MAP2K5

Summary

MAP2K5 (mitogen-activated protein kinase kinase 5, HGNC:6845) is a protein-coding gene on chromosome 15q23, encoding Dual specificity mitogen-activated protein kinase kinase 5 (Q13163). Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex.

The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase specifically interacts with and activates MAPK7/ERK5. This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs). The signal cascade mediated by this kinase is involved in growth factor stimulated cell proliferation and muscle cell differentiation. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been described.

Source: NCBI Gene 5607 — RefSeq curated summary.

At a glance

• GWAS associations: 50
• Clinical variants (ClinVar): 69 total
• Druggable target: yes — 69 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_145160

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6845
Approved symbol	MAP2K5
Name	mitogen-activated protein kinase kinase 5
Location	15q23
Locus type	gene with protein product
Status	Approved
Aliases	MEK5, MAPKK5, HsT17454
Ensembl gene	ENSG00000137764
Ensembl biotype	protein_coding
OMIM	602520
Entrez	5607

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 31 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000178640, ENST00000340972, ENST00000354498, ENST00000395476, ENST00000439036, ENST00000557869, ENST00000558021, ENST00000558274, ENST00000558392, ENST00000559262, ENST00000560086, ENST00000560591, ENST00000879769, ENST00000879770, ENST00000879771, ENST00000879772, ENST00000879773, ENST00000879774, ENST00000879775, ENST00000879776, ENST00000879777, ENST00000879778, ENST00000879779, ENST00000879780, ENST00000931464, ENST00000931465, ENST00000952134, ENST00000952135, ENST00000952136, ENST00000952137, ENST00000952138, ENST00000952139, ENST00000952140, ENST00000952141, ENST00000952142, ENST00000952143

RefSeq mRNA: 3 — MANE Select: NM_145160 NM_001206804, NM_002757, NM_145160

CCDS: CCDS10224, CCDS42051, CCDS55970

Canonical transcript exons

ENST00000178640 — 22 exons

Exon	Start	End
ENSE00001890016	67806646	67807114
ENSE00001917690	67542703	67543470
ENSE00003465875	67703337	67703408
ENSE00003476689	67769602	67769663
ENSE00003483295	67658553	67658614
ENSE00003491848	67586846	67586913
ENSE00003493902	67646388	67646469
ENSE00003496308	67563283	67563350
ENSE00003497335	67692479	67692552
ENSE00003515860	67748569	67748601
ENSE00003533272	67664597	67664645
ENSE00003562246	67693518	67693568
ENSE00003578756	67580754	67580823
ENSE00003594768	67630888	67630927
ENSE00003603916	67592926	67592974
ENSE00003615774	67727916	67727945
ENSE00003625694	67646231	67646299
ENSE00003631336	67550034	67550082
ENSE00003634063	67772707	67772752
ENSE00003668905	67748231	67748257
ENSE00003681520	67600685	67600749
ENSE00003693239	67585890	67585930

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 90.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.0886 / max 357.5144, expressed in 1813 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
147355	23.5591	1812
147357	0.3410	123
147359	0.3409	170
147358	0.3118	123
147361	0.2139	93
147360	0.1636	62
147356	0.1584	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	90.80	gold quality
olfactory bulb	UBERON:0002264	90.59	gold quality
left testis	UBERON:0004533	90.24	gold quality
parotid gland	UBERON:0001831	89.07	gold quality
testis	UBERON:0000473	88.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.77	gold quality
right frontal lobe	UBERON:0002810	88.68	gold quality
calcaneal tendon	UBERON:0003701	88.45	gold quality
gastrocnemius	UBERON:0001388	88.22	gold quality
muscle of leg	UBERON:0001383	88.06	gold quality
ventricular zone	UBERON:0003053	88.04	gold quality
type B pancreatic cell	CL:0000169	87.99	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.88	gold quality
prefrontal cortex	UBERON:0000451	87.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.64	gold quality
sural nerve	UBERON:0015488	87.56	gold quality
muscle layer of sigmoid colon	UBERON:0035805	87.31	gold quality
tendon of biceps brachii	UBERON:0008188	87.26	gold quality
male germ cell	CL:0000015	87.20	gold quality
left ovary	UBERON:0002119	87.14	gold quality
apex of heart	UBERON:0002098	87.04	gold quality
tendon	UBERON:0000043	87.03	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.99	gold quality
sperm	CL:0000019	86.92	gold quality
cingulate cortex	UBERON:0003027	86.74	gold quality
middle temporal gyrus	UBERON:0002771	86.64	gold quality
right adrenal gland	UBERON:0001233	86.63	gold quality
skin of abdomen	UBERON:0001416	86.61	gold quality
skin of leg	UBERON:0001511	86.60	gold quality
nucleus accumbens	UBERON:0001882	86.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.49

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
KLF2	Repression
KLF4	Activation
NOS3	Activation

Upstream regulators (CollecTRI, top): AP1, ENO1, ESR1, ESR2, KLF2, REST, STAT3, TLX3

Literature-anchored findings (GeneRIF, showing 39)

