DAPK2

gene
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Also known as DRP-1MGC119312

Summary

DAPK2 (death associated protein kinase 2, HGNC:2675) is a protein-coding gene on chromosome 15q22.31, encoding Death-associated protein kinase 2 (Q9UIK4). Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy.

This gene encodes a protein that belongs to the serine/threonine protein kinase family. This protein contains a N-terminal protein kinase domain followed by a conserved calmodulin-binding domain with significant similarity to that of death-associated protein kinase 1 (DAPK1), a positive regulator of programmed cell death. Overexpression of this gene was shown to induce cell apoptosis. It uses multiple polyadenylation sites.

Source: NCBI Gene 23604 — RefSeq curated summary.

At a glance

  • GWAS associations: 9
  • Clinical variants (ClinVar): 86 total
  • Druggable target: yes — 13 molecules with ChEMBL bioactivity
  • MANE Select transcript: NM_014326

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:2675
Approved symbolDAPK2
Namedeath associated protein kinase 2
Location15q22.31
Locus typegene with protein product
StatusApproved
AliasesDRP-1, MGC119312
Ensembl geneENSG00000035664
Ensembl biotypeprotein_coding
OMIM616567
Entrez23604

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 3 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000261891, ENST00000457488, ENST00000557867, ENST00000558064, ENST00000558069, ENST00000558076, ENST00000558482, ENST00000559007, ENST00000559306, ENST00000559731, ENST00000559897, ENST00000561162, ENST00000612884, ENST00000908660, ENST00000908661, ENST00000943723, ENST00000943724

RefSeq mRNA: 20 — MANE Select: NM_014326 NM_001363730, NM_001384997, NM_001384998, NM_001384999, NM_001385000, NM_001395279, NM_001395281, NM_001395282, NM_001395283, NM_001395284, NM_001395285, NM_001395286, NM_001395287, NM_001395288, NM_001395289, NM_001395290, NM_001395291, NM_001395292, NM_001395293, NM_014326

CCDS: CCDS10188, CCDS86463

Canonical transcript exons

ENST00000457488 — 12 exons

ExonStartEnd
ENSE000012816146390703663908600
ENSE000034665416397142363971561
ENSE000034736526404017064040267
ENSE000034871726391210863912197
ENSE000035294186392955163929577
ENSE000035355966393923263939361
ENSE000035877356393040763930455
ENSE000035918926398353363983754
ENSE000036529426392481663924861
ENSE000036808926392594163926093
ENSE000036884296391190863911991
ENSE000039781126404629864046485

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 96.74.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.5947 / max 371.8702, expressed in 1025 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter IDTPM avgSamples expressed
1504473.59471025

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
right lobe of thyroid glandUBERON:000111996.74gold quality
left lobe of thyroid glandUBERON:000112095.73gold quality
right atrium auricular regionUBERON:000663195.28gold quality
thyroid glandUBERON:000204695.14gold quality
right lungUBERON:000216794.92gold quality
cardiac atriumUBERON:000208194.72gold quality
gastrocnemiusUBERON:000138894.65gold quality
muscle of legUBERON:000138394.01gold quality
hindlimb stylopod muscleUBERON:000425293.52gold quality
muscle organUBERON:000163091.51gold quality
type B pancreatic cellCL:000016991.39gold quality
olfactory bulbUBERON:000226491.25gold quality
upper lobe of left lungUBERON:000895291.25gold quality
heart left ventricleUBERON:000208490.56gold quality
upper lobe of lungUBERON:000894890.47gold quality
cardiac ventricleUBERON:000208290.33gold quality
bloodUBERON:000017890.26gold quality
heartUBERON:000094888.84gold quality
sural nerveUBERON:001548888.81gold quality
apex of heartUBERON:000209888.80gold quality
cardiac muscle of right atriumUBERON:000337987.57gold quality
left ventricle myocardiumUBERON:000656687.53silver quality
duodenumUBERON:000211487.36gold quality
hair follicleUBERON:000207387.11gold quality
lungUBERON:000204886.88gold quality
myocardiumUBERON:000234986.68gold quality
diaphragmUBERON:000110386.48gold quality
mucosa of transverse colonUBERON:000499186.27gold quality
buccal mucosa cellCL:000233686.10silver quality
skeletal muscle tissueUBERON:000113486.06gold quality

Single-cell (SCXA)

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

ExperimentMarker?Max mean expression
E-ANND-3yes14.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CTNNB1, E2F1, KLF6, RARA, SP1, SPI1, TCF7L2

miRNA regulators (miRDB)

