MAPKAPK5

Summary

MAPKAPK5 (MAPK activated protein kinase 5, HGNC:6889) is a protein-coding gene on chromosome 12q24.12-q24.13, encoding MAP kinase-activated protein kinase 5 (Q8IW41). Tumor suppressor serine/threonine-protein kinase involved in mTORC1 signaling and post-transcriptional regulation.

The protein encoded by this gene is a tumor suppressor and member of the serine/threonine kinase family. In response to cellular stress and proinflammatory cytokines, this kinase is activated through its phosphorylation by MAP kinases including MAPK1/ERK, MAPK14/p38-alpha, and MAPK11/p38-beta. The encoded protein is found in the nucleus but translocates to the cytoplasm upon phosphorylation and activation. This kinase phosphorylates heat shock protein HSP27 at its physiologically relevant sites. Two alternately spliced transcript variants of this gene encoding distinct isoforms have been reported.

Source: NCBI Gene 8550 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurocardiofaciodigital syndrome (Strong, GenCC)
• GWAS associations: 10
• Clinical variants (ClinVar): 88 total — 6 pathogenic
• Phenotypes (HPO): 34
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003668

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6889
Approved symbol	MAPKAPK5
Name	MAPK activated protein kinase 5
Location	12q24.12-q24.13
Locus type	gene with protein product
Status	Approved
Aliases	PRAK, MK5
Ensembl gene	ENSG00000089022
Ensembl biotype	protein_coding
OMIM	606723
Entrez	8550

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 retained_intron, 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000546394, ENST00000547067, ENST00000547305, ENST00000547915, ENST00000549875, ENST00000550735, ENST00000551404, ENST00000552111, ENST00000553053, ENST00000602983

RefSeq mRNA: 11 — MANE Select: NM_003668 NM_001371479, NM_001371480, NM_001371481, NM_001371482, NM_001371483, NM_001371484, NM_001371485, NM_001371486, NM_001371487, NM_003668, NM_139078

CCDS: CCDS44975, CCDS44976

Canonical transcript exons

ENST00000550735 — 14 exons

Exon	Start	End
ENSE00001610970	111888885	111889000
ENSE00001727411	111868753	111868861
ENSE00001743986	111870271	111870360
ENSE00002429432	111842228	111842769
ENSE00003324103	111892967	111902222
ENSE00003327014	111871085	111871180
ENSE00003451946	111880447	111880527
ENSE00003460744	111890040	111890144
ENSE00003461085	111888488	111888618
ENSE00003466362	111885916	111886036
ENSE00003506902	111883581	111883768
ENSE00003551331	111865250	111865323
ENSE00003645648	111866156	111866231
ENSE00003684030	111867572	111867669

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 93.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.2808 / max 128.3385, expressed in 1809 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128052	13.9720	1806
128050	2.9143	1442
128051	1.3945	826

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	93.38	gold quality
mucosa of transverse colon	UBERON:0004991	92.50	gold quality
jejunal mucosa	UBERON:0000399	92.47	gold quality
transverse colon	UBERON:0001157	91.89	gold quality
colonic epithelium	UBERON:0000397	91.45	gold quality
gastrocnemius	UBERON:0001388	91.04	gold quality
ganglionic eminence	UBERON:0004023	90.89	gold quality
ventricular zone	UBERON:0003053	90.80	gold quality
body of pancreas	UBERON:0001150	90.76	gold quality
skin of leg	UBERON:0001511	90.74	gold quality
muscle of leg	UBERON:0001383	90.70	gold quality
skin of abdomen	UBERON:0001416	90.64	gold quality
left adrenal gland cortex	UBERON:0035825	90.60	gold quality
adrenal tissue	UBERON:0018303	90.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.45	gold quality
left adrenal gland	UBERON:0001234	90.43	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.33	gold quality
sural nerve	UBERON:0015488	90.27	gold quality
tibial nerve	UBERON:0001323	90.26	gold quality
left ovary	UBERON:0002119	90.22	gold quality
cortical plate	UBERON:0005343	90.11	gold quality
monocyte	CL:0000576	90.07	gold quality
right adrenal gland	UBERON:0001233	90.06	gold quality
tibial artery	UBERON:0007610	89.99	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.99	gold quality
popliteal artery	UBERON:0002250	89.98	gold quality
right ovary	UBERON:0002118	89.93	gold quality
upper lobe of left lung	UBERON:0008952	89.87	gold quality
calcaneal tendon	UBERON:0003701	89.86	gold quality
right adrenal gland cortex	UBERON:0035827	89.78	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.75

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PARP1

miRNA regulators (miRDB)

64 targeting MAPKAPK5, 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-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 22)

