O88764 (DAPK3_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 115. History...
Names and origin
|Protein names||Recommended name:|
Death-associated protein kinase 3
Short name=DAP kinase 3
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||448 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 By similarity. Ref.1 Ref.4 Ref.5
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 By similarity.
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. Interacts with 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 By similarity. Also binds to DAXX and PAWR, possibly in a ternary complex which plays a role in caspase activation. Interacts with AATF and CDC5L. Ref.3 Ref.4 Ref.6 Ref.7
Nucleus. Cytoplasm. Nucleus › PML body By similarity. Chromosome › centromere. Cytoplasm › cytoskeleton › microtubule organizing center › centrosome By similarity. Note: 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 By similarity. Ref.1 Ref.4 Ref.7 Ref.8
Ubiquitously expressed in all tissue types examined. High levels in brain, heart, lung and spleen, lower expression in kidney, liver, skeletal muscle and testis. Isoform 2 is expressed in the smooth muscle. Ref.1
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 By similarity.
The phosphorylation status is critical for its activity and its ability to oligomerize. 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. 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.
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.
|This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]|
|Isoform 1 (identifier: O88764-1) |
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: O88764-2) |
The sequence of this isoform differs from the canonical sequence as follows:
1-1: M → MIDSSCVPRILQKDSAMM
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 448||448||Death-associated protein kinase 3||PRO_0000085916|
|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 – 328||53||Interaction with AR By similarity|
|Region||277 – 306||30||Interaction with MYPT1 By similarity|
|Region||390 – 448||59||Interaction with CDC5L|
|Region||422 – 436||15||Leucine-zipper By similarity|
|Active site||139||1||Proton acceptor By similarity UniProtKB P53355|
|Binding site||42||1||ATP Probable Ref.4|
|Binding site||94||1||Inhibitor By similarity|
|Binding site||96||1||Inhibitor By similarity|
Amino acid modifications
|Modified residue||180||1||Phosphothreonine By similarity|
|Modified residue||225||1||Phosphothreonine By similarity|
|Modified residue||265||1||Phosphothreonine; by autocatalysis and ROCK1 By similarity|
|Modified residue||304||1||Phosphoserine; by DAPK1 By similarity|
|Modified residue||306||1||Phosphoserine; by autocatalysis and DAPK1 By similarity|
|Modified residue||307||1||Phosphoserine; by DAPK1 By similarity|
|Modified residue||313||1||Phosphoserine; by DAPK1 By similarity|
|Modified residue||321||1||Phosphoserine; by DAPK1 By similarity|
|Alternative sequence||1||1||M → MIDSSCVPRILQKDSAMM in isoform 2.||VSP_042061|
|Mutagenesis||42||1||K → A: Loss of kinase activity and of translocation into the cytoplasm. Ref.4|
|Mutagenesis||294||1||A → T: Causes dissociation from promyelocytic leukemia oncogenic bodies and increased blebbing-inducing potency; when associated with T-300. Ref.7|
|Mutagenesis||295||1||A → T: Causes dissociation from promyelocytic leukemia oncogenic bodies and increased blebbing-inducing potency; when associated with T-299. Ref.7|
|Mutagenesis||418 – 448||31||Missing: Prevents binding to ATF4 but not PAWR. Ref.4|
|||"Cloning and characterization of Dlk, a novel serine/threonine kinase that is tightly associated with chromatin and phosphorylates core histones."|
Koegel D., Ploettner O., Landsberg G., Christian S., Scheidtmann K.H.
Oncogene 17:2645-2654(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
|||"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].
|||"AATF -- a novel transcription factor that interacts with Dlk/ZIP kinase and interferes with apoptosis."|
Page G., Loedige I., Kogel D., Scheidtmann K.H.
FEBS Lett. 462:187-191(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH AATF.
|||"Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis."|
Page G., Kogel D., Rangnekar V., Scheidtmann K.H.
Oncogene 18:7265-7273(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH ATF4 AND PAWR, SUBCELLULAR LOCATION, MUTAGENESIS OF LYS-42.
|||"Zipper-interacting protein kinase induces Ca(2+)-free smooth muscle contraction via myosin light chain phosphorylation."|
Niiro N., Ikebe M.
J. Biol. Chem. 276:29567-29574(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: ALTERNATIVE SPLICING (ISOFORM 2), FUNCTION IN PHOSPHORYLATION OF MYL12B AND PPP1R12A.
|||"DAP-like kinase interacts with the rat homolog of Schizosaccharomyces pombe CDC5 protein, a factor involved in pre-mRNA splicing and required for G2/M phase transition."|
Engemann H., Heinzel V., Page G., Preuss U., Scheidtmann K.H.
Nucleic Acids Res. 30:1408-1417(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CDC5L.
|||"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, INTERACTION WITH PAWR, MUTAGENESIS OF ALA-294 AND ALA-295.
|||"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: SUBCELLULAR LOCATION.
|+||Additional computationally mapped references.|
|AJ006971 mRNA. Translation: CAA07360.1.|
BC062076 mRNA. Translation: AAH62076.1.
|RefSeq||NP_071991.1. NM_022546.1. |
3D structure databases
|SMR||O88764. Positions 2-276. |
Protein-protein interaction databases
|BioGrid||249061. 5 interactions.|
|IntAct||O88764. 2 interactions.|
Protocols and materials databases
Genome annotation databases
|UCSC||RGD:621766. rat. [O88764-1]|
|RGD||621766. Dapk3. |
Gene expression databases
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. SSF56112. 1 hit. |
|PROSITE||PS00107. PROTEIN_KINASE_ATP. 1 hit. |
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
|Accession||Primary (citable) accession number: O88764|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families