O43293 (DAPK3_HUMAN) Reviewed, UniProtKB/Swiss-Prot
Last modified May 1, 2013. Version 122. History...
Names and origin
|Protein names||Recommended name:|
Death-associated protein kinase 3
Short name=DAP kinase 3
Zipper-interacting protein kinase
|Organism||Homo sapiens (Human) [Reference proteome]|
|Taxonomic identifier||9606 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo|
|Sequence length||454 AA.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
Serine/threonine kinase which is involved in the regulation of apoptosis, autophagy, transcription, translation, actin cytoskeleton reorganization, cell motility, smooth muscle contraction, and mitosis, particularly cytokinesis. 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. Regulates myosin phosphorylation in both smooth muscle and non-muscle cells. In smooth muscle, regulates myosin either directly by phosphorylating MYL12B and MYL9 or through inhibition of smooth muscle myosin phosphatase (SMPP1M) via phosphorylation of PPP1R12A, and the inhibition of SMPP1M functions to enhance muscle responsiveness to Ca2+ and promote a contractile state. Enhances transcription from AR-responsive promoters in a hormone- and kinase-dependent manner. Phosphorylates STAT3 and enhances its transcriptional activity. Positively regulates the canonical Wnt/beta-catenin signaling through interaction with NLK and TCF7L2. Can disrupt the NLK-TCF7L2 complex thereby influencing the phosphorylation of TCF7L2 by NLK. Phosphorylates histone H3 on 'Thr-11' at centromeres during mitosis. Involved in the formation of promyelocytic leukemia protein nuclear body (PML-NB), one of many subnuclear domains in the eukaryotic cell nucleus, and which is involved in oncogenesis and viral infection. Phosphorylates RPL13A on 'Ser-77' upon interferon-gamma activation which is causing RPL13A release from the ribosome, its association with the GAIT complex and its subsequent involvement in transcript-selective translation inhibition. Ref.2 Ref.5 Ref.7 Ref.8 Ref.9 Ref.10 Ref.12 Ref.17 Ref.20 Ref.21 Ref.23 Ref.24
ATP + a protein = ADP + a phosphoprotein. Ref.2
Inhibited by pyridone 6 (K00225), a potent, ATP-competitive inhibitor. Phosphorylation at Thr-180, Thr-225 and Thr-265 is essential for activity. Oligomerization is required for full enzymatic activity. Ref.11 Ref.14 Ref.17
Monomer and homotrimer. Can also exist as homodimer or form heterodimers with ATF4. Homodimerization is required for activation segment autophosphorylation Both interactions require an intact leucine zipper domain and oligomerization is required for full enzymatic activity. Also binds to DAXX and PAWR, possibly in a ternary complex which plays a role in caspase activation. According to Ref.18, does not interact with PARW. Interacts with AATF, CDC5L, UBE2D1, UBE2D2 AND UBE2D3. Interacts with AR and this interaction is enhanced by AATF. Interacts (via leucine zipper) with TCP10L (via leucine zipper). Interacts (via kinase domain) with DAPK1 (via kinase domain). Interacts with STAT3, NLK and TCF7L2. Isoform 1 and isoform 2 can interact with myosin and PPP1R12A. Ref.5 Ref.7 Ref.9 Ref.11 Ref.12 Ref.13 Ref.18 Ref.20 Ref.21 Ref.23 Ref.24
Nucleus. Cytoplasm Ref.5 Ref.6 Ref.8 Ref.9 Ref.13 Ref.18 Ref.20 Ref.22. Nucleus › PML body. Chromosome › centromere. Cytoplasm › cytoskeleton › centrosome. Note: The phosphorylated form is anchored in the cytoplasm and/or prevented from being shuttled to the nucleus, whereas nuclear translocation or retention is maximal when it is not phosphorylated. Phosphorylation at Thr-299 promotes cytoplasmic localization. Relocates to the cytoplasm on binding PAWR where the complex appears to interact with actin filaments. Localizes to promyelocytic leukemia protein nuclear bodies (PML-NBs). Associated: with the centrosomes throughout the mitotic cell cycle, with the centromeres from prophase to anaphase and with the contractile ring during cytokinesis. Ref.5 Ref.6 Ref.8 Ref.9 Ref.13 Ref.18 Ref.20 Ref.22
Ubiquitinated. Ubiquitination mediated by the UBE2D3 E3 ligase does not lead to proteasomal degradation, but influences promyelocytic leukemia protein nuclear bodies (PML-NBs) formation in the nucleus.