• results imply that MK5 is involved in Hsp27-controlled F-actin dynamics in response to activation of the cAMP-dependent protein kinase pathway. (PMID:19166925)
• Data defined a novel MK5 interaction motif (FRIEDE) within both ERK4 and ERK3 that is essential for binding to the C-terminal region of MK5. (PMID:19473979)
• Several binding motifs for heat shock factor are dispersed in the mouse and rat promoter, and temperature shock transiently enhanced the MAP-kinase-activated kinase 5 transcript levels. (PMID:19484198)
• This review discusses the different characteristics of regulating the activity and subcellular localization of MK5 and RSK1 by PKA and the functional implications of these interactions. (PMID:20849292)
• Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathway. (PMID:21177870)
• Rheb inactivation by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of mTORC1 (PMID:21336308)
• IGF2BP1 promotes the velocity and directionality of tumor-derived cell migration by determining the cytoplasmic fate of two novel target mRNAs: MAPK4 and PTEN (PMID:22279049)
• these results firstly demonstrate that MK5 is degraded in response to doxorubicin and negatively regulates doxorubicin-induced apoptosis, providing novel insights into the molecular mechanism of doxorubicin resistance in hepatoma cells. (PMID:23022185)
• study shows Tip60 plays an essential role in oncogenic ras-induced senescence; revealed a cascade of posttranslational modifications involving p38, Tip60 and PRAK, 3 proteins essential for ras-induced senescence; these modifications are critical for prosenescent function of Tip60 and PRAK (PMID:23685072)
• Studies with specific phosphoantibodies indicate that MK5 phosphorylates Hsp40/DnaJB1 in vivo at Ser-149 or/and Ser-151 and Ser-171 in the C-terminal domain of Hsp40/DnaJB1. (PMID:24309468)
• Data indicate that the structurally most flexible regions during molecular dynamics (MD) simulations of the native mitogen-activated protein kinase-activated protein kinase MK5 model were the loop regions. (PMID:24651460)
• Data highlight that DJ-1 is the downstream interacting target for PRAK, and in response to oxidative stress PRAK may exert a cytoprotective effect by facilitating DJ-1 to sequester Daxx in the nucleus, thus preventing cell death. (PMID:25383140)
• Plasma MAPKAPK5 protein was found to positively associate with the 10-year change in paired associates learning assessment in asymptomatic older twins. (PMID:26080319)
• PRAK might be a potential therapeutic target of Alzheimer’s disease involved in receptor for advanced glycation end products-mediated cell signaling induced by Abeta (PMID:26758977)
• MK5 is being discussed as a putative novel regulator of cardiac fibroblast function. (Review) (PMID:28941148)
• Study identified the serine/threonine kinase MK5 as a positive regulator of YAP. MK5 physically interacted with YAP and counteracted CK1delta/epsilon-mediated YAP ubiquitination and degradation independent of LATS1/2. MK5 upregulation was associated with high levels of YAP expression and poor prognosis in clinical tumor samples, confirming its important role for YAP activity in human cancer. (PMID:31578200)
• Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly. (PMID:33442026)
• TLK1-mediated MK5-S354 phosphorylation drives prostate cancer cell motility and may signify distinct pathologies. (PMID:35064619)
• MAPKAPK5-AS1 drives the progression of hepatocellular carcinoma via regulating miR-429/ZEB1 axis. (PMID:35468721)
• Expanding the novel MAPKAPK5-related developmental disorder’s genotype-phenotype correlation: Patient report and 19 months of follow-up. (PMID:35575217)
• The TTYH3/MK5 Positive Feedback Loop regulates Tumor Progression via GSK3-beta/beta-catenin signaling in HCC. (PMID:35844789)
• Consolidating the association of biallelic MAPKAPK5 pathogenic variants with a distinct syndromic neurodevelopmental disorder. (PMID:36581449)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapkapk5	ENSDARG00000028082
mus_musculus	Mapkapk5	ENSMUSG00000029454
drosophila_melanogaster	MAPk-Ak2	FBGN0013987

Paralogs (6): DCX (ENSG00000077279), MKNK1 (ENSG00000079277), MKNK2 (ENSG00000099875), MAPKAPK3 (ENSG00000114738), CAMK4 (ENSG00000152495), MAPKAPK2 (ENSG00000162889)

Protein

Protein identifiers

MAP kinase-activated protein kinase 5 — Q8IW41 (reviewed: Q8IW41)

Alternative names: p38-regulated/activated protein kinase

All UniProt accessions (4): Q8IW41, F8VRP2, R4GN33, R4GN93

UniProt curated annotations — full annotation on UniProt →

Function. Tumor suppressor serine/threonine-protein kinase involved in mTORC1 signaling and post-transcriptional regulation. Phosphorylates FOXO3, ERK3/MAPK6, ERK4/MAPK4, HSP27/HSPB1, p53/TP53 and RHEB. Acts as a tumor suppressor by mediating Ras-induced senescence and phosphorylating p53/TP53. Involved in post-transcriptional regulation of MYC by mediating phosphorylation of FOXO3: phosphorylation of FOXO3 leads to promote nuclear localization of FOXO3, enabling expression of miR-34b and miR-34c, 2 post-transcriptional regulators of MYC that bind to the 3’UTR of MYC transcript and prevent MYC translation. Acts as a negative regulator of mTORC1 signaling by mediating phosphorylation and inhibition of RHEB. Part of the atypical MAPK signaling via its interaction with ERK3/MAPK6 or ERK4/MAPK4: the precise role of the complex formed with ERK3/MAPK6 or ERK4/MAPK4 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPK (ERK3/MAPK6 or ERK4/MAPK4), ERK3/MAPK6 (or ERK4/MAPK4) is phosphorylated and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6 (or ERK4/MAPK4). Mediates phosphorylation of HSP27/HSPB1 in response to PKA/PRKACA stimulation, inducing F-actin rearrangement.

Subunit / interactions. Interacts with ERK3/MAPK6 and ERK4/MAPK4 (via FRIEDE motif); the interaction is direct. Interacts with YWHAE; the interaction prevents phosphorylation of HSP27/HSPB1 leading to disrupt F-actin polymerization. Interacts with SQSTM1.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed ubiquitously.

Post-translational modifications. Phosphorylated on Thr-182 ERK3/MAPK6 or ERK4/MAPK4; which is the regulatory phosphorylation site and is located on the T-loop/loop 12, leading to activation. Phosphorylation at Thr-182 by p38-alpha/MAPK14, p38-beta/MAPK11 is subject to debate. Phosphorylated at Ser-115 by PKA/PRKACA, leading to localization to the cytoplasm. Autophosphorylated.