59 targeting DAPK2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNAMax scoreAvg scoremiRNA target_count
HSA-MIR-7110-3P100.0073.182486
HSA-MIR-6873-3P100.0071.422626
HSA-MIR-450099.9972.722367
HSA-MIR-34A-5P99.9971.211784
HSA-MIR-449A99.9971.051776
HSA-MIR-453199.9969.703181
HSA-LET-7A-5P99.9872.291790
HSA-LET-7B-5P99.9872.311790
HSA-LET-7C-5P99.9872.291790
HSA-LET-7E-5P99.9872.291790
HSA-LET-7F-5P99.9872.561784
HSA-LET-7G-5P99.9872.371784
HSA-LET-7I-5P99.9872.371788
HSA-MIR-98-5P99.9872.331787
HSA-MIR-34C-5P99.9770.451577
HSA-MIR-449B-5P99.9770.261580
HSA-MIR-3605-5P99.9667.12932
HSA-MIR-9983-3P99.9471.483631
HSA-MIR-515-5P99.9269.822343
HSA-MIR-519E-5P99.9269.622358
HSA-MIR-7162-3P99.8968.161682
HSA-MIR-1211999.8768.351653
HSA-MIR-797899.8666.90856
HSA-MIR-6817-3P99.7968.352126
HSA-MIR-3059-5P99.7069.932491
HSA-MIR-509399.6769.262291
HSA-MIR-4649-3P99.5666.901783
HSA-MIR-1252-3P99.5567.712862
HSA-MIR-519D-5P99.4169.302057
HSA-MIR-4687-5P99.1466.26488

Literature-anchored findings (GeneRIF, showing 27)

  • High frequency of promoter hypermethylation of the death-associated protein-kinase gene in nasopharyngeal carcinoma and its detection in the peripheral blood of patients (PMID:11839660)
  • distinct methylation pattern in bladder cancer with frequent methylation of RARbeta, DAPK, E-cadherin, and p16. (PMID:11839665)
  • gene expression in colorectal and gastric cancer silenced by DNA methylation and histone deacetylation (PMID:12087472)
  • Results implicate a novel role for DAPK2 in the regulation of normal myelopoiesis. (PMID:17347302)
  • DAPK2 as a novel Sp1-dependent target gene for E2F1 and KLF6 in cell death response. (PMID:18521079)
  • beta-catenin-induced down-regulation of DAPk-2 represents a novel signaling mechanism by which beta-catenin promotes the survival of malignant epithelial cells (PMID:18957423)
  • Results showed that the inactivation of RASSF1A, RARbeta2 and DAP-Kinase by hypermethylation is a key step in NPC tumorigenesis and progression. (PMID:19221469)
  • DRP-1 and ZIPk most likely evolved from their ancient ancestor gene DAPk by two gene duplication events that occurred close to the emergence of vertebrates (PMID:21408167)
  • Sodium butyrate induced DAPK1/2 expression in human gastric cancer cells and this expression prompted apoptosis by decreasing FAK levels. (PMID:22160140)
  • DAPK2 is upregulated in uterosacral ligaments in pelvic organ prolapse (PMID:23700042)
  • The tumor suppressor gene DAPK2 is induced by the myeloid transcription factors PU.1 and C/EBPalpha during granulocytic differentiation but repressed by PML-RARalpha in APL. (PMID:24038216)
  • The defect in chemotaxis in DAPK2-inactive granulocytes is likely a result of reduced polarization of the cells, mediated by a lack of MLC phosphorylation, resulting in radial F-actin and pseudopod formation. (PMID:24163421)
  • DAPK2 is a novel kinase of mTORC1 and is a potential new member of this multiprotein complex, modulating mTORC1 activity and autophagy levels under stress and steady-state conditions. (PMID:25361081)
  • DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function (PMID:25741596)
  • miR-520h suppresses Death-associated protein kinase 2 (DAPK2) expression, as restoring DAPK2 abolished miR-520h-promoted drug resistance, and knockdown of DAPK2 mitigated cell death caused by the depletion of miR-520h. (PMID:25982274)
  • This study links adipocyte expression of an autophagy-regulating kinase, lysosome-mediated clearance and fat cell lipid accumulation; it demonstrates obesity-related attenuated autophagy in adipocytes, and identifies DAPK2 dependence in this regulation. (PMID:26038578)
  • DAPK2-induced apoptosis is negatively regulated by Akt and 14-3-3 proteins. (PMID:26047703)
  • that Death-associated protein kinase 2 effector functions are influenced by the protein’s subcellular localization (PMID:26483415)
  • This study suggests that miR-520g contributes to tumor progression and drug resistance by post-transcriptionally downregulating DAPK2 in patients with epithelial ovarian cancer (PMID:27049921)
  • Thyroid hormone promotes selective autophagy via induction of DAPK2-SQSTM1 cascade, which in turn protects hepatocytes from diethylnitrosamine-induced hepatotoxicity or carcinogenesis. (PMID:27653365)
  • study reveals a unique calmodulin-independent mechanism for DAPK2 activation, critical to its function as a novel downstream effector of AMPK in autophagy (PMID:29717115)
  • remission effect of DAPK2 on placental cell oxidative damage and apoptosis in HDCP via mTOR activation (PMID:30243997)
  • The intracellular signaling pathways that lead to Ser289 phosphorylation are mutually-exclusive and different for each kinase. In addition, Ser289 phosphorylation in fact enhances DAPK1 catalytic activity, similar to the effect on DAPK2. Thus, Ser289 phosphorylation activates both DAPK1 and DAPK2, but in response to different intracellular signaling pathways. (PMID:31116076)
  • miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2. (PMID:32244500)
  • Cigarette smoking induces aberrant N(6)-methyladenosine of DAPK2 to promote non-small cell lung cancer progression by activating NF-kappaB pathway. (PMID:34298122)
  • 14-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites. (PMID:34413451)
  • Exosomal miR-133a-3p Derived from BMSCs Alleviates Cerebral Ischemia-Reperfusion Injury via Targeting DAPK2. (PMID:36636640)