The phosphorylation status is critical for: its intracellular localization, ability to oligomerize and its activity. The phosphorylated form is anchored in the cytoplasm and/or prevented from being shuttled to the nucleus, whereas nuclear translocation or retention is maximal when it is not phosphorylated. Phosphorylation increases the trimeric form, and its dephosphorylation shifts the equilibrium towards the monomeric form. Phosphorylation at Thr-180, Thr-225 and Thr-265 is essential for activity. Phosphorylation at Thr-299 promotes cytoplasmic localization. A species-specific loss of a key phosphorylation site in murine DAPK3 seems to direct it to the nucleus, while the presence of the Thr-299 site in human DAPK3 correlates with cytoplasmic localization. Both isoform 1 and isoform 2 can undergo autophosphorylation. Ref.5 Ref.9 Ref.11 Ref.14 Ref.16 Ref.17 Ref.22
The murine DAPK3 protein differs from the human ortholog, losing an important phosphorylation site and displaying distinct altered cellular localization. The murine protein localizes only to the nucleus while the human protein shows both nuclear and cytoplasmic localization. A different protein interaction capacity, with an important protein partner in the apoptosis pathway (PAWR), evolved in the murine system to maintain the basic membrane blebbing function in the apoptosis pathway.
Contains 1 protein kinase domain.
KM=6.2 µM for myosin (isoform 1)
KM=73 µM for MYL12B (isoform 2)
KM=10.4 µM for MYL12B (isoform 1)
Vmax=248 nmol/min/mg enzyme toward myosin (isoform 2)
Vmax=120 nmol/min/mg enzyme toward myosin (isoform 1)
Vmax=1.3 µmol/min/mg enzyme toward MYL12B (isoform 2)
Vmax=271 nmol/min/mg enzyme toward MYL12B (isoform 1)
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: O43293-1) |
Also known as: ZIPK-L;
This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
|Isoform 2 (identifier: O43293-2) |
Also known as: ZIPK-S;
The sequence of this isoform differs from the canonical sequence as follows:
313-322: LPPNNSYADF → ASPIVAPVDA
|Note: The internal splice site between exon 8 and the 3' UTR, which yields this truncated isoform, is non-canonical.|
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 454||454||Death-associated protein kinase 3||PRO_0000085914|
|Domain||13 – 275||263||Protein kinase|
|Nucleotide binding||19 – 27||9||ATP By similarity UniProtKB P53355|
|Region||161 – 204||44||Activation segment By similarity|
|Region||276 – 333||58||Interaction with AR|
|Region||278 – 311||34||Interaction with MYPT1|
|Region||395 – 454||60||Interaction with CDC5L By similarity|
|Region||427 – 441||15||Leucine-zipper|
|Active site||139||1||Proton acceptor By similarity UniProtKB P53355|
|Binding site||42||1||ATP Probable UniProtKB P53355|
Amino acid modifications
|Modified residue||50||1||Phosphoserine; by autocatalysis Ref.11|
|Modified residue||180||1||Phosphothreonine Ref.14 Ref.17|
|Modified residue||225||1||Phosphothreonine Ref.14|
|Modified residue||265||1||Phosphothreonine; by autocatalysis and ROCK1 Ref.11 Ref.14 Ref.16 Ref.17|
|Modified residue||299||1||Phosphothreonine; by autocatalysis, DAPK1 and ROCK1 Ref.9 Ref.14 Ref.17 Ref.22|
|Modified residue||306||1||Phosphothreonine; by autocatalysis Ref.14|
