Human Gene DAPK1 (ENST00000469640.6) Description and Page Index
  Description: 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 deaths signal, 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. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death. (from UniProt P53355)
RefSeq Summary (NM_004938): Death-associated protein kinase 1 is a positive mediator of gamma-interferon induced programmed cell death. DAPK1 encodes a structurally unique 160-kD calmodulin dependent serine-threonine kinase that carries 8 ankyrin repeats and 2 putative P-loop consensus sites. It is a tumor suppressor candidate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013].
Gencode Transcript: ENST00000469640.6
Gencode Gene: ENSG00000196730.13
Transcript (Including UTRs)
   Position: hg38 chr9:87,497,681-87,708,633 Size: 210,953 Total Exon Count: 25 Strand: +
Coding Region
   Position: hg38 chr9:87,499,078-87,707,364 Size: 208,287 Coding Exon Count: 24 

Page IndexSequence and LinksUniProtKB CommentsMalaCardsCTDRNA-Seq Expression
Microarray ExpressionRNA StructureProtein StructureOther SpeciesGO AnnotationsmRNA Descriptions
PathwaysOther NamesMethods
Data last updated: 2019-09-04

-  Sequence and Links to Tools and Databases
 
Genomic Sequence (chr9:87,497,681-87,708,633)mRNA (may differ from genome)Protein (1364 aa)
Gene SorterGenome BrowserOther Species FASTAGene interactionsTable SchemaBioGPS
CGAPEnsemblExonPrimerGeneCardsHGNCLynx
MGIneXtProtPubMedReactomeStanford SOURCEUniProtKB
Wikipedia

-  Comments and Description Text from UniProtKB
  ID: DAPK1_HUMAN
DESCRIPTION: RecName: Full=Death-associated protein kinase 1; Short=DAP kinase 1; EC=2.7.11.1;
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 deaths signal, 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. Phosphorylates PIN1 resulting in inhibition of its catalytic activity, nuclear localization, and cellular function. Phosphorylates TPM1, enhancing stress fiber formation in endothelial cells. Phosphorylates STX1A and significantly decreases its binding to STXBP1. Phosphorylates PRKD1 and regulates JNK signaling by binding and activating PRKD1 under oxidative stress. Phosphorylates BECN1, reducing its interaction with BCL2 and BCL2L1 and promoting the induction of autophagy. Phosphorylates TSC2, disrupting the TSC1-TSC2 complex and stimulating mTORC1 activity in a growth factor-dependent pathway. Phosphorylates RPS6, MYL9 and DAPK3. Acts as a signaling amplifier of NMDA receptors at extrasynaptic sites for mediating brain damage in stroke. Cerebral ischemia recruits DAPK1 into the NMDA receptor complex and it phosphorylates GRINB at Ser-1303 inducing injurious Ca(2+) influx through NMDA receptor channels, resulting in an irreversible neuronal death.
FUNCTION: Isoform 2 cannot induce apoptosis but can induce membrane blebbing.
CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
COFACTOR: Magnesium.
ENZYME REGULATION: Activated by Ca(2+)/calmodulin. Regulated by a locking mechanism, involving autophosphorylation at Ser-308 and calmodulin binding. In the inactive state, Ser-308 is phosphorylated. Activation involves its dephosphorylation and a release-of-autoinhibition mechanism where binding of calmodulin induces a conformational change that relieves the steric block of the active site by the autoinhibitory domain. Activity is modulated by UNC5B and NTN1. UNC5B activates it by inhibiting the phosphorylation at Ser-308, whereas NTN1 inhibits UNC5B-mediated activation of DAPK1. Endoplasmic-stress activates by causing Ser- 308 dephosphorylation.
SUBUNIT: Interacts with KLHL20. Interacts (via death domain) with MAPK1 and MAPK3. Interacts with MAP1B (via N-terminus). Interacts (via death domain) with UNC5B (via death domain). Interacts with PRKD1 in an oxidative stress-regulated manner. Interacts with PIN1, PDCD6, BECN1, GRINB, TSC2 and STX1A. Interacts (via kinase domain) with DAPK3 (via kinase domain).
INTERACTION: P27361:MAPK3; NbExp=4; IntAct=EBI-358616, EBI-73995; O75340:PDCD6; NbExp=3; IntAct=EBI-358616, EBI-352915;
SUBCELLULAR LOCATION: Isoform 1: Cytoplasm. Cytoplasm, cytoskeleton. Note=Colocalizes with MAP1B in the microtubules and cortical actin fibers.
SUBCELLULAR LOCATION: Isoform 2: Cytoplasm. Cytoplasm, cytoskeleton.
TISSUE SPECIFICITY: Isoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas.
INDUCTION: Up-regulated following treatment with IFNG/IFN-gamma.
DOMAIN: The autoinhibitory domain sterically blocks the substrate peptide-binding site by making both hydrophobic and electrostatic contacts with the kinase core.
PTM: Ubiquitinated by the BCR(KLHL20) E3 ubiquitin ligase complex, leading to its degradation by the proteasome.
PTM: Removal of the C-terminal tail of isoform 2 (correponding to amino acids 296-337 of isoform 2) by proteolytic cleavage stimulates maximally its membrane-blebbing function.
PTM: In response to mitogenic stimulation (PMA or EGF), phosphorylated at Ser-289; phosphorylation suppresses DAPK1 pro- apoptotic function. Autophosphorylation at Ser-308 inhibits its catalytic activity. Phosphorylation at Ser-734 by MAPK1 increases its catalytic activity and promotes cytoplasmic retention of MAPK1. Endoplasmic-stress can cause dephosphorylation at Ser-308.
SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. DAP kinase subfamily.
SIMILARITY: Contains 10 ANK repeats.
SIMILARITY: Contains 1 death domain.
SIMILARITY: Contains 1 protein kinase domain.
SEQUENCE CAUTION: Sequence=AAP35581.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the C-terminal part; Sequence=CAA53712.1; Type=Frameshift; Positions=462, 464;
WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/dapk1/";