Cross-species orthologs

4 orthologs

OrganismSymbolGene ID
danio_reriodapk2aENSDARG00000061096
danio_reriodapk2bENSDARG00000103666
mus_musculusDapk2ENSMUSG00000032380
rattus_norvegicusDapk2ENSRNOG00000017332

Paralogs (4): MYLK (ENSG00000065534), NEXN (ENSG00000162614), DAPK3 (ENSG00000167657), DAPK1 (ENSG00000196730)

Protein

Protein identifiers

Death-associated protein kinase 2Q9UIK4 (reviewed: Q9UIK4)

Alternative names: DAP-kinase-related protein 1

All UniProt accessions (5): Q9UIK4, H0YKW8, H0YL86, H0YLP5, H0YMK1

UniProt curated annotations — full annotation on UniProt →

Function. Calcium/calmodulin-dependent serine/threonine kinase involved in multiple cellular signaling pathways that trigger cell survival, apoptosis, and autophagy. Regulates both type I apoptotic and type II autophagic cell death signals, depending on the cellular setting. The former is caspase-dependent, while the latter is caspase-independent and is characterized by the accumulation of autophagic vesicles. Acts as a mediator of anoikis and a suppressor of beta-catenin-dependent anchorage-independent growth of malignant epithelial cells. May play a role in granulocytic maturation. Regulates granulocytic motility by controlling cell spreading and polarization. Isoform 2 is not regulated by calmodulin. It can phosphorylate MYL9. It can induce membrane blebbing and autophagic cell death.

Subunit / interactions. Homodimer in its autoinhibited state. Active as monomer. Isoform 2 but not isoform 1 can interact with ATF4. Interacts with 14-3-3 proteins YWHAB, YWHAE, YWHAG, YWHAH, YWHAQ, YWHAZ and SFN; the interaction requires DAPK2 phosphorylation at Thr-369 and suppresses DAPK2 kinase activity and DAPK2-induced apoptosis.

Subcellular location. Cytoplasm. Cytoplasmic vesicle. Autophagosome lumen.

Tissue specificity. Expressed in neutrophils and eosinophils. Isoform 2 is expressed in embryonic stem cells (at protein level). Isoform 1 is ubiquitously expressed in all tissue types examined with high levels in heart, lung and skeletal muscle.

Post-translational modifications. Autophosphorylation at Ser-318 inhibits its catalytic activity. Dephosphorylated at Ser-318 in response to activated Fas and TNF receptors.

Activity regulation. Activated by Ca(2+)/calmodulin. Regulated by a double locking mechanism, involving autophosphorylation at Ser-318, calmodulin binding, and dimerization. In the inactive state, Ser-318 is phosphorylated, and the kinase is dimeric. Activation involves: dephosphorylation at Ser-318, release-of-autoinhibition mechanism where calmodulin binding induces a conformational change that relieves the steric block of the active site by the autoinhibitory domain, and generation of the monomeric active form of the kinase.

Domain organisation. The autoinhibitory domain sterically blocks the substrate peptide-binding site by making both hydrophobic and electrostatic contacts with the kinase core.

Induction. Up-regulated during granulocytic maturation.

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

Isoforms (2)

UniProt IDNamesCanonical?
Q9UIK4-11, Alphayes
Q9UIK4-22, Beta

RefSeq proteins (20): NP_001350659, NP_001371926, NP_001371927, NP_001371928, NP_001371929, NP_001382208, NP_001382210, NP_001382211, NP_001382212, NP_001382213, NP_001382214, NP_001382215, NP_001382216, NP_001382217, NP_001382218, NP_001382219, NP_001382220, NP_001382221, NP_001382222, NP_055141* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR000719Prot_kinase_domDomain
IPR008271Ser/Thr_kinase_ASActive_site
IPR011009Kinase-like_dom_sfHomologous_superfamily
IPR017441Protein_kinase_ATP_BSBinding_site

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 (60 total): helix 15, mutagenesis site 12, strand 11, modified residue 4, region of interest 4, turn 3, sequence variant 2, sequence conflict 2, binding site 2, chain 1, domain 1, splice variant 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

11 structures.