• overexpression of MEK5 in APO- MCF-7 breast carcinoma cells shows that this MAPK signaling protein represents a potent survival molecule. (PMID:12219026)
• MEK5 overexpression is associated with metastatic prostate cancer, and stimulates proliferation, MMP-9 expression and invasion. MEK5 is a key signalling molecule associated with prostate carcinogenesis. (PMID:12618764)
• alternative splicing of MEK5alpha and MEK5beta may play a critical role in BMK1 activation and subsequent cell proliferation (PMID:14583600)
• nuclear localization of MEK5 and ERK5 is different from that of ERK1/2 and MEK1/2 in resting cells, indicating that each MAPK cascade uses distinct mechanisms (PMID:15075238)
• MEK5 may be one of the Stat3-regulated genes and plays its essential roles in oncogenesis (PMID:15378007)
• Genistein can affect the ERK5 MAPK signaling transduction pathway and induce the expressions of apoptosis related proteins to inhibit the proliferation of MDA-MB-231 cells. (PMID:16758967)
• Data suggest that HGF-induced effects in some mesothelioma cells are mediated via activation of a novel PI3K/ERK5/Fra-1 feedback pathway (PMID:17872495)
• ERK5 nuclear staining has been shown to be an independent marker of prognosis in CaP, and may prove useful as a stratification tool to identify a more aggressive/metastatic phenotype (PMID:18071319)
• MEK5/ERK5 signaling modulates endothelial cell migration and focal contact turnover (PMID:19605361)
• MEK5 activation by laminar shear stress inhibits inflammatory responses in microvascular endothelial cells, in part through ERK5-dependent induction of KLF4 (PMID:21166929)
• HCVne particles are capable of inducing the recently discovered ERK5 pathway, in a dose dependent way. (PMID:21767578)
• These results suggest that MEK5/ERK5 is important for FLT3-ITD induced hematopoietic transformation. (PMID:21820407)
• data indicate that the rs3743354 polymorphism in the MEK5 promoter may affect the risk of developing colorectal cancer (PMID:21861603)
• Variants in MEIS1, BTBD9, and MAP2K5/SKOR1 confer a significant risk of restless legs syndrome in a United States population. (PMID:21925394)
• Single nucleotide polymorphism in the MAP2K5 gene is associated with BMI and obesity. (PMID:22594783)
• MEK5/ERK5 signaling suppresses estrogen receptor expression and promotes hormone-independent tumorigenesis. (PMID:23950888)
• Specifically, CKS1B and MAP2K5 significantly inhibited hepatitis C viral RNA replication. PACSIN1, by contrast, inhibited hepatitis C virus infection by decreasing the level of viral protein p7. (PMID:24205826)
• MiR-330-3p and MAP2K5 are potentially important contributors to mood and anxiety-related traits (PMID:24436253)
• Inhibitors of apoptosis proteins regulate myogenic differentiation by directly suppressing MEKK2/3-MEK5-ERK5 signaling. (PMID:24975362)
• Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD (PMID:25142570)
• SEC16B, MC4R, MAP2K5 and KCTD15 (rs17782313, rs543874, rs2241423 and rs11084753) polymorphisms are associated with the risk for children obesity in China. (PMID:25637721)
• High MEK5 expression is associated with colorectal cancer. (PMID:25662172)
• Our findings confirm an association between the BTBD9, MEIS1, and MAP2K5/SKOR1 SNPs and periodic limb movements of sleep in an elderly cohort. (PMID:26498236)
• Results revealed the expression of MEK5 was higher in tumor tissues and provide evidence that MEK5 plays an important role in colorectal cancer progression. (PMID:27160304)
• Insights into a molecular mechanism by which MEK5 transcriptionally upregulated by Stat3 augments breast cancer cell EMT, which subsequently enhances cancer cell invasion and metastasis. This finding may suggest that Stat3 and MEK5/Erk5 pathways could be an effective therapeutic target for inhibition of breast cancer invasion and metastasis. (PMID:27878304)
• results confirmed the association of BTBD9 and MAP2K5/SKOR1 with primary Restless Legs Syndrome in Chinese population (PMID:28329290)
• For gain and loss of function studies, constitutively active MEK5 (CA-MEK5) and ERK5 shRNA lentiviruses were used to activate or knock down extracellular signal-regulated kinase 5 (ERK5). Our results confirmed that low concentrations of H2O2 promoted HUVECs angiogenesis in vitro, and ERK5 is an essential mediator of this process. Therefore, ERK5 may be a potential therapeutic target for promoting angiogenesis (PMID:28540300)
• When yeast genetic interaction partners held in common between human OPTN and ANG were validated in mammalian cells and zebrafish, MAP2K5 kinase emerged as a potential drug target for amyotrophic lateral sclerosis therapy (PMID:28596290)
• MAP2K5/SKOR1 may be associated with Chinese essential tremor patients. (PMID:29798820)
• Study in Chinese familial non-medullary thyroid carcinoma patients revealed that MAP2K5 variants A321T or M367 T can activate MAP2K5-ERK5 pathway, alter downstream gene expression, and subsequently induce thyroid epithelial cell malignant transformation. (PMID:30132833)
• MEK5 promotes lung adenocarcinoma. (PMID:30442718)
• MEK5 is a novel autophagy modulator (PMID:31005259)
• The MEK5-ERK5 Kinase Axis Controls Lipid Metabolism in Small-Cell Lung Cancer. (PMID:31969375)
• Identification of Novel Genetic Variants Related to Trabecular Bone Score in Community-Dwelling Older Adults. (PMID:33232597)
• Inhibition of MEK5/ERK5 signaling overcomes acquired resistance to the third generation EGFR inhibitor, osimertinib, via enhancing Bim-dependent apoptosis. (PMID:34245854)
• The Hedgehog-GLI Pathway Regulates MEK5-ERK5 Expression and Activation in Melanoma Cells. (PMID:34681917)
• Aberrant MEK5 signalling promotes clear cell renal cell carcinoma development via mTOR activation. (PMID:35713705)
• MEK5-ERK5 Axis Promotes Self-renewal and Tumorigenicity of Glioma Stem Cells. (PMID:36968222)
• Potentially functional genetic variants in RPS6KA4 and MAP2K5 in the MAPK signaling pathway predict HBV-related hepatocellular carcinoma survival. (PMID:37278562)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	map2k5	ENSDARG00000011851
mus_musculus	Map2k5	ENSMUSG00000058444
rattus_norvegicus	Map2k5	ENSRNOG00000007926
caenorhabditis_elegans		WBGENE00018034
caenorhabditis_elegans		WBGENE00018035