Disease relevance. Neurocardiofaciodigital syndrome (NCFD) [MIM:619869] An autosomal recessive syndrome characterized by severe developmental delay, variable brain anomalies, congenital heart defects, dysmorphic facial features, and a distinctive type of synpolydactyly with a supernumerary hypoplastic digit between the fourth and fifth digits of the hands and/or feet. Other features include eye abnormalities, hearing impairment, and electroencephalogram anomalies. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated following phosphorylation at Thr-182 by p38-alpha/MAPK14, p38-beta/MAPK11, ERK2/MAPK1, ERK3/MAPK6, and ERK4/MAPK4. Activated by stress-related extracellular stimuli; such as H(2)O(2), arsenite, anisomycin TNF alpha and also PMA and the calcium ionophore A23187; but to a lesser extent. In vitro, activated by SQSTM1. Inhibited by diterpenoid alkaloid noroxoaconitine.

Induction. Directly regulated by MYC: expression is activated by MYC, suggesting the existence of a feedback regulatory loop.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IW41-1	1	yes
Q8IW41-2	2

RefSeq proteins (11): NP_001358408, NP_001358409, NP_001358410, NP_001358411, NP_001358412, NP_001358413, NP_001358414, NP_001358415, NP_001358416, NP_003659, NP_620777 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR027442	MAPKAPK_C	Homologous_superfamily
IPR050205	CDPK_Ser/Thr_kinases	Family

Pfam: PF00069

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 (20 total): mutagenesis site 5, modified residue 4, sequence variant 2, sequence conflict 2, binding site 2, chain 1, domain 1, splice variant 1, coiled-coil region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IW41-F1	78.84	0.39

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): 148 (proton acceptor)

Ligand- & substrate-binding residues (2): 28–36; 51

Post-translational modifications (4): 115, 182, 212, 354

Mutagenesis-validated functional residues (5):

Position	Phenotype
51	kinase defective mutant, abolishes activity.
182	no p38-beta/mapk11-induced activation.
182	mimicks phosphorylation state and induces constitutive protein kinase activity.
212	mimicks phosphorylation state and displays a slightly higher protein kinase activity.
337	induces constitutive protein kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation
R-HSA-162582	Signal Transduction
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5633007	Regulation of TP53 Activity
R-HSA-5683057	MAPK family signaling cascades
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli

MSigDB gene sets: 289 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_DENDRITE_DEVELOPMENT, GOBP_CHROMOSOME_ORGANIZATION, XU_HGF_TARGETS_REPRESSED_BY_AKT1_UP, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_TELOMERE_ORGANIZATION, GOBP_NEUROGENESIS, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_CELLULAR_SENESCENCE, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, PUJANA_CHEK2_PCC_NETWORK, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE

GO Biological Process (14): regulation of translation (GO:0006417), signal transduction (GO:0007165), Ras protein signal transduction (GO:0007265), negative regulation of TOR signaling (GO:0032007), positive regulation of telomere maintenance (GO:0032206), positive regulation of transcription by RNA polymerase II (GO:0045944), protein autophosphorylation (GO:0046777), positive regulation of dendritic spine development (GO:0060999), cellular senescence (GO:0090398), stress-induced premature senescence (GO:0090400), regulation of signal transduction by p53 class mediator (GO:1901796), MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), regulation of intracellular signal transduction (GO:1902531)

GO Molecular Function (14): p53 binding (GO:0002039), protein serine/threonine kinase activity (GO:0004674), calcium/calmodulin-dependent protein kinase activity (GO:0004683), MAP kinase kinase activity (GO:0004708), calmodulin binding (GO:0005516), ATP binding (GO:0005524), calcium-dependent protein serine/threonine kinase activity (GO:0009931), mitogen-activated protein kinase binding (GO:0051019), 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-10 pathways:

Category	Pathways
Cellular Senescence	1
MAPK family signaling cascades	1
Regulation of TP53 Activity	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Generic Transcription Pathway	1
Transcriptional Regulation by TP53	1
Signal Transduction	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cellular process	2
protein binding	2
protein kinase activity	2
protein serine/threonine kinase activity	2
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
small GTPase-mediated signal transduction	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
protein phosphorylation	1
positive regulation of developmental process	1
dendritic spine development	1
regulation of dendritic spine development	1
cellular response to stress	1
cellular senescence	1
signal transduction by p53 class mediator	1
regulation of intracellular signal transduction	1
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
regulation of signal transduction	1
intracellular signal transduction	1
MAPK cascade	1
protein serine/threonine/tyrosine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1

Protein interactions and networks

STRING

560 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPKAPK5	HSPB1	P04792	841
MAPKAPK5	HSPB2	Q16082	812
MAPKAPK5	MAPK6	Q16659	800
MAPKAPK5	HSPB3	Q12988	728
MAPKAPK5	YWHAE	P29360	523
MAPKAPK5	MAPK7	Q13164	505
MAPKAPK5	MAPK12	P53778	504
MAPKAPK5	DNAJB1	P25685	493
MAPKAPK5	TLK1	Q9UKI8	474
MAPKAPK5	TAB1	Q15750	463
MAPKAPK5	ATP7A	Q04656	453
MAPKAPK5	CDC25B	P30305	436
MAPKAPK5	CARD14	Q9BXL6	427
MAPKAPK5	RASGRP4	Q8TDF6	426
MAPKAPK5	PPM1A	P35813	423