-  MalaCards Disease Associations
  MalaCards Gene Search: DAPK1
Diseases sorted by gene-association score: pediatric lymphoma (17), cervical squamous cell carcinoma (9), cervical cancer, somatic (9), cholecystitis (7), triple-receptor negative breast cancer (7), bladder cancer, somatic (7), mediastinal malignant lymphoma (6), mediastinal gray zone lymphoma (5), lung cancer (3), nasopharyngeal carcinoma (2), urinary bladder cancer (2)

-  Comparative Toxicogenomics Database (CTD)
  The following chemicals interact with this gene           more ... click here to view the complete list

-  RNA-Seq Expression Data from GTEx (53 Tissues, 570 Donors)
  Highest median expression: 26.39 RPKM in Ovary
Total median expression: 336.98 RPKM



View in GTEx track of Genome Browser    View at GTEx portal     View GTEx Body Map

+  Microarray Expression Data
  Press "+" in the title bar above to open this section.

-  mRNA Secondary Structure of 3' and 5' UTRs
 
RegionFold EnergyBasesEnergy/Base
Display As
5' UTR -277.70535-0.519 Picture PostScript Text
3' UTR -331.201269-0.261 Picture PostScript Text

The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.

-  Protein Domain and Structure Information
  InterPro Domains: Graphical view of domain structure
IPR002110 - Ankyrin_rpt
IPR020683 - Ankyrin_rpt-contain_dom
IPR000488 - Death
IPR020676 - Death-assoc_prot_kinase
IPR011029 - DEATH-like
IPR011009 - Kinase-like_dom
IPR020675 - Myosin_light_ch_kinase-rel
IPR000719 - Prot_kinase_cat_dom
IPR017441 - Protein_kinase_ATP_BS
IPR002290 - Ser/Thr_dual-sp_kinase_dom
IPR008271 - Ser/Thr_kinase_AS

Pfam Domains:
PF00023 - Ankyrin repeat
PF00531 - Death domain
PF00069 - Protein kinase domain