Paralogs (8): MAP2K4 (ENSG00000065559), MAP2K7 (ENSG00000076984), MAP3K4 (ENSG00000085511), MAP2K2 (ENSG00000126934), NEK1 (ENSG00000137601), MAP2K1 (ENSG00000169032), MAP3K2 (ENSG00000169967), MAP3K3 (ENSG00000198909)

Protein

Protein identifiers

Dual specificity mitogen-activated protein kinase kinase 5 — Q13163 (reviewed: Q13163)

Alternative names: MAPK/ERK kinase 5

All UniProt accessions (5): Q13163, A0A087WWX7, A0A087X0Z8, A6NK28, H7BZL1

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex. Activation of this pathway appears to play a critical role in protecting cells from stress-induced apoptosis, neuronal survival and cardiac development and angiogenesis. As part of the MAPK/ERK signaling pathway, acts as a negative regulator of apoptosis in cardiomyocytes via promotion of STUB1/CHIP-mediated ubiquitination and degradation of ICER-type isoforms of CREM.

Subunit / interactions. Interacts with PARD6A, MAP3K3 and MAPK7. Forms a complex with SQSTM1 and PRKCZ or PRKCI. (Microbial infection) Interacts with Yersinia YopJ.

Tissue specificity. Expressed in many adult tissues. Abundant in heart and skeletal muscle.

Post-translational modifications. Activated by phosphorylation on Ser/Thr by MAP kinase kinase kinases. (Microbial infection) Yersinia YopJ may acetylate Ser/Thr residues, preventing phosphorylation and activation, thus blocking the MAPK signaling pathway.

Domain organisation. Binds MAP3K2/MAP3K3 and MAPK7 via non-overlapping residues of the PB1 domain. This domain also mediates interactions with SQSTM1 and PARD6A.

Miscellaneous. Incomplete sequence.

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

Isoforms (4)

UniProt ID	Names	Canonical?
Q13163-1	B	yes
Q13163-2	A
Q13163-3	C
Q13163-4	4

RefSeq proteins (3): NP_001193733, NP_002748, NP_660143* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000270	PB1_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR034851	PB1_MAP2K5	Domain
IPR052468	Dual_spec_MAPK_kinase	Family
IPR053793	PB1-like	Domain

Pfam: PF00069, PF00564

Enzyme classification (BRENDA):

• EC 2.7.12.2 — mitogen-activated protein kinase kinase (BRENDA: 38 organisms, 149 substrates, 134 inhibitors, 6 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.0533	1
ERK2	0.0002	1
K52R-[ERK2]	0.0001	1
K53M-[P38ALPHA]	0.0002	1
P38ALPHA	0.0002	1

Catalyzed reactions (Rhea), 3 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (32 total): strand 6, region of interest 4, splice variant 3, sequence variant 3, mutagenesis site 3, domain 2, binding site 2, modified residue 2, turn 2, helix 2, chain 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2NPT	X-RAY DIFFRACTION	1.75
2O2V	X-RAY DIFFRACTION	1.83
4IC7	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13163-F1	79.20	0.41

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): 283 (proton acceptor)

Ligand- & substrate-binding residues (2): 195; 172–180

Post-translational modifications (2): 311, 315

Mutagenesis-validated functional residues (3):

Position	Phenotype
195	inactivation.
311	inactivation.
315	inactivation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-198765	Signalling to ERK5
R-HSA-162582	Signal Transduction
R-HSA-166520	Signaling by NTRKs
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 275 (showing top): BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_RESPONSE_TO_PEPTIDE, NKX25_02, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, GOBP_NEGATIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_REGULATION_OF_HETEROTYPIC_CELL_CELL_ADHESION, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOBP_CELLULAR_RESPONSE_TO_FLUID_SHEAR_STRESS, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_CELL_MIGRATION_INVOLVED_IN_SPROUTING_ANGIOGENESIS, GOBP_GROWTH, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, DARWICHE_SKIN_TUMOR_PROMOTER_UP