|Modified residue||309||1||Phosphoserine; by DAPK1 Ref.9|
|Modified residue||311||1||Phosphoserine; by autocatalysis and DAPK1 Ref.9 Ref.14|
|Modified residue||312||1||Phosphoserine; by DAPK1 Ref.9|
|Modified residue||318||1||Phosphoserine; by DAPK1 Ref.9|
|Modified residue||326||1||Phosphoserine; by DAPK1 Ref.9|
|Alternative sequence||313 – 322||10||LPPNNSYADF → ASPIVAPVDA in isoform 2.||VSP_042059|
|Alternative sequence||323 – 454||132||Missing in isoform 2.||VSP_042060|
|Natural variant||112||1||T → M in a colorectal adenocarcinoma sample; somatic mutation. Ref.26||VAR_040438|
|Natural variant||161||1||D → N in an ovarian mucinous carcinoma sample; somatic mutation. Ref.26||VAR_040439|
|Natural variant||216||1||P → S in a lung neuroendocrine carcinoma sample; somatic mutation. Ref.26||VAR_040440|
|Mutagenesis||42||1||K → A: Loss of kinase activity at low concentrations of ATP. Ref.17|
|Mutagenesis||161||1||D → A: Loss of kinase activity. Ref.17|
|Mutagenesis||225||1||T → A: Loss of kinase activity. Ref.17|
|Mutagenesis||265||1||T → A: Loss of phosphorylation by ROCK1, catalytically inactive. Ref.17|
|Mutagenesis||299||1||T → A: Loss of phosphorylation by ROCK1. Ref.17|
Helix Strand Turn
|Helix||9 – 12||4|
|Beta strand||13 – 21||9|
|Beta strand||23 – 32||10|
|Turn||33 – 35||3|
|Beta strand||38 – 46||9|
|Helix||49 – 51||3|
|Beta strand||53 – 56||4|
|Helix||58 – 70||13|
|Beta strand||79 – 84||6|
|Beta strand||86 – 94||9|
|Helix||101 – 108||8|
|Helix||113 – 132||20|
|Helix||142 – 144||3|
|Beta strand||145 – 148||4|
|Beta strand||150 – 154||5|
|Beta strand||157 – 159||3|
|Helix||181 – 183||3|
|Helix||186 – 189||4|
|Helix||197 – 212||16|
|Helix||222 – 230||9|
|Helix||238 – 241||4|
|Helix||246 – 253||8|
|Helix||260 – 262||3|
|Helix||266 – 271||6|
|Helix||273 – 280||8|
|||"ZIP kinase, a novel serine/threonine kinase which mediates apoptosis."|
Kawai T., Matsumoto M., Takeda K., Sanjo H., Akira S.
Mol. Cell. Biol. 18:1642-1651(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
|||"ZIP kinase identified as a novel myosin regulatory light chain kinase in HeLa cells."|
Murata-Hori M., Suizu F., Iwasaki T., Kikuchi A., Hosoya H.
FEBS Lett. 451:81-84(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
Tissue: Cervix carcinoma.
|||"Complete sequencing and characterization of 21,243 full-length human cDNAs."|
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
|||"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."|
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
|||"Novel ZIP kinase isoform lacks leucine zipper."|
Takamoto N., Komatsu S., Komaba S., Niiro N., Ikebe M.
Arch. Biochem. Biophys. 456:194-203(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 165-454 (ISOFORM 2), ALTERNATIVE SPLICING, FUNCTION IN PHOSPHORYLATION OF MYOSIN; PPP1R12A AND MYL12B, SUBCELLULAR LOCATION, BIOPHYSICOCHEMICAL PROPERTIES, INTERACTION WITH PPP1R12A AND MYOSIN, AUTOPHOSPHORYLATION, TISSUE SPECIFICITY.
Tissue: Urinary bladder.
|||"DAP-like kinase, a member of the death-associated protein kinase family, associates with centrosomes, centromers, and the contractile ring during mitosis."|
Preuss U., Bierbaum H., Buchenau P., Scheidtmann K.H.