PDBMethodResolution (Å)
2A2AX-RAY DIFFRACTION1.47
1ZUZX-RAY DIFFRACTION1.91
1WRZX-RAY DIFFRACTION2
7A6YX-RAY DIFFRACTION2.5
7A6RX-RAY DIFFRACTION2.7
2CKEX-RAY DIFFRACTION2.8
1ZWSX-RAY DIFFRACTION2.9
6PAWX-RAY DIFFRACTION2.95
2A27X-RAY DIFFRACTION3
1WMKX-RAY DIFFRACTION3.6
1Z9XX-RAY DIFFRACTION3.93

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9UIK4-F186.410.74

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): 149 (proton acceptor)

Ligand- & substrate-binding residues (2): 29–37; 52

Post-translational modifications (4): 318, 349, 369, 299

Mutagenesis-validated functional residues (12):

PositionPhenotype
52loss of activity, apoptotic function and of autophosphorylation.
299–330loss of ca(2+)-calmodulin binding, increase in activity, loss of autophosphorylation.
299no effect on ca(2+)-calmodulin independent phosphorylation or apoptotic activity.
318loss of ca(2+)-calmodulin independent phosphorylation, increase in apoptotic activity.
318abolishes apoptotic activity.
320no effect on ca(2+)-calmodulin independent phosphorylation or apoptotic activity.
323no effect on ca(2+)-calmodulin independent phosphorylation or apoptotic activity.
329no effect on ca(2+)-calmodulin independent phosphorylation or apoptotic activity.
367no effect on interaction with ywhae.
368no effect on interaction with ywhae.
369interaction with ywhae is reduced.
370interaction with ywhae is increased.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

IDPathway
R-HSA-418889Caspase activation via Dependence Receptors in the absence of ligand

MSigDB gene sets: 244 (showing top): MORF_RAGE, GOBP_REGULATION_OF_AUTOPHAGY, MORF_FLT1, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, MODULE_45, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, MORF_ESR1, MODULE_16, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_LEUKOCYTE_CHEMOTAXIS, MODULE_118

GO Biological Process (12): protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), regulation of autophagy (GO:0010506), intracellular signal transduction (GO:0035556), regulation of apoptotic process (GO:0042981), positive regulation of apoptotic process (GO:0043065), anoikis (GO:0043276), protein autophosphorylation (GO:0046777), positive regulation of neutrophil chemotaxis (GO:0090023), neutrophil migration (GO:1990266), positive regulation of eosinophil chemotaxis (GO:2000424), regulation of intrinsic apoptotic signaling pathway (GO:2001242)

GO Molecular Function (10): protein serine/threonine kinase activity (GO:0004674), calmodulin binding (GO:0005516), ATP binding (GO:0005524), identical protein binding (GO:0042802), 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), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytoplasmic vesicle (GO:0031410), autophagosome lumen (GO:0034423), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

CategoryPathways
Caspase activation via extrinsic apoptotic signalling pathway1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
apoptotic process3
intracellular anatomical structure2
positive regulation of granulocyte chemotaxis2
protein kinase activity2
protein binding2
intracellular membrane-bounded organelle2
cellular anatomical structure2
cytoplasm2
phosphorylation1
protein modification process1
programmed cell death1
apoptotic signaling pathway1
execution phase of apoptosis1
autophagy1
regulation of catabolic process1
signal transduction1
regulation of programmed cell death1
regulation of apoptotic process1
positive regulation of programmed cell death1
protein phosphorylation1
neutrophil chemotaxis1
regulation of neutrophil chemotaxis1
positive regulation of neutrophil migration1
granulocyte migration1
eosinophil chemotaxis1
positive regulation of eosinophil migration1
regulation of eosinophil chemotaxis1
intrinsic apoptotic signaling pathway1
regulation of intracellular signal transduction1
regulation of apoptotic signaling pathway1
adenyl ribonucleotide binding1
purine ribonucleoside triphosphate binding1
nucleoside phosphate binding1
heterocyclic compound binding1
kinase activity1
phosphotransferase activity, alcohol group as acceptor1
catalytic activity, acting on a protein1
binding1
transferase activity, transferring phosphorus-containing groups1
catalytic activity1