GO Biological Process (21): negative regulation of transcription by RNA polymerase II (GO:0000122), MAPK cascade (GO:0000165), signal transduction (GO:0007165), heart development (GO:0007507), positive regulation of cell growth (GO:0030307), negative regulation of interleukin-8 production (GO:0032717), negative regulation of heterotypic cell-cell adhesion (GO:0034115), negative regulation of smooth muscle cell apoptotic process (GO:0034392), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of transcription by RNA polymerase II (GO:0045944), insulin-like growth factor receptor signaling pathway (GO:0048009), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of protein metabolic process (GO:0051247), negative regulation of response to cytokine stimulus (GO:0060761), ERK5 cascade (GO:0070375), cellular response to growth factor stimulus (GO:0071363), cellular response to laminar fluid shear stress (GO:0071499), negative regulation of cell migration involved in sprouting angiogenesis (GO:0090051), negative regulation of chemokine (C-X-C motif) ligand 2 production (GO:2000342), negative regulation of extrinsic apoptotic signaling pathway in absence of ligand (GO:2001240), protein phosphorylation (GO:0006468)

GO Molecular Function (11): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase activity (GO:0004708), protein tyrosine kinase activity (GO:0004713), ATP binding (GO:0005524), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (1): spindle (GO:0005819)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by NTRK1 (TRKA)	1
Signaling by Receptor Tyrosine Kinases	1
Signaling by NTRKs	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
MAPK cascade	2
negative regulation of DNA-templated transcription	1
intracellular signaling cassette	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
animal organ development	1
circulatory system development	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
negative regulation of cytokine production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
negative regulation of cell-cell adhesion	1
heterotypic cell-cell adhesion	1
regulation of heterotypic cell-cell adhesion	1
regulation of cell-cell adhesion involved in gastrulation	1
negative regulation of muscle cell apoptotic process	1
smooth muscle cell apoptotic process	1
regulation of smooth muscle cell apoptotic process	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
positive regulation of DNA-templated transcription	1
cell surface receptor protein tyrosine kinase signaling pathway	1
positive regulation of cell population proliferation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
positive regulation of macromolecule metabolic process	1
protein metabolic process	1
regulation of protein metabolic process	1
response to cytokine	1
negative regulation of response to stimulus	1

Protein interactions and networks

STRING

2572 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP2K5	MAP3K3	Q99759	866
MAP2K5	MAPK7	Q13164	840
MAP2K5	BTBD9	Q96Q07	784
MAP2K5	SUCLG2	Q96I99	676
MAP2K5	KLF2	Q9Y5W3	673
MAP2K5	MEIS1	O00470	668
MAP2K5	JUN	P05412	660
MAP2K5	TRAF4	Q9BUZ4	645
MAP2K5	MAP3K2	Q9Y2U5	644
MAP2K5	MEF2C	Q06413	642
MAP2K5	PRKCZ	Q05513	630
MAP2K5	AKAP6	Q13023	616
MAP2K5	LGALS4	P56470	612
MAP2K5	ANKRD28	O15084	604
MAP2K5	CCM2	Q9BSQ5	588

IntAct

68 interactions, top by confidence:

A	B	Type	Score
MAP2K5	MAPK7	psi-mi:“MI:0915”(physical association)	0.860
MAP2K5	MAPK7	psi-mi:“MI:0914”(association)	0.860
MAP3K2	MAP2K5	psi-mi:“MI:0915”(physical association)	0.800
MAP3K3	MAP2K5	psi-mi:“MI:2364”(proximity)	0.730
MAP2K5	LNX2	psi-mi:“MI:0915”(physical association)	0.670
MAP2K5	SQSTM1	psi-mi:“MI:0915”(physical association)	0.670
HSP90AB1	MAP2K5	psi-mi:“MI:0915”(physical association)	0.670
MAP2K5	DUSP21	psi-mi:“MI:0915”(physical association)	0.560
MAP2K5	ZNF426	psi-mi:“MI:0915”(physical association)	0.560
MAP2K5	PFDN5	psi-mi:“MI:0915”(physical association)	0.560
MAP2K5	GUCD1	psi-mi:“MI:0915”(physical association)	0.560
MAP2K5	C3orf36	psi-mi:“MI:0915”(physical association)	0.560
MAP2K5	ZNF620	psi-mi:“MI:0915”(physical association)	0.560
MAP3K3	TCP1	psi-mi:“MI:0914”(association)	0.560
MAP2K5	GRB2	psi-mi:“MI:0915”(physical association)	0.400
MAP2K5	VIM	psi-mi:“MI:0915”(physical association)	0.400
SIRT3		psi-mi:“MI:0915”(physical association)	0.400
MAP2K5	STAMBP	psi-mi:“MI:0915”(physical association)	0.370
MAP2K5	XRCC6	psi-mi:“MI:0915”(physical association)	0.370
MAP2K5	RPL28	psi-mi:“MI:0915”(physical association)	0.370
MAP2K5	ESRRA	psi-mi:“MI:0915”(physical association)	0.370
ASRGL1	MAP2K5	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (180): MAP2K5 (Affinity Capture-RNA), MAP2K5 (Two-hybrid), MAP2K5 (Co-localization), MAPK7 (Affinity Capture-MS), MAP3K2 (Affinity Capture-MS), MAP3K3 (Affinity Capture-MS), TRAF7 (Affinity Capture-MS), C10orf88 (Affinity Capture-MS), CDC37 (Affinity Capture-MS), MAP2K5 (Two-hybrid), MAP2K5 (Affinity Capture-MS), PIK3CG (Negative Genetic), MAP2K5 (Negative Genetic), PPP1CC (Negative Genetic), MAP2K5 (Negative Genetic)

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

Diamond homologs: A0A194VNL2, A0A1S4CGX4, A4K2M3, A4K2P5, A4K2Q5, A4K2S1, A4K2T0, A4K2W5, A4K2Y1, A8XJW8, A9RWC9, A9S5R3, A9SR33, B0XPE4, C4YLK8, E1BK52, F1NBT0, G4N6Z6, G4NEB8, G5EDF7, O00506, O09110, O14733, O54748, O80396, O94804, O95819, P06784, P08018, P0CY25, P10506, P29678, P31938, P32490, P32491, P33886, P36506, P36507, P45985, P46734

SIGNOR signaling

16 interactions.