Protein Data Bank (PDB) 3-D Structure
MuPIT help

1IG1
- X-ray MuPIT

1JKK
- X-ray MuPIT

1JKL
- X-ray MuPIT
To conserve bandwidth, only the images from the first 3 structures are shown.
1JKS - X-ray MuPIT 1JKT - X-ray MuPIT 1P4F - X-ray MuPIT
1WVW - X-ray MuPIT 1WVX - X-ray MuPIT 1WVY - X-ray MuPIT
1YR5 - X-ray MuPIT 2W4J - X-ray MuPIT 2W4K - X-ray MuPIT
2X0G - X-ray MuPIT 2XUU - X-ray MuPIT 2XZS - X-ray MuPIT
2Y0A - X-ray MuPIT 2Y4P - X-ray MuPIT 2Y4V - X-ray MuPIT
2YAK - X-ray MuPIT 3DFC - X-ray MuPIT 3DGK - X-ray MuPIT
3EH9 - X-ray MuPIT 3EHA - X-ray MuPIT 3F5G - X-ray MuPIT
3F5U - X-ray MuPIT 3GU4 - X-ray MuPIT 3GU5 - X-ray MuPIT
3GU6 - X-ray MuPIT 3GU7 - X-ray MuPIT 3GU8 - X-ray MuPIT
3GUB - X-ray MuPIT 3ZXT - X-ray MuPIT


ModBase Predicted Comparative 3D Structure on P53355
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The pictures above may be empty if there is no ModBase structure for the protein. The ModBase structure frequently covers just a fragment of the protein. You may be asked to log onto ModBase the first time you click on the pictures. It is simplest after logging in to just click on the picture again to get to the specific info on that model.

-  Orthologous Genes in Other Species
  Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
MouseRatZebrafishD. melanogasterC. elegansS. cerevisiae
Genome BrowserGenome BrowserNo orthologNo orthologNo orthologNo ortholog
Gene Details     
Gene Sorter     
MGIRGD    
Protein SequenceProtein Sequence    
AlignmentAlignment    

-  Gene Ontology (GO) Annotations with Structured Vocabulary
  Molecular Function:
GO:0000166 nucleotide binding
GO:0004672 protein kinase activity
GO:0004674 protein serine/threonine kinase activity
GO:0004683 calmodulin-dependent protein kinase activity
GO:0005515 protein binding
GO:0005516 calmodulin binding
GO:0005524 ATP binding
GO:0005525 GTP binding
GO:0016301 kinase activity
GO:0016740 transferase activity
GO:0017075 syntaxin-1 binding
GO:0042802 identical protein binding

Biological Process:
GO:0006417 regulation of translation
GO:0006468 protein phosphorylation
GO:0006915 apoptotic process
GO:0007165 signal transduction
GO:0008625 extrinsic apoptotic signaling pathway via death domain receptors
GO:0010506 regulation of autophagy
GO:0010508 positive regulation of autophagy
GO:0016310 phosphorylation
GO:0017148 negative regulation of translation
GO:0035556 intracellular signal transduction
GO:0042981 regulation of apoptotic process
GO:0043066 negative regulation of apoptotic process
GO:0043280 positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
GO:0046777 protein autophosphorylation
GO:0071346 cellular response to interferon-gamma
GO:0071447 cellular response to hydroperoxide
GO:0097190 apoptotic signaling pathway
GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
GO:2000310 regulation of N-methyl-D-aspartate selective glutamate receptor activity

Cellular Component:
GO:0005737 cytoplasm
GO:0005856 cytoskeleton
GO:0005886 plasma membrane
GO:0015629 actin cytoskeleton