IntAct

48 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
MAPK14	OBSL1	psi-mi:“MI:0914”(association)	0.790
AGER	MAPKAPK5	psi-mi:“MI:0915”(physical association)	0.660
AGER	MAPKAPK5	psi-mi:“MI:2364”(proximity)	0.660
AGER	MAPKAPK5	psi-mi:“MI:0403”(colocalization)	0.660
MAPK6	ECI2	psi-mi:“MI:0914”(association)	0.530
MAPKAPK5	TP53	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MAPKAPK5	HSPB1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MAPKAPK5	SRPK2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
SRPK1	MAPKAPK5	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MAPKAPK5	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
MAPKAPK5	HSPD1	psi-mi:“MI:0915”(physical association)	0.400
HMGB1	MAPKAPK5	psi-mi:“MI:0915”(physical association)	0.370
MAPKAPK5	LSR	psi-mi:“MI:0915”(physical association)	0.370
MAPKAPK5	CDCA8	psi-mi:“MI:0915”(physical association)	0.370
ZNF576	MAPKAPK5	psi-mi:“MI:0915”(physical association)	0.370
MAPKAPK5	TAB1	psi-mi:“MI:0915”(physical association)	0.370
MAPKAPK5	RPL13	psi-mi:“MI:0915”(physical association)	0.370
ZNF282	MAPKAPK5	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (85): MAPKAPK5 (Two-hybrid), TP53 (Biochemical Activity), MAPK9 (Co-localization), MAPK1 (Co-localization), EIF4EBP1 (Co-localization), HSPB1 (Biochemical Activity), MAPKAPK5 (Biochemical Activity), MAPKAPK5 (Affinity Capture-Western), HSPB1 (Affinity Capture-Western), HSPB1 (Biochemical Activity), MAPKAPK5 (Affinity Capture-MS), MAPKAPK5 (Affinity Capture-MS), MAPKAPK5 (Affinity Capture-MS), MAPKAPK5 (Two-hybrid), MAPKAPK5 (Reconstituted Complex)

ESM2 similar proteins: A2AQW0, A6NI28, A7MBL8, B2RQE8, F1LXF1, O08874, O35099, O54992, O88382, O94806, O94967, P11274, P15056, P28028, P34908, Q02241, Q04982, Q07139, Q15139, Q15542, Q16513, Q5R6M6, Q62101, Q641K1, Q6NRZ4, Q6P3Q6, Q6PAJ1, Q6PCS4, Q6ZN16, Q8BPM2, Q8BWW9, Q8CGF6, Q8CID0, Q8IVH8, Q8IW41, Q8K1Y2, Q8VDD9, Q8WWQ0, Q924I2, Q99683

Diamond homologs: A0A509AFG4, A0A509AQE6, A0A5K1K8H0, A2ZVI7, D2I3C6, O08605, O15075, O15865, O54992, O75582, O75676, O77708, P08413, P10665, P11275, P11798, P11801, P15791, P18652, P18653, P18654, P25323, P28582, P28652, P49137, P49138, P49139, P51812, P53683, P62345, Q06850, Q0V7M1, Q13554, Q13557, Q15349, Q15418, Q16644, Q18846, Q2HJF7, Q38868

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
MAPKAPK5	up-regulates	TP53	phosphorylation
MAPKAPK5	up-regulates	MAPK4	phosphorylation
MAPK1	up-regulates	MAPKAPK5	phosphorylation
MAPKAPK5	up-regulates	DNAJB1	phosphorylation
MAPKAPK5	“up-regulates activity”	PLA2G4A	phosphorylation
MAPKAPK5	“down-regulates activity”	RHEB	phosphorylation
TLK1	“up-regulates activity”	MAPKAPK5	phosphorylation
MAPK4	“up-regulates activity”	MAPKAPK5	phosphorylation
MAPK6	“up-regulates activity”	MAPKAPK5	phosphorylation
MAPKAPK5	“up-regulates activity”	JUN	phosphorylation
MAPKAPK5	“up-regulates activity”	FOXO3	phosphorylation
MAPKAPK5	“up-regulates activity”	PARK7	phosphorylation
SRC	“up-regulates quantity”	MAPKAPK5	phosphorylation
MAPKAPK5	“up-regulates activity”	FOXO1	phosphorylation
MAPK11	up-regulates	MAPKAPK5	phosphorylation
MAPK14	“up-regulates activity”	MAPKAPK5	phosphorylation
MAPKAPK5	up-regulates	TH	phosphorylation
MAPKAPK5	unknown	EEF2K	phosphorylation
MAPKAPK5	“up-regulates activity”	KALRN	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 35 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
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	5	23.8×	4e-04
Signaling by Interleukins	5	10.0×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein phosphorylation	6	12.3×	2e-03
intracellular signal transduction	7	8.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	0
Uncertain significance	52
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
1686938	NM_003668.4(MAPKAPK5):c.207_208dup (p.Ala70fs)	Pathogenic
1686939	NM_003668.4(MAPKAPK5):c.1077dup (p.Leu360fs)	Pathogenic
2502375	NM_003668.4(MAPKAPK5):c.1180C>T (p.Arg394Ter)	Pathogenic
2502376	NM_003668.4(MAPKAPK5):c.671del (p.Leu224fs)	Pathogenic
2502377	NM_003668.4(MAPKAPK5):c.1303C>T (p.Gln435Ter)	Pathogenic
2502378	NM_003668.4(MAPKAPK5):c.320G>T (p.Gly107Val)	Pathogenic

SpliceAI

2697 predictions. Top by Δscore:

Variant	Effect	Δscore
12:111842768:AGGTA:A	donor_loss	1.0000
12:111842770:G:GG	donor_gain	1.0000
12:111865319:GTTAG:G	donor_gain	1.0000
12:111865320:T:G	donor_gain	1.0000
12:111866148:A:AG	acceptor_gain	1.0000
12:111866149:A:G	acceptor_gain	1.0000
12:111866151:TCTA:T	acceptor_loss	1.0000
12:111866153:TA:T	acceptor_loss	1.0000
12:111866154:A:AG	acceptor_gain	1.0000
12:111866155:G:A	acceptor_loss	1.0000
12:111866155:G:GG	acceptor_gain	1.0000
12:111866155:GA:G	acceptor_gain	1.0000
12:111866155:GAGT:G	acceptor_gain	1.0000
12:111866155:GAGTC:G	acceptor_gain	1.0000
12:111866228:TGAGG:T	donor_loss	1.0000
12:111866229:G:GT	donor_gain	1.0000
12:111866229:GAG:G	donor_gain	1.0000
12:111866229:GAGGT:G	donor_loss	1.0000
12:111866230:AGG:A	donor_loss	1.0000
12:111866231:GGTAT:G	donor_loss	1.0000
12:111867566:TTTAA:T	acceptor_loss	1.0000
12:111867567:TTAA:T	acceptor_loss	1.0000
12:111867568:TAAGG:T	acceptor_loss	1.0000
12:111867569:AAGG:A	acceptor_loss	1.0000
12:111867570:AGGTA:A	acceptor_loss	1.0000
12:111868751:AG:A	acceptor_gain	1.0000
12:111868752:GG:G	acceptor_gain	1.0000
12:111871079:TTTCA:T	acceptor_loss	1.0000
12:111871080:TTCA:T	acceptor_loss	1.0000
12:111871082:CAGG:C	acceptor_loss	1.0000

AlphaMissense

3137 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:111865299:G:A	G29E	1.000
12:111865320:T:A	V36D	1.000
12:111866162:T:G	C39W	1.000
12:111866194:T:C	L50P	1.000
12:111866196:A:G	K51E	1.000
12:111866197:A:T	K51I	1.000
12:111866198:A:C	K51N	1.000
12:111866198:A:T	K51N	1.000
12:111870317:G:C	R147T	1.000
12:111870317:G:T	R147I	1.000
12:111870318:A:C	R147S	1.000
12:111870318:A:T	R147S	1.000
12:111870319:G:C	D148H	1.000
12:111870320:A:C	D148A	1.000
12:111870320:A:G	D148G	1.000
12:111870320:A:T	D148V	1.000
12:111870321:C:A	D148E	1.000
12:111870321:C:G	D148E	1.000
12:111870323:T:A	L149H	1.000
12:111870327:G:C	K150N	1.000
12:111870327:G:T	K150N	1.000
12:111870334:A:G	N153D	1.000
12:111870335:A:G	N153S	1.000
12:111870336:T:A	N153K	1.000
12:111870336:T:G	N153K	1.000
12:111870338:T:C	L154P	1.000
12:111871105:T:G	C168W	1.000
12:111871106:G:C	D169H	1.000
12:111871107:A:C	D169A	1.000
12:111871107:A:G	D169G	1.000

dbSNP variants (sampled 300 via entrez): RS1000102324 (12:111846556 C>G,T), RS1000122251 (12:111865630 G>A,C), RS1000219735 (12:111884697 G>A), RS1000278909 (12:111885942 G>T), RS1000306834 (12:111841570 C>A,G), RS1000387389 (12:111859556 G>A), RS1000416856 (12:111863591 G>A), RS1000552316 (12:111883242 G>A), RS1000628417 (12:111871973 A>G), RS1000680343 (12:111841187 C>T), RS1000752683 (12:111864721 G>C,T), RS1000780130 (12:111876798 T>C), RS1000828910 (12:111850918 G>A,T), RS1000847717 (12:111878367 A>G), RS1000960113 (12:111851116 T>C)

Disease associations

OMIM: gene MIM:606723 | disease phenotypes: MIM:619869

GenCC curated gene-disease

Disease	Classification	Inheritance
neurocardiofaciodigital syndrome	Strong	Autosomal recessive

Mondo (2): neurocardiofaciodigital syndrome (MONDO:0859247), syndromic disease (MONDO:0002254)

Orphanet (0):

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000341	Narrow forehead
HP:0000365	Hearing impairment
HP:0000518	Cataract
HP:0000543	Optic disc pallor
HP:0000639	Nystagmus
HP:0000647	Sclerocornea
HP:0001159	Syndactyly
HP:0001320	Cerebellar vermis hypoplasia
HP:0001508	Failure to thrive
HP:0001518	Small for gestational age
HP:0001631	Atrial septal defect
HP:0001636	Tetralogy of Fallot
HP:0001643	Patent ductus arteriosus
HP:0002079	Hypoplasia of the corpus callosum
HP:0002198	Dilated fourth ventricle
HP:0002280	Enlarged cisterna magna
HP:0002389	Cavum septum pellucidum
HP:0003577	Congenital onset
HP:0004322	Short stature
HP:0006956	Lateral ventricle dilatation
HP:0008070	Sparse hair
HP:0010442	Polydactyly
HP:0011220	Prominent forehead
HP:0011344	Severe global developmental delay

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST004131_54	Inflammatory bowel disease	2.000000e-09
GCST004132_84	Crohn’s disease	7.000000e-07
GCST004346_54	Psoriasis	2.000000e-08
GCST005329_1	Coffee consumption	2.000000e-16
GCST005951_1	Body mass index	4.000000e-12
GCST005951_75	Body mass index	2.000000e-11
GCST010988_503	Adult body size	2.000000e-08
GCST012044_4	Tea consumption	1.000000e-07
GCST90002397_211	Mean spheric corpuscular volume	3.000000e-12
GCST90016667_20	Spleen volume	1.000000e-140

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006782	cups of coffee per day measurement
EFO:0004340	body mass index
EFO:0010091	tea consumption measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013577	Syndrome	C23.550.288.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3094 (SINGLE PROTEIN), CHEMBL6066553 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 39,333 (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
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL297453	EPIGALOCATECHIN GALLATE	3	22,804
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
CHEMBL3704901	ZUNSEMETINIB	2	191
CHEMBL495727	AT-9283	2	1,376
CHEMBL1908397	KW-2449	1	622
CHEMBL259084	MLN-8054	1	2,430