A	Effect	B	Mechanism
MAP2K5	up-regulates	MAPK7	phosphorylation
MAP3K2	up-regulates	MAP2K5	phosphorylation
MAP3K3	up-regulates	MAP2K5	phosphorylation
SL-327	down-regulates	MAP2K5	“chemical inhibition”
BIX-02188	down-regulates	MAP2K5	“chemical inhibition”
3-[[3-[(dimethylamino)methyl]anilino]-phenylmethylidene]-N,N-dimethyl-2-oxo-1H-indole-6-carboxamide	down-regulates	MAP2K5	“chemical inhibition”
GHR	“up-regulates activity”	MAP2K5	phosphorylation
MAP2K5	“up-regulates activity”	MAPK7	phosphorylation
MAP3K2	up-regulates	MAP2K5
MAPK7	up-regulates	MAP2K5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 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
Signaling by Interleukins	6	14.3×	1e-03
Cytokine Signaling in Immune system	6	9.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	34
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

5243 predictions. Top by Δscore:

Variant	Effect	Δscore
15:67550030:TTA:T	acceptor_loss	1.0000
15:67550031:TAG:T	acceptor_loss	1.0000
15:67550032:A:AG	acceptor_gain	1.0000
15:67550032:AG:A	acceptor_gain	1.0000
15:67550033:G:GA	acceptor_gain	1.0000
15:67550033:G:T	acceptor_loss	1.0000
15:67550033:GG:G	acceptor_gain	1.0000
15:67550033:GGAT:G	acceptor_gain	1.0000
15:67550079:GAAT:G	donor_gain	1.0000
15:67550080:AAT:A	donor_gain	1.0000
15:67550080:AATGT:A	donor_loss	1.0000
15:67550081:AT:A	donor_gain	1.0000
15:67550082:TGT:T	donor_loss	1.0000
15:67550083:G:GG	donor_gain	1.0000
15:67550084:TAAG:T	donor_loss	1.0000
15:67563264:ATTAT:A	acceptor_gain	1.0000
15:67563270:T:TA	acceptor_gain	1.0000
15:67563277:A:AG	acceptor_gain	1.0000
15:67563278:A:G	acceptor_gain	1.0000
15:67563280:CAGAT:C	acceptor_loss	1.0000
15:67563281:A:AG	acceptor_gain	1.0000
15:67563281:AGA:A	acceptor_loss	1.0000
15:67563282:G:GA	acceptor_gain	1.0000
15:67563282:GAT:G	acceptor_gain	1.0000
15:67563346:CATAT:C	donor_gain	1.0000
15:67563347:ATAT:A	donor_gain	1.0000
15:67563348:TAT:T	donor_gain	1.0000
15:67563349:AT:A	donor_gain	1.0000
15:67563350:TG:T	donor_loss	1.0000
15:67563351:G:GA	donor_loss	1.0000

AlphaMissense

2931 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:67550077:T:C	F60S	1.000
15:67630927:G:C	K195N	1.000
15:67630927:G:T	K195N	1.000
15:67664606:G:C	G270R	1.000
15:67664607:G:A	G270D	1.000
15:67664610:T:C	L271P	1.000
15:67664619:T:G	L274W	1.000
15:67664639:C:G	H281D	1.000
15:67664643:G:C	R282T	1.000
15:67664643:G:T	R282I	1.000
15:67664644:A:C	R282S	1.000
15:67664644:A:T	R282S	1.000
15:67664645:G:C	D283H	1.000
15:67692479:A:C	D283A	1.000
15:67692479:A:T	D283V	1.000
15:67692480:C:A	D283E	1.000
15:67692480:C:G	D283E	1.000
15:67692484:A:G	K285E	1.000
15:67692486:G:C	K285N	1.000
15:67692486:G:T	K285N	1.000
15:67692488:C:A	P286H	1.000
15:67692493:A:G	N288D	1.000
15:67692495:T:A	N288K	1.000
15:67692495:T:G	N288K	1.000
15:67692500:T:C	L290P	1.000
15:67692514:G:A	G295R	1.000
15:67692514:G:C	G295R	1.000
15:67692515:G:A	G295E	1.000
15:67692515:G:T	G295V	1.000
15:67692521:T:A	V297D	1.000

dbSNP variants (sampled 300 via entrez): RS1000006673 (15:67576564 T>A), RS1000009955 (15:67621505 G>C,T), RS1000021981 (15:67577061 G>A,C,T), RS1000056320 (15:67570927 C>G), RS1000070866 (15:67627616 C>T), RS1000071257 (15:67713464 G>A), RS1000072087 (15:67668033 T>C), RS1000076642 (15:67620027 C>G,T), RS1000082142 (15:67669620 T>C), RS1000083516 (15:67623207 A>T), RS1000102708 (15:67768367 C>G,T), RS1000107668 (15:67685591 CATTAT>C), RS1000110987 (15:67775861 T>G), RS1000115872 (15:67543155 T>A,C), RS1000159312 (15:67614760 G>A)