Protein interactions and networks

STRING

1761 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
DAPK2CALML3P27482825
DAPK2CALML5Q9NZT1825
DAPK2CALML6Q8TD86813
DAPK2CALML4Q96GE6813
DAPK2CALM1P02593740
DAPK2BECN1Q14457736
DAPK2ATG14Q6ZNE5620
DAPK2UNC5BQ8IZJ1573
DAPK2VMP1Q96GC9529
DAPK2MGMTP16455510
DAPK2IFNGP01579507
DAPK2RASSF1Q9NS23507
DAPK2PIK3C3Q8NEB9503
DAPK2TMEM74Q96NL1496
DAPK2MIB1Q86YT6486
DAPK2MAP1LC3CQ9BXW4486

IntAct

21 interactions, top by confidence:

ABTypeScore
DAPK2FAM9Bpsi-mi:“MI:0915”(physical association)0.670
DAPK2DAPK2psi-mi:“MI:0915”(physical association)0.590
CCDC91DAPK2psi-mi:“MI:0915”(physical association)0.560
DAPK2YWHAEpsi-mi:“MI:0915”(physical association)0.400
SFNDAPK2psi-mi:“MI:0915”(physical association)0.400
Bub1PEX10psi-mi:“MI:0914”(association)0.350
RACGAP1STX18psi-mi:“MI:0914”(association)0.350
LLGL2RBBP6psi-mi:“MI:0914”(association)0.350
TUBGCP5DNAJC6psi-mi:“MI:0914”(association)0.350
KLC3KLC1psi-mi:“MI:0914”(association)0.350
SLKENSApsi-mi:“MI:0914”(association)0.350
DAPK2CCDC91psi-mi:“MI:0915”(physical association)0.000

BioGRID (20): DAPK2 (Biochemical Activity), FAM9B (Two-hybrid), DAPK2 (Affinity Capture-MS), DAPK2 (Affinity Capture-MS), DAPK2 (Affinity Capture-MS), DAPK2 (Affinity Capture-MS), DAPK2 (Affinity Capture-MS), TP73 (Affinity Capture-Western), ATG5 (Affinity Capture-Western), CCDC91 (Two-hybrid), DAPK2 (Proximity Label-MS), DAPK2 (Affinity Capture-MS), DAPK2 (Affinity Capture-MS), DAPK2 (Affinity Capture-Western), DAPK2 (Affinity Capture-MS)

ESM2 similar proteins: A8X6H4, O70150, O75582, P10665, P11275, P11798, P18652, P18653, P18654, P28583, P51812, Q13557, Q14012, Q15349, Q2HJF7, Q38869, Q38871, Q38872, Q39016, Q42396, Q54CY9, Q54SJ5, Q5F3L1, Q5R4K3, Q5RCC4, Q5ZKI0, Q63450, Q63531, Q6DEH3, Q6GLS4, Q6P2M8, Q6PFQ0, Q6PHZ2, Q7TPS0, Q869W6, Q8BW96, Q8IU85, Q8RWL2, Q8VDF3, Q91YS8

Diamond homologs: A0A509AFG4, A0A5K1K8H0, A2AAJ9, A2ZVI7, A4IFM7, A8C984, A8WXF6, B9FKW9, C0HKC8, C0HKC9, E9PT87, O02827, O43293, O44997, O54784, O62305, O70150, O75147, O80673, O88764, O94768, P07313, P08414, P11801, P13234, P15735, P18653, P20689, P29294, P31325, P34101, P43292, P53355, P53681, Q00168, Q00771, Q0KHT7, Q0V7M1, Q10KY3, Q14012

SIGNOR signaling

2 interactions.

AEffectBMechanism
DAPK2“down-regulates activity”DAPK2phosphorylation
DAPK2“down-regulates activity”RPTORphosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 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:

PathwayPartnersFoldFDR
Membrane Trafficking618.5×3e-05
Vesicle-mediated transport617.4×3e-05
Signaling by Rho GTPases514.2×5e-04
Signaling by Rho GTPases, Miro GTPases and RHOBTB3513.9×5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance61
Likely benign2
Benign3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3007 predictions. Top by Δscore:

VariantEffectΔscore
15:63911900:TTAC:Tdonor_loss1.0000
15:63911903:CCCA:Cdonor_gain1.0000
15:63911905:CA:Cdonor_loss1.0000
15:63911906:A:Cdonor_loss1.0000
15:63911987:GAAAG:Gacceptor_gain1.0000
15:63911988:AAAG:Aacceptor_gain1.0000
15:63911989:AAG:Aacceptor_gain1.0000
15:63911990:AG:Aacceptor_gain1.0000
15:63911992:C:CCacceptor_gain1.0000
15:63912002:C:CTacceptor_gain1.0000
15:63912128:A:ACdonor_gain1.0000
15:63912129:C:CCdonor_gain1.0000
15:63912134:T:TAdonor_gain1.0000
15:63939376:G:GCacceptor_gain1.0000
15:63968923:A:Tacceptor_gain1.0000
15:63983529:TCACA:Tdonor_loss1.0000
15:63983530:CA:Cdonor_loss1.0000
15:63983531:A:ACdonor_gain1.0000
15:63983531:AC:Adonor_loss1.0000
15:63983531:ACAG:Adonor_gain1.0000
15:63983532:C:CAdonor_gain1.0000
15:63983532:CA:Cdonor_gain1.0000
15:63983532:CAG:Cdonor_gain1.0000
15:63983532:CAGC:Cdonor_gain1.0000
15:63983532:CAGCT:Cdonor_gain1.0000
15:63983750:GGCCA:Gacceptor_gain1.0000
15:63983751:GCCA:Gacceptor_gain1.0000
15:63983751:GCCAC:Gacceptor_gain1.0000
15:63983752:CCA:Cacceptor_gain1.0000
15:63983752:CCAC:Cacceptor_gain1.0000

AlphaMissense

2472 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
15:63924824:A:GW284R1.000
15:63924824:A:TW284R1.000
15:63929569:C:TG214D1.000
15:63930408:A:GW211R1.000
15:63930408:A:TW211R1.000
15:63939236:A:CF193L1.000
15:63939236:A:TF193L1.000
15:63939238:A:GF193L1.000
15:63939249:C:TG189E1.000
15:63939291:G:TA175D1.000
15:63939302:G:CD171E1.000
15:63939302:G:TD171E1.000
15:63939303:T:AD171V1.000
15:63939303:T:CD171G1.000
15:63939303:T:GD171A1.000
15:63939304:C:GD171H1.000
15:63939353:G:CN154K1.000
15:63939353:G:TN154K1.000
15:63971423:C:AK151N1.000
15:63971423:C:GK151N1.000
15:63971427:A:GL150P1.000
15:63971430:T:AD149V1.000
15:63971470:C:AG136W1.000
15:63983691:C:AK52N1.000
15:63983691:C:GK52N1.000
15:63983745:A:CF34L1.000
15:63983745:A:TF34L1.000
15:63983747:A:GF34L1.000
15:63924822:C:AW284C0.999
15:63924822:C:GW284C0.999

dbSNP variants (sampled 300 via entrez): RS1000107348 (15:63935552 C>T), RS1000145543 (15:63918191 C>A,G,T), RS1000151449 (15:63926045 C>T), RS1000159768 (15:63957927 G>A), RS1000168350 (15:64032856 T>C), RS1000186708 (15:63999802 G>A), RS1000199066 (15:64022736 T>C), RS1000209320 (15:63954313 T>C), RS1000223287 (15:63937992 A>G), RS1000257474 (15:64028669 T>C), RS1000259669 (15:63971369 G>A), RS1000284577 (15:64010962 G>A), RS1000286353 (15:64045314 T>A), RS1000311443 (15:63965235 G>A,C), RS1000331546 (15:63923744 A>G)

Disease associations

OMIM: gene MIM:616567 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

StudyTraitp-value
GCST004068_48Venous thromboembolism adjusted for sickle cell variant rs77121243-T3.000000e-06
GCST004490_24Cerebrospinal fluid t-tau:AB1-42 ratio3.000000e-08
GCST004616_62Platelet distribution width6.000000e-10
GCST006904_4Cerebral amyloid deposition (PET imaging)1.000000e-06
GCST008403_12Arterial stiffness index1.000000e-06
GCST009507_6Triglyceride levels1.000000e-07
GCST010242_40HDL cholesterol levels4.000000e-15
GCST010250_2Systolic blood pressure x dichotomous lifestyle risk score interaction (2df test)3.000000e-06
GCST010251_1Systolic blood pressure x dichotomous lifestyle risk score interaction (1df test)5.000000e-07

EFO canonical traits (8, from GWAS)

EFO IDTrait name
EFO:0007708t-tau:beta-amyloid 1-42 ratio measurement
EFO:0007984platelet component distribution width
EFO:0007707cerebral amyloid deposition measurement
EFO:0004517arterial stiffness measurement
EFO:0004530triglyceride measurement
EFO:0004612high density lipoprotein cholesterol measurement
EFO:0006335systolic blood pressure
EFO:0010724lifestyle measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3123 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

13 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 116,167 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

MoleculeNamePhasePatents
CHEMBL1287853FEDRATINIB43,554
CHEMBL1789941RUXOLITINIB411,547
CHEMBL502835NINTEDANIB48,545
CHEMBL535SUNITINIB479,020
CHEMBL608533MIDOSTAURIN47,259
CHEMBL603469LESTAURTINIB3
CHEMBL91829RUBOXISTAURIN377
CHEMBL1721885SU-0148132363
CHEMBL475251R-4062762
CHEMBL513909BI-25362895
CHEMBL1908394GSK-46136411,093
CHEMBL1908397KW-24491622
CHEMBL259084MLN-805412,430

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Death-associated kinase (DAPK) family

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.