Eur. J. Cell Biol. 82:447-459(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
|||"ZIP kinase triggers apoptosis from nuclear PML oncogenic domains."|
Kawai T., Akira S., Reed J.C.
Mol. Cell. Biol. 23:6174-6186(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH DAXX AND PAWR.
|||"Novel mitosis-specific phosphorylation of histone H3 at Thr11 mediated by Dlk/ZIP kinase."|
Preuss U., Landsberg G., Scheidtmann K.H.
Nucleic Acids Res. 31:878-885(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
|||"Death-associated protein kinase phosphorylates ZIP kinase, forming a unique kinase hierarchy to activate its cell death functions."|
Shani G., Marash L., Gozuacik D., Bialik S., Teitelbaum L., Shohat G., Kimchi A.
Mol. Cell. Biol. 24:8611-8626(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, PHOSPHORYLATION AT THR-299; SER-309; SER-311; SER-312; SER-318 AND SER-326, INTERACTION WITH DAPK1, SUBCELLULAR LOCATION.
|||"DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression."|
Mukhopadhyay R., Ray P.S., Arif A., Brady A.K., Kinter M., Fox P.L.
Mol. Cell 32:371-382(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
|||"Activation segment dimerization: a mechanism for kinase autophosphorylation of non-consensus sites."|
Pike A.C., Rellos P., Niesen F.H., Turnbull A., Oliver A.W., Parker S.A., Turk B.E., Pearl L.H., Knapp S.
EMBO J. 27:704-714(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 9-289 IN COMPLEX WITH PYRIDONE 6, ENZYME REGULATION, SUBUNIT, PHOSPHORYLATION AT SER-50 AND THR-265.
|||"Physical and functional interactions between STAT3 and ZIP kinase."|
Sato N., Kawai T., Sugiyama K., Muromoto R., Imoto S., Sekine Y., Ishida M., Akira S., Matsuda T.
Int. Immunol. 17:1543-1552(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN PHOSPHORYLATION OF STAT3, INTERACTION WITH STAT3.
|||"TCP10L is expressed specifically in spermatogenic cells and binds to death associated protein kinase-3."|
Yu H., Jiang D., Guo Z., Saiyin H., Guo J., Wang X., Yu L.
Int. J. Androl. 28:163-170(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TCP10L, SUBCELLULAR LOCATION.
|||"Regulation of zipper-interacting protein kinase activity in vitro and in vivo by multisite phosphorylation."|
Graves P.R., Winkfield K.M., Haystead T.A.
J. Biol. Chem. 280:9363-9374(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-180; THR-225; THR-265; THR-299; THR-306 AND SER-311, ENZYME REGULATION.
|||"The death-associated protein kinases: structure, function, and beyond."|
Bialik S., Kimchi A.
Annu. Rev. Biochem. 75:189-210(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON FUNCTION.
|||"Phosphorylation of threonine-265 in zipper-interacting protein kinase plays an important role in its activity and is induced by IL-6 family cytokines."|
Sato N., Kamada N., Muromoto R., Kawai T., Sugiyama K., Watanabe T., Imoto S., Sekine Y., Ohbayashi N., Ishida M., Akira S., Matsuda T.
Immunol. Lett. 103:127-134(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-265.
|||"ROCK1 phosphorylates and activates zipper-interacting protein kinase."|
Hagerty L., Weitzel D.H., Chambers J., Fortner C.N., Brush M.H., Loiselle D., Hosoya H., Haystead T.A.
J. Biol. Chem. 282:4884-4893(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, ENZYME REGULATION, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT THR-180; THR-265 AND THR-299, MUTAGENESIS OF LYS-42; ASP-161; THR-225; THR-265 AND THR-299.
|||"ZIPK: a unique case of murine-specific divergence of a conserved vertebrate gene."|
Shoval Y., Pietrokovski S., Kimchi A.