Disease associations

OMIM: gene MIM:602520 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

50 associations (top):

Study	Trait	p-value
GCST000056_3	Restless legs syndrome	1.000000e-15
GCST000830_6	Body mass index	1.000000e-18
GCST001159_4	Restless legs syndrome	1.000000e-22
GCST001415_1	Body mass index	2.000000e-09
GCST001953_12	Obesity	6.000000e-13
GCST001953_57	Obesity	1.000000e-11
GCST002461_25	Body mass index	3.000000e-07
GCST002541_103	Menarche (age at onset)	2.000000e-13
GCST002701_14	Verbal declarative memory	1.000000e-06
GCST002759_29	Motion sickness	3.000000e-09
GCST002783_27	Body mass index	3.000000e-10
GCST002783_292	Body mass index	2.000000e-18
GCST002783_548	Body mass index	2.000000e-17
GCST002783_60	Body mass index	9.000000e-11
GCST004065_106	Waist circumference	5.000000e-09
GCST004065_82	Waist circumference	2.000000e-08
GCST004495_122	BMI (adjusted for smoking behaviour)	5.000000e-14
GCST004495_123	BMI (adjusted for smoking behaviour)	2.000000e-11
GCST004497_4	Body mass index (joint analysis main effects and smoking interaction)	4.000000e-13
GCST004497_5	Body mass index (joint analysis main effects and smoking interaction)	9.000000e-11
GCST004499_52	BMI in non-smokers	1.000000e-12
GCST004499_53	BMI in non-smokers	1.000000e-10
GCST004557_107	Body mass index	1.000000e-10
GCST004557_208	Body mass index	2.000000e-09
GCST004557_239	Body mass index	8.000000e-13
GCST004557_27	Body mass index	7.000000e-13
GCST004558_104	Body mass index (joint analysis main effects and physical activity interaction)	6.000000e-09
GCST004558_159	Body mass index (joint analysis main effects and physical activity interaction)	2.000000e-12
GCST004558_177	Body mass index (joint analysis main effects and physical activity interaction)	2.000000e-10
GCST004558_24	Body mass index (joint analysis main effects and physical activity interaction)	6.000000e-12

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004703	age at menarche
EFO:0004874	memory performance
EFO:0006805	word list delayed recall measurement
EFO:0006928	motion sickness
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004338	body weight
EFO:0004530	triglyceride measurement
EFO:0009819	comparative body size at age 10, self-reported

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4948 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

69 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 502,505 (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
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1173655	AFATINIB	4	15,144
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289601	LENVATINIB	4	8,784
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL180022	NERATINIB	4	9,404
CHEMBL1873475	IBRUTINIB	4	7,994
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2105717	CABOZANTINIB	4	11,177
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL554	LAPATINIB	4
CHEMBL939	GEFITINIB	4
CHEMBL1091644	LINSITINIB	3
CHEMBL2105728	CRENOLANIB	3
CHEMBL223360	LINIFANIB	3
CHEMBL274654	ORANTINIB	3
CHEMBL31965	CANERTINIB	3
CHEMBL3264002	AVUTOMETINIB	3
CHEMBL3544983	TESEVATINIB	3
CHEMBL377300	BRIVANIB	3

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — STE7 family

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

Ligand	Action	Affinity	Parameter
BIX02189	Inhibition	8.82	pIC50
BIX02188	Inhibition	8.37	pIC50

ChEMBL bioactivities

134 potent at pChembl≥5 of 137 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.80	Kd	0.16	nM	PLX-4720
9.05	Kd	0.888	nM	CHEMBL5653589
8.99	ED50	1.014	nM	CHEMBL5653589
8.89	Kd	1.3	nM	CHEMBL5415503
8.82	IC50	1.5	nM	CHEMBL2381342
8.74	Kd	1.8	nM	NINTEDANIB
8.60	Kd	2.5	nM	FORETINIB
8.55	Kd	2.8	nM	CHEMBL5193786
8.55	Kd	2.8	nM	DEFOSBARASERTIB
8.54	Kd	2.9	nM	STAUROSPORINE
8.48	Kd	3.3	nM	DASATINIB
8.37	IC50	4.3	nM	CHEMBL4303171
8.17	Kd	6.7	nM	CHEMBL5633837
8.15	Kd	7	nM	LESTAURTINIB
8.14	Kd	7.3	nM	CHEMBL1241674
8.13	Kd	7.4	nM	CHEMBL1908396
8.09	Kd	8.2	nM	BOSUTINIB
8.00	IC50	10.1	nM	STAUROSPORINE
7.60	IC50	25	nM	CHEMBL4635883
7.57	IC50	26.9	nM	STAUROSPORINE
7.50	Kd	32	nM	DOVITINIB
7.42	Kd	38	nM	CHEMBL4571241
7.39	Kd	41	nM	CRENOLANIB
7.39	IC50	40.4	nM	STAUROSPORINE
7.39	Kd	41	nM	R-406
7.34	Kd	46	nM	SUNITINIB
7.33	Kd	47	nM	AT-9283
7.33	Kd	47	nM	CHEMBL1474834
7.31	Kd	49	nM	VANDETANIB
7.28	Kd	52	nM	CHEMBL5925779
7.28	Kd	52	nM	CHEMBL6002416
7.28	Kd	52	nM	CHEMBL5951969
7.24	Kd	58	nM	CHEMBL3688339
7.24	Kd	58	nM	CHEMBL386051
7.22	Kd	60	nM	CANERTINIB
7.20	Kd	63	nM	NERATINIB
7.19	IC50	65	nM	STAUROSPORINE
7.13	Kd	74	nM	AST-487
7.12	Kd	75	nM	SU-014813
7.09	Kd	82	nM	BARASERTIB
7.06	Kd	88	nM	CHEMBL4098896
7.02	Kd	96	nM	ERLOTINIB
7.00	Kd	99	nM	CHEMBL1908395
6.92	Kd	120	nM	KW-2449
6.91	Kd	124	nM	CHEMBL3808844
6.85	Kd	140	nM	AXITINIB
6.84	Kd	146	nM	AEW-541
6.83	Kd	147	nM	AZD-7762
6.82	Kd	150	nM	CHEMBL3425865
6.80	Kd	160	nM	FORETINIB

