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MGP000787

UniProt Annotations

Entry Information
Gene Namedeath-associated protein kinase 1
Protein EntryDAPK1_HUMAN
UniProt IDP53355
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=4; Name=1; Synonyms=Alpha; IsoId=P53355-1; Sequence=Displayed; Name=2; Synonyms=s-DAPK-1; IsoId=P53355-2; Sequence=VSP_042053, VSP_042054, VSP_042055; Name=3; Synonyms=Beta; IsoId=P53355-3; Sequence=VSP_042056; Name=4; IsoId=P53355-4; Sequence=VSP_054478; Note=No experimental confirmation available.;
Catalytic ActivityATP + a protein = ADP + a phosphoprotein.
CofactorName=Mg(2+); Xref=ChEBI:CHEBI:18420;
DomainThe autoinhibitory domain sterically blocks the substrate peptide-binding site by making both hydrophobic and electrostatic contacts with the kinase core.
Enzyme RegulationActivated 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. {ECO:0000269|PubMed:11579085, ECO:0000269|PubMed:15729359, ECO:0000269|PubMed:17056602}.
FunctionCalcium/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. Required together with DAPK3 for phosphorylation of RPL13A upon interferon-gamma activation which is causing RPL13A involvement in transcript- selective translation inhibition.
FunctionIsoform 2 cannot induce apoptosis but can induce membrane blebbing.
InductionUp-regulated following treatment with IFNG/IFN-gamma. {ECO:0000269|PubMed:7828849}.
InteractionSelf; NbExp=6; IntAct=EBI-358616, EBI-358616; Q14457:BECN1; NbExp=4; IntAct=EBI-358616, EBI-949378; Q9Y2M5:KLHL20; NbExp=11; IntAct=EBI-358616, EBI-714379; Q38SD2:LRRK1; NbExp=2; IntAct=EBI-358616, EBI-1050422; Q5S007:LRRK2; NbExp=2; IntAct=EBI-358616, EBI-5323863; P27361:MAPK3; NbExp=5; IntAct=EBI-358616, EBI-73995; O75340:PDCD6; NbExp=3; IntAct=EBI-358616, EBI-352915; P14618:PKM; NbExp=3; IntAct=EBI-358616, EBI-353408; P14618-1:PKM; NbExp=2; IntAct=EBI-358616, EBI-4304679;
PtmIn 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. {ECO:0000269|PubMed:11579085, ECO:0000269|PubMed:15616583, ECO:0000269|PubMed:15729359, ECO:0000269|PubMed:16213824, ECO:0000269|PubMed:17056602, ECO:0000269|PubMed:21406692}.
PtmRemoval of the C-terminal tail of isoform 2 (corresponding to amino acids 296-337 of isoform 2) by proteolytic cleavage stimulates maximally its membrane-blebbing function. {ECO:0000269|PubMed:18422656}.
PtmUbiquitinated by the BCR(KLHL20) E3 ubiquitin ligase complex, leading to its degradation by the proteasome. {ECO:0000269|PubMed:20389280}.
Sequence CautionSequence=AAP35581.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the C-terminal part.; Evidence={ECO:0000305}; Sequence=CAA53712.1; Type=Frameshift; Positions=462, 464; Evidence={ECO:0000305};
SimilarityBelongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. DAP kinase subfamily. {ECO:0000305}.
SimilarityContains 10 ANK repeats. {ECO:0000255|PROSITE- ProRule:PRU00023}.
SimilarityContains 1 death domain. {ECO:0000255|PROSITE- ProRule:PRU00064}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationIsoform 1: Cytoplasm. Cytoplasm, cytoskeleton. Note=Colocalizes with MAP1B in the microtubules and cortical actin fibers.
Subcellular LocationIsoform 2: Cytoplasm. Cytoplasm, cytoskeleton.
SubunitInteracts 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). {ECO:0000269|PubMed:11573098, ECO:0000269|PubMed:12730201, ECO:0000269|PubMed:14505650, ECO:0000269|PubMed:15367680, ECO:0000269|PubMed:15616583, ECO:0000269|PubMed:15729359, ECO:0000269|PubMed:16132846, ECO:0000269|PubMed:17703233, ECO:0000269|PubMed:18195017, ECO:0000269|PubMed:18974095, ECO:0000269|PubMed:19180116, ECO:0000269|PubMed:20389280, ECO:0000269|PubMed:21497122, ECO:0000269|Ref.35, ECO:0000269|Ref.36}.
Tissue SpecificityIsoform 2 is expressed in normal intestinal tissue as well as in colorectal carcinomas. {ECO:0000269|PubMed:18422656}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/DAPK1ID417ch9q21.html";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/dapk1/";
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