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — MAPKAPK subfamily

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
compound 16 [PMID: 18945615]	Inhibition	7.62	pIC50
Galapagos MAPKAPK5 inhibitor D	Inhibition	7.43	pIC50
compound 16 [PMID: 17480064]	Inhibition	6.09	pIC50

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
Pyrrolopyridine, 16	IC50	8.5 nM
JMC502647 Compound 8	IC50	10 nM
3-chloro-4-[(3,5-difluoro-2-pyridinyl)methoxy]-1-[2-[2-(2-hydroxypropan-2-yl)pyrimidin-4-yl]-5-methyl-4-pyridinyl]-6-methylpyridin-2-one	IC50	21 nM	US-9115089: Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
Pyrrolopyridine, 9	IC50	66 nM
Pyrrolopyridine, 23	IC50	126 nM

ChEMBL bioactivities

144 potent at pChembl≥5 of 158 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	IC50	5	nM	CHEMBL1231206
8.10	Kd	8	nM	MLN-8054
8.00	Ki	10	nM	CHEMBL1978448
7.62	IC50	24	nM	CHEMBL461139
7.55	IC50	28	nM	CHEMBL461140
7.36	Kd	43.66	nM	CHEMBL5653589
7.33	ED50	46.98	nM	CHEMBL5653589
7.20	Ki	63.1	nM	CHEMBL1997129
7.20	Ki	63.1	nM	CHEMBL226403
7.20	Ki	63.1	nM	GW843682X
7.10	Ki	79.43	nM	CHEMBL1975138
7.09	IC50	81	nM	CHEMBL226403
7.06	IC50	88	nM	CHEMBL1956685
7.00	IC50	100	nM	CHEMBL226403
6.90	Ki	125.9	nM	CHEMBL539474
6.89	IC50	129	nM	STAUROSPORINE
6.85	IC50	140	nM	CHEMBL388566
6.83	IC50	148	nM	CHEMBL1956684
6.80	IC50	159	nM	CHEMBL1231206
6.80	IC50	160	nM	CHEMBL1231206
6.71	IC50	195	nM	CHEMBL1956682
6.70	Ki	199.5	nM	CHEMBL592030
6.68	IC50	210	nM	CHEMBL226471
6.64	IC50	227	nM	CHEMBL1956684
6.62	IC50	239	nM	CHEMBL1956574
6.60	Ki	251.2	nM	CHEMBL1966722
6.60	Ki	251.2	nM	CHEMBL226471
6.60	Ki	251.2	nM	CHEMBL1986328
6.59	IC50	258	nM	STAUROSPORINE
6.57	Kd	272	nM	CHEMBL3688339
6.57	Kd	270	nM	STAUROSPORINE
6.54	IC50	290	nM	CHEMBL1956686
6.53	IC50	295	nM	STAUROSPORINE
6.50	Ki	316.2	nM	CHEMBL1989805
6.49	IC50	327	nM	CHEMBL1956573
6.46	IC50	350	nM	CHEMBL5777804
6.41	IC50	390	nM	CHEMBL1956567
6.41	IC50	392	nM	CHEMBL1956570
6.40	Ki	398.1	nM	CHEMBL2006263
6.40	Ki	398.1	nM	CHEMBL2000832
6.40	Ki	398.1	nM	CHEMBL2004544
6.40	Ki	398.1	nM	CHEMBL1988173
6.40	Ki	398.1	nM	CHEMBL1973540
6.36	IC50	437	nM	CHEMBL1956573
6.35	IC50	445	nM	CHEMBL1956682
6.30	IC50	500	nM	CHEMBL225519
6.30	Ki	501.2	nM	CHEMBL1997349
6.23	Kd	589	nM	AT-9283
6.20	Ki	631	nM	CHEMBL1991429
6.20	Ki	631	nM	CHEMBL1975233

