	1.000
15:52046688:C:A	N76K	1.000
15:52046688:C:G	N76K	1.000
15:52046780:T:A	V107D	1.000
15:52046867:T:C	L136P	1.000
15:52046870:T:C	L137P	1.000
15:52046875:G:A	G139R	1.000
15:52046875:G:C	G139R	1.000
15:52046875:G:T	G139W	1.000
15:52046876:G:A	G139E	1.000
15:52046879:T:C	L140P	1.000
15:52046903:T:A	V148E	1.000
15:52046906:T:C	L149P	1.000
15:52046912:G:C	R151T	1.000
15:52046912:G:T	R151I	1.000
15:52046913:A:C	R151S	1.000

dbSNP variants (sampled 300 via entrez): RS1000053982 (15:52043833 A>C,G), RS1000091896 (15:51993427 A>G), RS1000123528 (15:52034369 G>A), RS1000160156 (15:52014142 C>T), RS1000169703 (15:52052598 A>T), RS1000200218 (15:52019301 G>A), RS1000233401 (15:52063818 A>G), RS1000234258 (15:52050859 T>C), RS1000254447 (15:51977154 C>T), RS1000296282 (15:52059480 G>A), RS1000302134 (15:52024407 T>C), RS1000317617 (15:52060225 A>G), RS1000335500 (15:52019183 C>T), RS1000387636 (15:51988401 G>A), RS1000408008 (15:51982531 T>A)

Disease associations

OMIM: gene MIM:602904 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004751_6	Serum uric acid levels in response to allopurinol in gout	8.000000e-07
GCST90020053_13	Frailty index	3.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004761	uric acid measurement
EFO:0009885	frailty measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5121 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 190,024 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL939	GEFITINIB	4	117,814
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL3544964	RAVOXERTINIB	2	1,243
CHEMBL1908397	KW-2449	1	622
CHEMBL296468	BMS-387032	1	2,075

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — ERK subfamily

Binding affinities (BindingDB)

5 measured of 5 human assays (5 total across all organisms); most potent 5 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine	KD	150 nM
CI-1033	KD	1700 nM
BMS-387072	KD	1800 nM
GEFITINIB	IC50	2300 nM	US-9416123: Kinase modulators for the treatment of cancer
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM

ChEMBL bioactivities

232 potent at pChembl≥5 of 245 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	IC50	0.02	nM	CHEMBL5880878
10.70	IC50	0.02	nM	CHEMBL5904041
10.70	IC50	0.02	nM	CHEMBL5852694
10.70	IC50	0.02	nM	CHEMBL5997841
10.70	IC50	0.02	nM	CHEMBL5928779
10.64	IC50	0.023	nM	CHEMBL5927076
10.64	IC50	0.023	nM	CHEMBL5789951
10.60	IC50	0.025	nM	CHEMBL5883378
10.59	IC50	0.026	nM	CHEMBL5819187
10.52	IC50	0.03	nM	CHEMBL6025904
10.52	IC50	0.03	nM	CHEMBL6015393
10.46	IC50	0.035	nM	CHEMBL5966825
10.44	IC50	0.036	nM	CHEMBL5820291
10.42	IC50	0.038	nM	CHEMBL5992641
10.36	IC50	0.044	nM	CHEMBL5770357
10.14	IC50	0.073	nM	CHEMBL5893541
10.10	IC50	0.079	nM	CHEMBL5768479
10.09	IC50	0.082	nM	CHEMBL6019772
10.07	IC50	0.085	nM	CHEMBL5846765
10.06	IC50	0.088	nM	CHEMBL6002255
9.99	IC50	0.102	nM	CHEMBL5840701
9.99	IC50	0.103	nM	CHEMBL5914503
9.96	IC50	0.109	nM	CHEMBL5988799
9.96	IC50	0.111	nM	CHEMBL5768349
9.88	IC50	0.131	nM	CHEMBL5870176
9.88	IC50	0.132	nM	CHEMBL5835341
9.85	IC50	0.14	nM	CHEMBL5927313
9.83	IC50	0.149	nM	CHEMBL5977337
9.78	IC50	0.168	nM	CHEMBL6026429
9.76	IC50	0.173	nM	CHEMBL5958147
9.67	IC50	0.215	nM	CHEMBL6024181
9.51	IC50	0.311	nM	CHEMBL6054742
9.51	IC50	0.311	nM	CHEMBL5786221
9.51	IC50	0.311	nM	CHEMBL5821708
9.50	IC50	0.316	nM	CHEMBL6002081
9.50	IC50	0.316	nM	CHEMBL5783483
9.42	IC50	0.38	nM	CHEMBL5762132
9.41	IC50	0.39	nM	CHEMBL5988077
9.39	IC50	0.408	nM	CHEMBL5988990
9.33	IC50	0.465	nM	CHEMBL5993832
9.33	IC50	0.47	nM	CHEMBL5813092
9.29	IC50	0.514	nM	CHEMBL5934638
9.29	IC50	0.512	nM	CHEMBL6056771
9.22	IC50	0.6	nM	CHEMBL5821135
9.22	IC50	0.6	nM	CHEMBL5937468
9.18	IC50	0.661	nM	CHEMBL6027174
9.18	IC50	0.66	nM	CHEMBL5766442
9.18	IC50	0.655	nM	CHEMBL5981367
9.16	IC50	0.69	nM	CHEMBL5763773
9.15	IC50	0.707	nM	CHEMBL5743783