PLoS Genet. 3:1884-1893(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, ABSENCE OF INTERACTION WITH PARW.
|||"Dlk/ZIP kinase, a novel Ser/Thr-specific protein kinase with multiple functions."|
Signal Transduct. 7:248-259(2007)
Cited for: REVIEW ON FUNCTION.
|||"Physical and functional interactions between ZIP kinase and UbcH5."|
Ohbayashi N., Okada K., Kawakami S., Togi S., Sato N., Ikeda O., Kamitani S., Muromoto R., Sekine Y., Kawai T., Akira S., Matsuda T.
Biochem. Biophys. Res. Commun. 372:708-712(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH UBE2D1; UBE2D2 AND UBE2D3, FUNCTION, SUBCELLULAR LOCATION.
|||"ZIP kinase plays a crucial role in androgen receptor-mediated transcription."|
Leister P., Felten A., Chasan A.I., Scheidtmann K.H.
Oncogene 27:3292-3300(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH AR.
|||"Phosphorylation-dependent control of ZIPK nuclear import is species specific."|
Weitzel D.H., Chambers J., Haystead T.A.
Cell. Signal. 23:297-303(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT THR-299, SUBCELLULAR LOCATION.
|||"Zipper-interacting protein kinase (ZIPK) modulates canonical Wnt/beta-catenin signaling through interaction with Nemo-like kinase and T-cell factor 4 (NLK/TCF4)."|
Togi S., Ikeda O., Kamitani S., Nakasuji M., Sekine Y., Muromoto R., Nanbo A., Oritani K., Kawai T., Akira S., Matsuda T.
J. Biol. Chem. 286:19170-19177(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH NLK AND TCF7L2.
|||"New modularity of DAP-kinases: alternative splicing of the DRP-1 gene produces a ZIPk-like isoform."|
Shoval Y., Berissi H., Kimchi A., Pietrokovski S.
PLoS ONE 6:E17344-E17344(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH ATF4.
|||"Crystal structure of human ZIP kinase."|
Kursula P., Vahokoski J., Wilmanns M.
Submitted (JUN-2006) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (3.1 ANGSTROMS) OF 1-277.
|||"Patterns of somatic mutation in human cancer genomes."|
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. Stratton M.R.
Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] MET-112; ASN-161 AND SER-216.
|+||Additional computationally mapped references.|
|AB007144 mRNA. Translation: BAA24955.1.|
AB022341 mRNA. Translation: BAA81746.1.
AK074799 mRNA. Translation: BAG52004.1.
BC126430 mRNA. Translation: AAI26431.1.
BC126432 mRNA. Translation: AAI26433.1.
AB265224 mRNA. Translation: BAF34614.1.
|RefSeq||NP_001339.1. NM_001348.1. |
3D structure databases
Protein-protein interaction databases
|IntAct||O43293. 8 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENST00000301264; ENSP00000301264; ENSG00000167657. |
ENST00000545797; ENSP00000442973; ENSG00000167657.
|UCSC||uc002lzc.1. human. |
|HGNC||HGNC:2676. DAPK3. |
|MIM||603289. gene. |
Enzyme and pathway databases
|Reactome||REACT_578. Apoptosis. |
Gene expression databases
|GermOnline||ENSG00000167657. Homo sapiens. |
Family and domain databases
|InterPro||IPR011009. Kinase-like_dom. |
|PANTHER||PTHR22964. PTHR22964. 1 hit. |
|Pfam||PF00069. Pkinase. 1 hit. |
|SMART||SM00220. S_TKc. 1 hit. |
|SUPFAM||SSF56112. Kinase_like. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|ChiTaRS||DAPK3. human. |
|Accession||Primary (citable) accession number: O43293|
Secondary accession number(s): A0AVN4, B3KQE2, Q05JY4
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
|Disclaimer||Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.|
|Human and mouse protein kinases|
Human and mouse protein kinases: classification and index
|Human chromosome 19|
Human chromosome 19: entries, gene names and cross-references to MIM
|Human entries with polymorphisms or disease mutations|
List of human entries with polymorphisms or disease mutations
|Human polymorphisms and disease mutations|
Index of human polymorphisms and disease mutations
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
Index of Protein Data Bank (PDB) cross-references
Index of protein domains and families