LigandMeasureValue
StaurosporineKD1.7 nM
PKC-412KD190 nM
3-(4-morpholin-4-ylpyrido[2,3]furo[2,4-b]pyrimidin-2-yl)phenolKD2400 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamideKD2600 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamideKD3500 nM

ChEMBL bioactivities

53 potent at pChembl≥5 of 55 total, top 44 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChemblTypeValueUnitMolecule
8.80Kd1.6nMSTAUROSPORINE
8.52Kd3nMSTAUROSPORINE
8.28IC505.21nMSTAUROSPORINE
8.26IC505.56nMSTAUROSPORINE
8.14IC507.25nMSTAUROSPORINE
8.00IC5010nMCHEMBL3103192
7.66IC5022nMCHEMBL4764610
7.54Kd29nMFEDRATINIB
7.47Kd34nMCHEMBL4465866
7.22Kd60nMCHEMBL4576489
7.21Kd62nMR-406
7.20Kd63nMLESTAURTINIB
7.10Kd79nMCHEMBL5303531
7.03Kd94nMCHEMBL1241674
7.01Kd97nMRUXOLITINIB
6.82Kd150nMSUNITINIB
6.77IC50170nMCHEMBL3799389
6.40Kd400nMSU-014813
6.35Kd450nMCHEMBL3921246
6.33Kd470nMSUNITINIB
6.24IC50570nMCHEMBL3797466
6.23IC50590nMCHEMBL3799585
6.21Kd610nMSP-600125
6.08IC50830nMCHEMBL513703
6.06Kd870nMTAE-684
6.05Kd890nMMIDOSTAURIN
6.03Kd930nMBI-2536
6.00IC501000nMTP-030-1
6.00IC501000nMTP-030-2
6.00IC501000nMTP-030n
5.96Kd1100nMCHEMBL464552
5.89Kd1300nMCHEMBL2425628
5.75Kd1800nMKW-2449
5.64IC502300nMCHEMBL3797480
5.60IC502512nMCHEMBL5549980
5.60Kd2500nMCHEMBL379218
5.58Kd2600nMRUBOXISTAURIN
5.57Kd2700nMPI-103
5.54Kd2900nMGSK-461364
5.51IC503070nMSULFURETIN
5.50Kd3200nMNINTEDANIB
5.47Kd3400nMCHEMBL1908395
5.20IC506340nMCHEMBL4087337
5.04Kd9100nMMLN-8054

PubChem BioAssay actives

50 with measured affinity, of 663 total; 36 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