PubChem BioAssay actives

122 with measured affinity, of 572 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
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl]propane-1-sulfonamide	624721: Binding constant for MEK5 kinase domain	kd	0.0002	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148687: Binding affinity to human MAP2K5 incubated for 45 mins by Kinobead based pull down assay	kd	0.0009	uM
N-[3-[2-[2-ethoxy-4-(4-methylpiperazin-1-yl)anilino]-7-oxo-8-[[(2R)-oxolan-2-yl]methyl]pyrido[2,3-d]pyrimidin-6-yl]phenyl]-3-(trifluoromethyl)benzamide	1988547: Binding affinity to MEK5 (unknown origin) assessed as dissociation constant by KINOME scan assay	kd	0.0013	uM
3-[N-[3-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-N,N-dimethyl-1H-indole-6-carboxamide	1567603: Inhibition of GST-tagged MEK5 (unknown origin) expressed in baculovirus expression system incubated for 90 mins by HTS assay	ic50	0.0015	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624721: Binding constant for MEK5 kinase domain	kd	0.0018	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624721: Binding constant for MEK5 kinase domain	kd	0.0025	uM
4-(3,6-dichloro-2-fluorobenzoyl)-N-(1-methylpyrazol-4-yl)-1H-pyrrole-2-carboxamide	1909535: Binding affinity to wild type human partial length MEK5 (L98 to P448 residues) expressed in mammalian expression system by Kinomescan binding assay	kd	0.0028	uM
2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide	624721: Binding constant for MEK5 kinase domain	kd	0.0028	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	624721: Binding constant for MEK5 kinase domain	kd	0.0029	uM
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide;hydrate	624721: Binding constant for MEK5 kinase domain	kd	0.0033	uM
3-[N-[3-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-1H-indole-6-carboxamide	1720300: Inhibition of MEK5 (unknown origin)	ic50	0.0043	uM
2-[2-methyl-5-[3-(3,4,5-trimethoxyphenyl)-2H-pyrazolo[3,4-b]pyridin-5-yl]anilino]ethanol	2137776: Binding affinity to human MEK5 assessed as dissociation constant by Adp-glo assay	kd	0.0067	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	624721: Binding constant for MEK5 kinase domain	kd	0.0070	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624721: Binding constant for MEK5 kinase domain	kd	0.0073	uM
1-[4-(6,7-dimethoxyquinolin-4-yl)oxy-2-methoxyphenyl]-3-[1-(1,3-thiazol-2-yl)ethyl]urea	624721: Binding constant for MEK5 kinase domain	kd	0.0074	uM
Bosutinib	624721: Binding constant for MEK5 kinase domain	kd	0.0082	uM
2-[(3S)-3-aminopiperidin-1-yl]-4-[[2,6-di(propan-2-yl)-4-pyridinyl]amino]pyrimidine-5-carboxamide	1668842: Inhibition of human MEK5 using ERK5 as substrate in presence of [gamma-33P]-ATP by hotspot kinase assay	ic50	0.0250	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	624721: Binding constant for MEK5 kinase domain	kd	0.0320	uM
N-[4-(6,7-dimethoxyquinazolin-4-yl)oxy-3-fluorophenyl]-6-ethyl-1,2-dimethyl-4-oxoquinoline-3-carboxamide	1626966: Binding affinity to human MEK5	kd	0.0380	uM
1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine	1425042: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0410	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624721: Binding constant for MEK5 kinase domain	kd	0.0410	uM
Sunitinib	624721: Binding constant for MEK5 kinase domain	kd	0.0460	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1425042: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0470	uM
6-(1,3-benzodioxol-5-yl)-N-methyl-N-[(2-methyl-1,3-thiazol-4-yl)methyl]quinazolin-4-amine	594092: Binding affinity to human Mek5	kd	0.0470	uM
Vandetanib	624721: Binding constant for MEK5 kinase domain	kd	0.0490	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425042: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0580	uM
6-(2,6-dichlorophenyl)-8-methyl-2-(3-methylsulfanylanilino)pyrido[2,3-d]pyrimidin-7-one	624721: Binding constant for MEK5 kinase domain	kd	0.0580	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	624721: Binding constant for MEK5 kinase domain	kd	0.0600	uM
Neratinib	624721: Binding constant for MEK5 kinase domain	kd	0.0630	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624721: Binding constant for MEK5 kinase domain	kd	0.0740	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	624721: Binding constant for MEK5 kinase domain	kd	0.0750	uM
2-[ethyl-[3-[4-[[5-[2-(3-fluoroanilino)-2-oxoethyl]-1H-pyrazol-3-yl]amino]quinazolin-7-yl]oxypropyl]amino]ethyl dihydrogen phosphate	1425042: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0820	uM
3-cyano-N-[2,4-difluoro-3-[2-(3-methoxy-1H-pyrazolo[5,4-b]pyridin-5-yl)ethynyl]phenyl]benzenesulfonamide	1486194: Binding affinity to partial length human MEK5 expressed in HEK293 cells by active-site-dependent competition assay	kd	0.0880	uM