-  Descriptions from all associated GenBank mRNAs
  CR749834 - Homo sapiens mRNA; cDNA DKFZp781I035 (from clone DKFZp781I035).
KX533481 - UNVERIFIED: Homo sapiens Death-associated protein kinase 1-like (DAPK) mRNA, complete sequence.
AK296839 - Homo sapiens cDNA FLJ56562 complete cds, highly similar to Death-associated protein kinase 1 (EC 2.7.11.1).
AB208871 - Homo sapiens mRNA for Hypothetical protein DKFZp781I035 variant protein.
X76104 - H.sapiens DAP-kinase mRNA.
BC003614 - Homo sapiens mRNA similar to death-associated protein kinase 1 (cDNA clone IMAGE:2988875).
AK295119 - Homo sapiens cDNA FLJ60536 complete cds, highly similar to Death-associated protein kinase 1 (EC 2.7.11.1).
BC113660 - Homo sapiens death-associated protein kinase 1, mRNA (cDNA clone MGC:142220 IMAGE:8322712), complete cds.
BC143733 - Homo sapiens death-associated protein kinase 1, mRNA (cDNA clone MGC:177264 IMAGE:9052247), complete cds.
BC143759 - Homo sapiens death-associated protein kinase 1, mRNA (cDNA clone MGC:177290 IMAGE:9052273), complete cds.
BC143730 - Homo sapiens cDNA clone IMAGE:9052244.
KJ891027 - Synthetic construct Homo sapiens clone ccsbBroadEn_00421 DAPK1 gene, encodes complete protein.
AB385199 - Synthetic construct DNA, clone: pF1KB9239, Homo sapiens DAPK1 gene for death-associated protein kinase 1, complete cds, without stop codon, in Flexi system.
HQ258533 - Synthetic construct Homo sapiens clone IMAGE:100072962 death-associated protein kinase 1 (DAPK1) (DAPK1) gene, encodes complete protein.
BT006935 - Homo sapiens death-associated protein kinase 1 mRNA, complete cds.
JD462458 - Sequence 443482 from Patent EP1572962.
JD467487 - Sequence 448511 from Patent EP1572962.
JD125457 - Sequence 106481 from Patent EP1572962.
JD077318 - Sequence 58342 from Patent EP1572962.
AK127855 - Homo sapiens cDNA FLJ45958 fis, clone PLACE7011559, highly similar to Death-associated protein kinase 1 (EC 2.7.1.-).
EF090258 - Homo sapiens death-associated protein kinase beta (DAPK1) mRNA, partial cds.
JD484437 - Sequence 465461 from Patent EP1572962.
JD251527 - Sequence 232551 from Patent EP1572962.
JD499406 - Sequence 480430 from Patent EP1572962.
JD180476 - Sequence 161500 from Patent EP1572962.
JD373113 - Sequence 354137 from Patent EP1572962.
JD202761 - Sequence 183785 from Patent EP1572962.
JD520098 - Sequence 501122 from Patent EP1572962.
JD467940 - Sequence 448964 from Patent EP1572962.
JD235116 - Sequence 216140 from Patent EP1572962.
JD516297 - Sequence 497321 from Patent EP1572962.
JD229783 - Sequence 210807 from Patent EP1572962.

-  Biochemical and Signaling Pathways
  KEGG - Kyoto Encyclopedia of Genes and Genomes
hsa05200 - Pathways in cancer
hsa05219 - Bladder cancer

Reactome (by CSHL, EBI, and GO)

Protein P53355 (Reactome details) participates in the following event(s):

R-HSA-418849 DAPK binds UNC5B
R-HSA-418889 Ligand-independent caspase activation via DCC
R-HSA-5357769 Caspase activation via extrinsic apoptotic signalling pathway
R-HSA-109581 Apoptosis
R-HSA-5357801 Programmed Cell Death

-  Other Names for This Gene
  Alternate Gene Symbols: B7ZLD2, DAPK, DAPK1_HUMAN, KX533481, P53355, Q14CQ7, Q1W5W0, Q68CP8, Q6ZRZ3, Q9BTL8, uc064ucg.1
UCSC ID: uc064ucg.1
RefSeq Accession: NM_004938
Protein: P53355 (aka DAPK1_HUMAN or DAK1_HUMAN)
CCDS: CCDS43842.1

-  Methods, Credits, and Use Restrictions
  Click here for details on how this gene model was made and data restrictions if any.