CompoundAssayTypeValueUnit
(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-one435153: Binding constant for full-length DAPK2kd0.0016uM
N-[2-[2-aminoethyl(methyl)amino]-5-[[3-cyano-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl]amino]phenyl]acetamide1301624: Inhibition of Dapk2 (unknown origin) by quantitative PCRic500.0100uM
4-fluoro-2-methoxy-11-oxo-5-propan-2-yl-3-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]-6H-indolo[2,3-b]quinoline-8-carbonitrile1700701: Inhibition of human DAPK2ic500.0220uM
Fedratinib625077: Binding constant for DAPK2 kinase domainkd0.0290uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide1526172: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged DAPK2 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assaykd0.0340uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide1526172: Binding affinity to recombinant full-length N-terminal His-FLAG-GST-tagged DAPK2 (unknown origin) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assaykd0.0600uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one625077: Binding constant for DAPK2 kinase domainkd0.0620uM
(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-one507893: Binding affinity to DAPK2kd0.0630uM
2-[[1-(3-chlorophenyl)-4-oxo-5H-pyrazolo[5,4-d]pyrimidin-6-yl]sulfanyl]propanamide1966660: Binding affinity to DAPK2 (unknown origin) assessed as dissociation constantkd0.0790uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol625077: Binding constant for DAPK2 kinase domainkd0.0940uM
Ruxolitinib625077: Binding constant for DAPK2 kinase domainkd0.0970uM
Sunitinib435153: Binding constant for full-length DAPK2kd0.1500uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]cyclopropanecarboxamide1298196: Inhibition of DAPK2 (unknown origin)ic500.1700uM
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-carboxamide435153: Binding constant for full-length DAPK2kd0.4000uM
6-[[4-[(Z)-[2-(4-ethylphenyl)imino-3-methyl-4-oxo-1,3-thiazolidin-5-ylidene]methyl]-2-pyridinyl]amino]pyridine-3-carboxylic acid1323334: Binding affinity to human DAPK2 expressed in Escherichia coli BL21 cells incubated for 1 hr by active site directed binding competition assaykd0.4500uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]-3-methylbut-2-enamide1298196: Inhibition of DAPK2 (unknown origin)ic500.5700uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]butanamide1298196: Inhibition of DAPK2 (unknown origin)ic500.5900uM
14,15-diazatetracyclo[7.6.1.02,7.013,16]hexadeca-1(15),2,4,6,9(16),10,12-heptaen-8-one256651: Average Binding Constant for DAPK2; NA=Not Active at 10 uMkd0.6100uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]-2,2-dimethylpropanamide1298196: Inhibition of DAPK2 (unknown origin)ic500.8300uM
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-diamine625077: Binding constant for DAPK2 kinase domainkd0.8700uM
Midostaurin435153: Binding constant for full-length DAPK2kd0.8900uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide625077: Binding constant for DAPK2 kinase domainkd0.9300uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide625077: Binding constant for DAPK2 kinase domainkd1.1000uM
(4-hydroxypiperidin-1-yl)-[4-[[4-[4-(3-methylsulfonylpropoxy)indol-1-yl]pyrimidin-2-yl]amino]cyclohexyl]methanone769524: Binding affinity to DAPK2 (unknown origin)kd1.3000uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone625077: Binding constant for DAPK2 kinase domainkd1.8000uM
N-[2-hydroxy-3-(3-nitroso-1H-indol-2-yl)-1H-indol-5-yl]pentanamide1298196: Inhibition of DAPK2 (unknown origin)ic502.3000uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine625077: Binding constant for DAPK2 kinase domainkd2.5000uM
5-[4-[2-aminoethyl(ethyl)amino]-3-(1,2,4-triazol-4-yl)anilino]-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbonitrile2066655: Inhibition of human DAPK2 expressed in HEK293 cells incubated for 2 hrs by NanoBRET assayic502.5119uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione256651: Average Binding Constant for DAPK2; NA=Not Active at 10 uMkd2.6000uM
3-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenol435153: Binding constant for full-length DAPK2kd2.7000uM
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide625077: Binding constant for DAPK2 kinase domainkd2.9000uM
(2Z)-2-[(3,4-dihydroxyphenyl)methylidene]-6-hydroxy-1-benzofuran-3-one1446697: Inhibition of human DAPK2ic503.0700uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate625077: Binding constant for DAPK2 kinase domainkd3.2000uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride625077: Binding constant for DAPK2 kinase domainkd3.4000uM
(2Z)-2-[(3,4-dihydroxyphenyl)methylidene]-5-methoxy-1-benzofuran-3-one1446697: Inhibition of human DAPK2ic506.3400uM
4-[[9-chloro-7-(2,6-difluorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]benzoic acid625077: Binding constant for DAPK2 kinase domainkd9.1000uM

CTD chemical–gene interactions

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

ChemicalActions (top 5)PubMed papers
Tretinoinaffects binding, affects reaction, increases reaction, increases expression4
sodium arsenitedecreases expression, affects cotreatment, increases abundance3
Estradiolincreases expression, increases reaction3
Valproic Acidaffects cotreatment, decreases expression, increases methylation3
Aflatoxin B1decreases expression, decreases methylation3
Particulate Matterincreases abundance, decreases expression2
aristolochic acid Iincreases expression1
triphenyl phosphateaffects expression1
lead acetatedecreases expression1
trichostatin Aincreases expression1
perfluorooctanoic acidincreases expression1
benzo(e)pyreneincreases methylation1
aflatoxin B2decreases methylation1
cupric chloridedecreases expression1
bafilomycin Aaffects reaction, increases expression, increases reaction1
tamibaroteneincreases expression1
di-n-butylphosphoric acidaffects expression1
usnic acidincreases expression1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, decreases expression1
cacalolincreases expression1
dorsomorphindecreases expression, affects cotreatment1
jinfukangaffects cotreatment, decreases expression1
Bortezomibdecreases expression, increases response to substance1
Decitabineincreases expression1
Sunitinibincreases expression1
Arsenic Trioxideincreases cleavage, increases expression, affects reaction1
Vorinostataffects cotreatment, decreases expression1
Air Pollutantsdecreases expression, increases abundance1
Amiodaroneincreases expression1
Arsenicaffects cotreatment, decreases expression, increases abundance1

ChEMBL screening assays

185 unique, capped per target: 185 binding

Representative assays (with source publication via chembl_document):

Assay IDTypeDescriptionSource paper
CHEMBL1034094BindingInhibition of DAPK2 at 3 uMDiscovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

CellosaurusNameCategorySex
CVCL_SK33HAP1 DAPK2 (-)Cancer cell lineMale

Clinical trials (associated diseases)

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

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.