O88764 (DAPK3_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Death-associated protein kinase 3
Short name=DAP kinase 3
EC=2.7.11.1

Alternative name(s):
DAP-like kinase
Short name=Dlk
MYPT1 kinase
ZIP-kinase

Gene names

Name:	Dapk3
Synonyms:	Zipk

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	448 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.1 Ref.4
Cofactor	Magnesium. Ref.1 Ref.4
Enzyme regulation	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.
Subunit structure	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
Subcellular location	Nucleus. Cytoplasm. Nucleus › PML body By similarity. Chromosome › centromere. Cytoplasm › cytoskeleton › 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
Tissue specificity	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
Post-translational modification	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.
Miscellaneous	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.
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. DAP kinase subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Transcription Transcription regulation
Cellular component	Centromere Chromosome Cytoplasm Cytoskeleton Nucleus
Coding sequence diversity	Alternative splicing
Ligand	ATP-binding Nucleotide-binding
Molecular function	Activator Chromatin regulator Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW chromatin modification Inferred from electronic annotation. Source: UniProtKB-KW induction of apoptosis Inferred from mutant phenotype Ref.4. Source: UniProtKB intracellular protein kinase cascade Inferred from direct assay Ref.4. Source: UniProtKB neuron differentiation Inferred from direct assay PubMed 12445468. Source: RGD positive regulation of canonical Wnt receptor signaling pathway Inferred from electronic annotation. Source: Compara positive regulation of extrinsic apoptotic signaling pathway in absence of ligand Inferred from mutant phenotype PubMed 21172653. Source: UniProtKB protein autophosphorylation Inferred from sequence or structural similarity PubMed 18239682. Source: UniProtKB regulation of transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	PML body Inferred from electronic annotation. Source: UniProtKB-SubCell chromosome, centromeric region Inferred from electronic annotation. Source: UniProtKB-SubCell cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell microtubule organizing center Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay Ref.4. Source: UniProtKB
Molecular_function	ATP binding Inferred from direct assay Ref.4. Source: UniProtKB calmodulin-dependent protein kinase activity Traceable author statement PubMed 12445468. Source: RGD protein homodimerization activity Inferred from sequence or structural similarity PubMed 18239682. Source: UniProtKB
Complete GO annotation...

Alternative products

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
Molecule processing
	Chain	1 – 448	448	Death-associated protein kinase 3		PRO_0000085916
Regions
	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
Sites
	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
Natural variations
	Alternative sequence	1	1	M → MIDSSCVPRILQKDSAMM in isoform 2.		VSP_042061
Experimental info
	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

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1998. Version 1. Checksum: 843C0FD0BF0C1EEA	FASTA	448	51,450
	10 20 30 40 50 60 MSTFRQEDVE DHYEMGEELG SGQFAIVRKC QQKGTGMEYA AKFIKKRRLP SSRRGVSREE 70 80 90 100 110 120 IEREVSILRE IRHPNIITLH DVFENKTDVV LILELVSGGE LFDFLAEKES LTEDEATQFL 130 140 150 160 170 180 KQILDGVHYL HSKRIAHFDL KPENIMLLDK HAASPRIKLI DFGIAHRIEA GSEFKNIFGT 190 200 210 220 230 240 PEFVAPEIVN YEPLGLEADM WSIGVITYIL LSGASPFLGE TKQETLTNIS AVNYDFDEEY 250 260 270 280 290 300 FSSTSELAKD FIRRLLVKDP KRRMTIAQSL EHSWIKVRRR EDGARKPERR RLRAARLREY 310 320 330 340 350 360 SLKSHSSMPR NTSYASFERF SRVLEDVAAA EQGLRELQRG RRQCRERVCA LRVAAEQREA 370 380 390 400 410 420 RCRDGSAGLG RDLRRLRTEL GRTEALRTRA QEEARAALLG AGGLKRRLCR LENRYDALAA 430 440 QVAAEVQFVR DLVRALEQER LQAECGVR
	Isoform 2 [UniParc]. Checksum: 1AC035BCAB567234	FASTA	465	53,326
	10 20 30 40 50 60 MIDSSCVPRI LQKDSAMMST FRQEDVEDHY EMGEELGSGQ FAIVRKCQQK GTGMEYAAKF 70 80 90 100 110 120 IKKRRLPSSR RGVSREEIER EVSILREIRH PNIITLHDVF ENKTDVVLIL ELVSGGELFD 130 140 150 160 170 180 FLAEKESLTE DEATQFLKQI LDGVHYLHSK RIAHFDLKPE NIMLLDKHAA SPRIKLIDFG 190 200 210 220 230 240 IAHRIEAGSE FKNIFGTPEF VAPEIVNYEP LGLEADMWSI GVITYILLSG ASPFLGETKQ 250 260 270 280 290 300 ETLTNISAVN YDFDEEYFSS TSELAKDFIR RLLVKDPKRR MTIAQSLEHS WIKVRRREDG 310 320 330 340 350 360 ARKPERRRLR AARLREYSLK SHSSMPRNTS YASFERFSRV LEDVAAAEQG LRELQRGRRQ 370 380 390 400 410 420 CRERVCALRV AAEQREARCR DGSAGLGRDL RRLRTELGRT EALRTRAQEE ARAALLGAGG 430 440 450 460 LKRRLCRLEN RYDALAAQVA AEVQFVRDLV RALEQERLQA ECGVR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"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.
[2]	"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]. Tissue: Prostate.
[3]	"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.
[4]	"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.
[5]	"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.
[6]	"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.
[7]	"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.
[8]	"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.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AJ006971 mRNA. Translation: CAA07360.1. BC062076 mRNA. Translation: AAH62076.1.
IPI	IPI00212517.
RefSeq	NP_071991.1. NM_022546.1.
UniGene	Rn.60353.
3D structure databases
ProteinModelPortal	O88764.
SMR	O88764. Positions 2-276.
ModBase	Search...
Protein-protein interaction databases
IntAct	O88764. 2 interactions.
Proteomic databases
PaxDb	O88764.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	64391.
KEGG	rno:64391.
UCSC	RGD:621766. rat.
Organism-specific databases
CTD	1613.
RGD	621766. Dapk3.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233016.
HOVERGEN	HBG101549.
InParanoid	O88764.
KO	K08803.
OMA	IRVEIFE.
OrthoDB	EOG4VDPZK.
Gene expression databases
Genevestigator	O88764.
GermOnline	ENSRNOG00000020383. Rattus norvegicus.
Family and domain databases
InterPro	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. [Graphical view]
PANTHER	PTHR22964. PTHR22964. 1 hit.
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
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. [Graphical view]
ProtoNet	Search...
Other
NextBio	613146.

Entry information

Entry name

DAPK3_RAT

Accession

Primary (citable) accession number: O88764

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 28, 2003
Last sequence update:	November 1, 1998
Last modified:	April 3, 2013
This is version 106 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program