PubChem BioAssay actives

91 with measured affinity, of 454 total; 30 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-(4-ethoxyphenyl)-N-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]triazolo[4,5-d]pyrimidin-5-amine	1697366: Inhibition of ERK3 (unknown origin) expressed in HEK293 cells cotransfected with nano-luciferase by NanoBRET assay	ic50	0.0130	uM
N-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-3-(1-methylpyrazol-3-yl)triazolo[4,5-d]pyrimidin-5-amine	1697357: Binding affinity to wild-type human partial length ERK3 (M1 to P413 residues) expressed in bacterial expression system by kinomescan method	kd	0.0350	uM
3-(4-methoxyphenyl)-N-[(3R)-1-pyridin-4-ylpyrrolidin-3-yl]triazolo[4,5-d]pyrimidin-5-amine	1697366: Inhibition of ERK3 (unknown origin) expressed in HEK293 cells cotransfected with nano-luciferase by NanoBRET assay	ic50	0.0380	uM
5-fluoro-2-[5-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]triazolo[4,5-d]pyrimidin-3-yl]benzonitrile	1697366: Inhibition of ERK3 (unknown origin) expressed in HEK293 cells cotransfected with nano-luciferase by NanoBRET assay	ic50	0.0550	uM
trans-(1R,3R)-3-N-[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yl]cyclopentane-1,3-diamine	1697359: Binding affinity to recombinant wild-type ERK3 (9 to 327 residues) (unknown origin) expressed in Escherichia coli by microscale thermophoresis assay	kd	0.1200	uM
4-N-[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yl]cyclohexane-1,4-diamine	1697359: Binding affinity to recombinant wild-type ERK3 (9 to 327 residues) (unknown origin) expressed in Escherichia coli by microscale thermophoresis assay	kd	0.1300	uM
N-[4-(aminomethyl)cyclohexyl]-3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-amine	1697364: Inhibition of recombinant His6-GST fusion tagged ERK3 (1 to 471 residues) (unknown origin) expressed in Sf21 insect cells using MK5 K51A mutant as substrate by ADP-Glo assay	ic50	0.1380	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624887: Binding constant for ERK3 kinase domain	kd	0.1700	uM
3-[3-(4-methylpiperazin-1-yl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine	2135398: Inhibition of ERK3 (unknown origin)	ic50	0.2100	uM
(4-hydroxypiperidin-1-yl)-[4-[[4-[4-(3-methylsulfonylpropoxy)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]methanone	769518: Binding affinity to ERK3 (unknown origin)	kd	0.3300	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435289: Binding constant for ERK3 kinase domain	kd	0.4800	uM
N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]piperidine-4-carboxamide	435289: Binding constant for ERK3 kinase domain	kd	0.5000	uM
cis-(1S,3R)-3-N-[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yl]cyclopentane-1,3-diamine	1697365: Inhibition of recombinant full length His6-GST fusion tagged ERK3 (1 to 721 residues) (unknown origin) using MK5 K51A mutant as substrate by ADP-Glo assay	ic50	0.8600	uM
4-[[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yl]amino]cyclohexane-1-carboxamide	1697357: Binding affinity to wild-type human partial length ERK3 (M1 to P413 residues) expressed in bacterial expression system by kinomescan method	kd	0.9800	uM
Fedratinib	624887: Binding constant for ERK3 kinase domain	kd	1.2000	uM
trans-(1S,3S)-3-N-[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yl]cyclopentane-1,3-diamine	1697364: Inhibition of recombinant His6-GST fusion tagged ERK3 (1 to 471 residues) (unknown origin) expressed in Sf21 insect cells using MK5 K51A mutant as substrate by ADP-Glo assay	ic50	1.3300	uM
Vandetanib	435289: Binding constant for ERK3 kinase domain	kd	1.5000	uM
Gefitinib	435289: Binding constant for ERK3 kinase domain	kd	1.6000	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	435289: Binding constant for ERK3 kinase domain	kd	1.7000	uM
3-(4-methoxyphenyl)-N-[(3S)-1-pyridin-4-ylpyrrolidin-3-yl]triazolo[4,5-d]pyrimidin-5-amine	1697363: Inhibition of recombinant His6-GST fusion tagged ERK3 (1 to 365 residues) (unknown origin) expressed in Sf21 insect cells using MK5 K51A mutant as substrate by ADP-Glo assay	ic50	1.8000	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	624887: Binding constant for ERK3 kinase domain	kd	3.1000	uM