Erlotinib	624721: Binding constant for MEK5 kinase domain	kd	0.0960	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624721: Binding constant for MEK5 kinase domain	kd	0.0990	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624721: Binding constant for MEK5 kinase domain	kd	0.1200	uM
N-[4-(6,7-dimethoxyquinolin-4-yl)oxy-3-fluorophenyl]-4-ethoxy-1-(4-fluoro-2-methylphenyl)pyrazole-3-carboxamide	2146581: Binding affinity to MAP2K5 in human Hs-578T cells	kd	0.1240	uM
Axitinib	624721: Binding constant for MEK5 kinase domain	kd	0.1400	uM
7-[3-(azetidin-1-yl)cyclobutyl]-5-(3-phenylmethoxyphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1425042: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.1460	uM
3-(carbamoylamino)-5-(3-fluorophenyl)-N-[(3S)-piperidin-3-yl]thiophene-2-carboxamide	1425042: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.1470	uM
4-[6-(3,4,5-trimethoxyphenyl)-[1,2]thiazolo[4,3-b]pyridin-3-yl]morpholine	1205959: Binding affinity to human MEK5	kd	0.1500	uM
7-dimethylphosphoryl-3-[2-[[(3S,5S)-5-fluoropiperidin-3-yl]amino]thieno[3,2-d]pyrimidin-4-yl]-1H-indole-6-carbonitrile	2092604: Inhibition of MAP2K5 (unknown origin) by discoverX kinomescan assay	ic50	0.1700	uM
3-[3-[N-[4-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-1H-indol-6-yl]-N-ethylprop-2-ynamide	1425042: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.1770	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	624721: Binding constant for MEK5 kinase domain	kd	0.1800	uM
Sorafenib	624721: Binding constant for MEK5 kinase domain	kd	0.1900	uM
Nilotinib	624721: Binding constant for MEK5 kinase domain	kd	0.1900	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624721: Binding constant for MEK5 kinase domain	kd	0.2000	uM
2-[(3S)-3-aminopiperidin-1-yl]-4-[3-(trifluoromethyl)anilino]pyrimidine-5-carboxamide	1668842: Inhibition of human MEK5 using ERK5 as substrate in presence of [gamma-33P]-ATP by hotspot kinase assay	ic50	0.2400	uM
Ibrutinib	1425042: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.2430	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	624721: Binding constant for MEK5 kinase domain	kd	0.2600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	4
Estradiol	affects expression, decreases expression, increases expression	4
bisphenol A	decreases expression, decreases methylation, increases methylation, affects cotreatment, increases expression	3
Valproic Acid	affects cotreatment, decreases expression	3
bisphenol S	increases expression, increases methylation, affects cotreatment	2
Arsenic	increases abundance, affects methylation, decreases expression	2
aristolochic acid I	decreases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
methylselenic acid	increases expression	1
afimoxifene	decreases response to substance	1
sodium arsenite	decreases expression, increases abundance	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	affects cotreatment, affects expression	1
manganese chloride	decreases expression, increases abundance	1
potassium chromate(VI)	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
cadmium acetate	increases expression	1
caffeic acid	affects cotreatment, decreases expression	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	decreases expression	1
perfluorooctane sulfonic acid	affects expression, affects cotreatment	1
4-methoxycinnamate methyl ester	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
trans-10,cis-12-conjugated linoleic acid	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
perfluorobutanesulfonic acid	affects expression, affects cotreatment	1
Resveratrol	increases expression, increases reaction	1

ChEMBL screening assays

207 unique, capped per target: 205 binding, 1 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1061190	Functional	Concentration-dependent inhibition of ERK5 phosphorylation shift in EGF-stimulated HeLa cells	The selectivity of protein kinase inhibitors: a further update. — Biochem J
CHEMBL1114904	Binding	Inhibition of MAP2K5 at 5 uM	Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors. — Bioorg Med Chem Lett
CHEMBL4124008	ADMET	Activation of MEK5 in EGF-stimulated human MDA-MB-231 cells assessed as increase in pERK5 levels preincubated for 30 mins followed by EGF stimulation measured after 15 mins by Western blot analysis relative to control	Structure activity relationships of anthranilic acid-based compounds on cellular and in vivo mitogen activated protein kinase-5 signaling pathways. — Bioorg Med Chem Lett

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_D7U5	Ubigene A-549 MAP2K5 KO	Cancer cell line	Male
CVCL_D8PW	Ubigene HCT 116 MAP2K5 KO	Cancer cell line	Male
CVCL_D9J5	Ubigene HEK293 MAP2K5 KO	Transformed cell line	Female
CVCL_E0H4	Ubigene HeLa MAP2K5 KO	Cancer cell line	Female
CVCL_SW47	HAP1 MAP2K5 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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