PubChem BioAssay actives

64 with measured affinity, of 2013 total; 43 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
(15R)-15-methyl-5-(6-methyl-3-pyridinyl)-11-thia-6,14,17-triazatetracyclo[8.8.0.02,7.012,18]octadeca-1(10),2(7),3,5,8,12(18)-hexaen-13-one	2167719: Inhibition of recombinant PRAK (unknown origin) expressed in Escherichia coli using KKKALSRQLSVAA as substrate incubated for 1 hr followed by substrate addition in presence of ATP	ic50	0.0050	uM
4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid	353638: Binding affinity to PRAK2	kd	0.0080	uM
6-[2-[(E)-2-[4-(morpholin-4-ylmethyl)phenyl]ethenyl]-4-pyridinyl]-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one	410059: Inhibition of MK5	ic50	0.0240	uM
6-[2-[(E)-2-[4-[2-(dimethylamino)ethoxy]phenyl]ethenyl]-4-pyridinyl]-3,7-dihydropyrrolo[2,3-d]pyrimidin-4-one	410059: Inhibition of MK5	ic50	0.0280	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148714: Binding affinity to human MAPKAPK5 incubated for 45 mins by Kinobead based pull down assay	kd	0.0437	uM
2-(2-quinolin-3-yl-4-pyridinyl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one	1799072: Kinase Selectivity Assay from Article 10.1021/jm0611004: “Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2).”	ic50	0.0810	uM
4-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]furan-2-carboxamide	648671: Inhibition of MAPKAPK5	ic50	0.0880	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	1715288: Inhibition of human MAPKAPK5 using KKLNRTLSVA as substrate by [gamma-33P]-ATP assay	ic50	0.1290	uM
2-(2-phenyl-4-pyridinyl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one	1799072: Kinase Selectivity Assay from Article 10.1021/jm0611004: “Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2).”	ic50	0.1400	uM
5-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]furan-3-carboxamide	648671: Inhibition of MAPKAPK5	ic50	0.1480	uM
5-[8-(4-morpholin-4-ylanilino)-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-2,3-dihydroisoindol-1-one	648671: Inhibition of MAPKAPK5	ic50	0.1950	uM
2-[2-(2-fluorophenyl)-4-pyridinyl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one	1799072: Kinase Selectivity Assay from Article 10.1021/jm0611004: “Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2).”	ic50	0.2100	uM
5-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]-2,3-dihydroisoindol-1-one	648671: Inhibition of MAPKAPK5	ic50	0.2390	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425067: 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	0.2720	uM
4-[8-[4-(4-methylpiperazin-1-yl)anilino]imidazo[1,2-a]pyrazin-5-yl]-1H-pyridin-2-one	648671: Inhibition of MAPKAPK5	ic50	0.2900	uM
4-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]thiophene-2-carboxamide	648670: Inhibition of MAPKAPK5 in synovial fibroblast from rheumatoid arthritis patient assessed as inhibition of TNF-alpha-induced MMP1 expression incubated for 30 mins prior to TNFalpha-challenge measured after 48 hrs by ELISA	ic50	0.3270	uM
4-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]-1H-pyridin-2-one	648671: Inhibition of MAPKAPK5	ic50	0.3900	uM
5-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]thiophene-2-carboxamide	648670: Inhibition of MAPKAPK5 in synovial fibroblast from rheumatoid arthritis patient assessed as inhibition of TNF-alpha-induced MMP1 expression incubated for 30 mins prior to TNFalpha-challenge measured after 48 hrs by ELISA	ic50	0.3920	uM
2-pyridin-4-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one	1799072: Kinase Selectivity Assay from Article 10.1021/jm0611004: “Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2).”	ic50	0.5000	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1425067: 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	0.5890	uM
(4S,6Z,9S,10S)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,15,17-tetraene-2,8-dione	553090: Inhibition of MK5 by TR-FRET based LanthaScreen assay	ic50	0.6400	uM
N-(4-morpholin-4-ylphenyl)-5-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-amine	648671: Inhibition of MAPKAPK5	ic50	0.8160	uM
N-(4-morpholin-4-ylphenyl)-5-(1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine	648671: Inhibition of MAPKAPK5	ic50	0.8290	uM
4-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]benzamide	648670: Inhibition of MAPKAPK5 in synovial fibroblast from rheumatoid arthritis patient assessed as inhibition of TNF-alpha-induced MMP1 expression incubated for 30 mins prior to TNFalpha-challenge measured after 48 hrs by ELISA	ic50	0.9140	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	507606: Binding affinity to MAPKAPK5	kd	0.9300	uM
[(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl] 3,4,5-trihydroxybenzoate	1420023: Inhibition of PRAK (unknown origin)	ic50	1.0000	uM
3-[3-[N-[4-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-1H-indol-6-yl]-N-ethylprop-2-ynamide	1425067: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.1140	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624923: Binding constant for MAPKAPK5 kinase domain	kd	1.2000	uM
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637107: Inhibition of full-length recombinant human His-tagged MAPKAPK5 expressed in baculovirus expression system by Z’-LYTE assay	ic50	1.4000	uM
N-(4-morpholin-4-ylphenyl)-5-(2H-triazol-4-yl)imidazo[1,2-a]pyrazin-8-amine	648671: Inhibition of MAPKAPK5	ic50	1.4900	uM
7,8-dichloro-9-methyl-1-oxospiro[2,4-dihydropyrido[3,4-b]indole-3,4’-piperidine]-4-carbonitrile	643955: Inhibition of MK5 using ATP as substrate	ic50	1.7000	uM
(E)-1-[6-[(3-acetyl-2,4,6-trihydroxy-5-methylphenyl)methyl]-5,7-dihydroxy-2,2-dimethylchromen-8-yl]-3-phenylprop-2-en-1-one	127098: Inhibition of p38-regulated activated kinase (PRAK)	ic50	1.9000	uM
2-fluoro-4-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]benzamide	648671: Inhibition of MAPKAPK5	ic50	2.3900	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	624923: Binding constant for MAPKAPK5 kinase domain	kd	2.8000	uM
2-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]-1,3-thiazole-5-carboxamide	648671: Inhibition of MAPKAPK5	ic50	2.8200	uM
Ruxolitinib	1425067: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.1180	uM
5-[8-(4-morpholin-4-ylanilino)imidazo[1,2-a]pyrazin-5-yl]-1,3-thiazole-2-carboxamide	648671: Inhibition of MAPKAPK5	ic50	3.2000	uM
3-[4-amino-7-[3-(azetidin-1-ylmethyl)cyclobutyl]pyrrolo[2,3-d]pyrimidin-5-yl]phenol	1291029: Inhibition of MAPKAPK5 (unknown origin) in presence of [gamma33P]ATP	ic50	3.7000	uM
4-[8-[4-(4-methylpiperazin-1-yl)anilino]-[1,2,4]triazolo[1,5-a]pyrazin-5-yl]-1H-pyridin-2-one	648671: Inhibition of MAPKAPK5	ic50	3.7300	uM
N-[(2R)-1-[[5-[(4-cyanophenyl)methyl]-1,3,4-thiadiazol-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-1-(trifluoromethyl)cyclohexane-1-carboxamide	1947508: Inhibition of human PRAK	ic50	8.6000	uM
4-[6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637107: Inhibition of full-length recombinant human His-tagged MAPKAPK5 expressed in baculovirus expression system by Z’-LYTE assay	ic50	9.6000	uM
5-[[6-chloro-5-(4-phenylphenyl)-1H-benzimidazol-2-yl]oxy]-2-methylbenzoic acid	1471634: Inhibition of full length recombinant human N-terminal His6-tagged PRAK expressed in baculovirus infected Sf21 cells	ic50	10.0000	uM
2-anilino-7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one	1336078: Inhibition of human recombinant full length His-tagged MAPKAPK5 expressed in baculovirus expression system	ic50	10.0000	uM