Crizotinib	1697359: Binding affinity to recombinant wild-type ERK3 (9 to 327 residues) (unknown origin) expressed in Escherichia coli by microscale thermophoresis assay	kd	3.4000	uM
N’-(1,8-dimethylimidazo[1,2-a]quinoxalin-4-yl)ethane-1,2-diamine	624887: Binding constant for ERK3 kinase domain	kd	4.3000	uM
cis-(1R,3S)-3-N-[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yl]cyclopentane-1,3-diamine	1697364: Inhibition of recombinant His6-GST fusion tagged ERK3 (1 to 471 residues) (unknown origin) expressed in Sf21 insect cells using MK5 K51A mutant as substrate by ADP-Glo assay	ic50	4.6000	uM
6-[(3,4-dichlorobenzoyl)amino]-N-(1,3-thiazol-2-yl)naphthalene-2-carboxamide	1577091: Binding affinity to wild-type human partial length ERK3 (M1 to P413 residues) expressed in bacterial expression system measured after 1 hr by kinomescan method	kd	5.3200	uM
[4-[[3-(4-methoxyphenyl)triazolo[4,5-d]pyrimidin-5-yl]amino]cyclohexyl]methanol	1697364: Inhibition of recombinant His6-GST fusion tagged ERK3 (1 to 471 residues) (unknown origin) expressed in Sf21 insect cells using MK5 K51A mutant as substrate by ADP-Glo assay	ic50	5.4000	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624887: Binding constant for ERK3 kinase domain	kd	5.5000	uM
trans-(1R,3R)-3-N-[3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]cyclopentane-1,3-diamine	1697364: Inhibition of recombinant His6-GST fusion tagged ERK3 (1 to 471 residues) (unknown origin) expressed in Sf21 insect cells using MK5 K51A mutant as substrate by ADP-Glo assay	ic50	5.5000	uM
trans-(1R,3R)-3-N-[1-(4-methoxyphenyl)triazolo[4,5-c]pyridin-6-yl]cyclopentane-1,3-diamine	1697364: Inhibition of recombinant His6-GST fusion tagged ERK3 (1 to 471 residues) (unknown origin) expressed in Sf21 insect cells using MK5 K51A mutant as substrate by ADP-Glo assay	ic50	8.0000	uM
trans-(1R,3R)-3-N-[9-(4-methoxyphenyl)purin-2-yl]cyclopentane-1,3-diamine	1697364: Inhibition of recombinant His6-GST fusion tagged ERK3 (1 to 471 residues) (unknown origin) expressed in Sf21 insect cells using MK5 K51A mutant as substrate by ADP-Glo assay	ic50	9.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	affects expression, affects methylation, increases abundance, increases expression	4
sodium arsenite	increases abundance, increases expression, affects cotreatment	3
tetrachlorodian	decreases reaction, increases expression, affects expression	2
Air Pollutants	affects expression, affects methylation, increases abundance, increases expression	2
Dihydrotestosterone	increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Valproic Acid	affects expression, decreases expression	2
Cyclosporine	increases expression	2
Soot	affects methylation, decreases expression	2
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
oxybenzone	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
coumarin	decreases phosphorylation	1
1-nitropyrene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta(c)quinoline	decreases reaction, increases expression	1
ProstaCaid	decreases expression	1
bisphenol AF	increases expression	1
Gefitinib	decreases reaction, increases expression	1
Wortmannin	decreases reaction, increases expression	1

ChEMBL screening assays

98 unique, capped per target: 98 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004485	Binding	Binding affinity to human recombinant MAPK6 expressed in Escherichia coli assessed as thermal shift by differential scanning fluorimetry	Discovery of a potent and selective inhibitor for human carbonyl reductase 1 from propionate scanning applied to the macrolide zearalenone. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1WQ	Abcam HeLa MAPK6 KO	Cancer cell line	Female
CVCL_SW95	HAP1 MAPK6 (-) 1	Cancer cell line	Male
CVCL_SW96	HAP1 MAPK6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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