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	1
cinnamaldehyde	increases expression	1
beta-lapachone	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
epigallocatechin gallate	decreases activity	1
KN 62	decreases activity	1
KT 5823	decreases activity	1
rottlerin	decreases activity	1
CGP 52608	affects binding, increases reaction	1
U 0126	decreases activity	1
K 7174	increases expression	1
asparanin A	decreases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	increases methylation	1
Chelating Agents	affects binding, increases expression	1
Copper	increases expression, affects binding	1
Doxorubicin	decreases expression	1
Environmental Pollutants	affects expression	1
Methapyrilene	decreases methylation	1
Phthalic Acids	increases methylation	1
Valproic Acid	affects expression	1
Vinblastine	affects response to substance	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	increases expression	1
Paclitaxel	affects response to substance	1
Cadmium Chloride	decreases expression	1
Genistein	decreases expression	1

ChEMBL screening assays

425 unique, capped per target: 418 binding, 7 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004127	Binding	Inhibition of PRAK at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem
CHEMBL1963728	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: MAPKAPK5	PubChem BioAssay data set

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3AT	Abcam HEK293T MAPKAPK5 KO	Transformed cell line	Female
CVCL_D7US	Ubigene A-549 MAPKAPK5 KO	Cancer cell line	Male
CVCL_D8QC	Ubigene HCT 116 MAPKAPK5 KO	Cancer cell line	Male
CVCL_D9JV	Ubigene HEK293 MAPKAPK5 KO	Transformed cell line	Female
CVCL_E0HM	Ubigene HeLa MAPKAPK5 KO	Cancer cell line	Female
CVCL_SX07	HAP1 MAPKAPK5 (-) 1	Cancer cell line	Male
CVCL_XQ28	HAP1 MAPKAPK5 (-) 2	Cancer cell line	Male
CVCL_XQ29	HAP1 MAPKAPK5 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00027456	PHASE2	COMPLETED	Leptin to Treat Severe Insulin Resistance - Pilot Study
NCT00213447	Not specified	COMPLETED	T Cell Response in Hypersensitivity Syndrome
NCT02240888	Not specified	COMPLETED	Vaccination in Inflammatory Rheumatic Disease (VACCIMIL). The Impact of Antirheumatic Treatment on Antibody Response
NCT02526082	Not specified	ACTIVE_NOT_RECRUITING	Long-term Follow-up of the Helsinki Businessmen Study
NCT02637518	Not specified	UNKNOWN	Comprehensive Validation of Frailty Assessment Tools in Older Adults in Different Clinical and Social Settings
NCT02971072	Not specified	COMPLETED	Neurophysiology of Weakness and Exercise in Rotator Cuff Tendinopathy
NCT02974569	Not specified	COMPLETED	Improving Symptom Self-management in Adolescents & Young Adults With Cancer
NCT03265561	Not specified	COMPLETED	Spinal Infection Management With Structural Allograft
NCT04190342	Not specified	COMPLETED	Effects of a Traditional Chinese Exercise Program on Symptom Cluster in Breast Cancer Patients
NCT04874584	Not specified	COMPLETED	Culturally Tailored Nurse Coaching Study for Cancer Symptom Management
NCT04909489	Not specified	UNKNOWN	PDR and SKYD of Dyslipidemia’s Characteristics From the Oxidative Stress Enhancement Caused by Inhibition of Serine Metabolic Pathway
NCT05218122	Not specified	UNKNOWN	Characteristics of LKDS and PBSS of KOA Based on the Enhancement of Inflammatory Response by TGF-β/Smad Pathway Inhibited
NCT05266118	Not specified	COMPLETED	Patient Reported Symptoms the First Week After Intensive Care Unit Discharge and up to Hospital Discharge
NCT05321966	Not specified	COMPLETED	The Effect of Video Training on Symptom Burden Patients Undergoing Hemodialysis Treatment
NCT05818748	Not specified	UNKNOWN	Effect Of Virtual Reality Distraction on Symptom Control and Anxiety in Children With Leukemia
NCT05837988	Not specified	UNKNOWN	Construction of Symptom Network in Maintenance Hemodialysis Patients
NCT06143436	Not specified	UNKNOWN	TCM Constitution, Pattern Types, and Disease Factors in Primary Lung Cancer.
NCT06222008	Not specified	UNKNOWN	Study on Symptom Clusters During Chemotherapy in Ovarian Cancer Patients With Different Chinese Medicine Constitution
NCT06412107	Not specified	COMPLETED	Somatic Acupressure for Symptom Cluster Management in Breast Cancer Survivors
NCT06847360	Not specified	RECRUITING	Home-based Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) for IBS Pain
NCT07281300	Not specified	RECRUITING	Mindfulness-Oriented Respiratory Distress Symptom Intervention for Lung Cancer
NCT07315672	Not specified	RECRUITING	Acupressure for Cough in Lung Cancer Survivors
NCT07479654	Not specified	NOT_YET_RECRUITING	AI-Enabled Frailty Risk Prediction in Adult Congenital Heart Disease
NCT07495358	Not specified	NOT_YET_RECRUITING	Development and Usability Evaluation of a Knowledge Graph-Based Symptom Management System for Patients With Breast Cancer Undergoing Chemotherapy
NCT07576114	Not specified	RECRUITING	Comparison of Gluteal Muscle Activation and Core Strengthening in Dead Butt Syndrome Syndrome