DAPK2 (death-associated protein kinase 2)

2016-04-01   Mafalda Pinto  , Valdemar Máximo  

Identity

HGNC
LOCATION
15q22.31
LOCUSID
ALIAS
DRP-1,DRP1
FUSION GENES

Abstract

Short communication on DAPK2, with data on DNA and on the protein encoded.

DNA/RNA

Note

DAPK2 is a gene that codes for a protein that belongs to the serine/threonine protein kinase family.
Atlas Image
Blue highlighting indicates alternating exons; Red highlighting indicates amino acids encoded across a splice junction.

Transcription

DPAK2 has 13 transcripts (3 coding), 75 orthologues and 11 paralogues (MYLK4, MYLK3, STK17A, DAPK3, DAPK1, OBSCN, SPEG, TTN, MYLK, STK17B, MYKL2) (ENSG00000035664).

Proteins

Atlas Image
Schematic diagram of DAPK2 protein structure. The 42 KDa DAPK2 protein kinase bears three domain structures. A kinase domain on its N-terminal region determines specificity and allows for homodimerization through its basic loop. It is followed by a calcium/calmodulin (CaM)-regulated Serine/Threonine binding domain, which dictates kinase catalytic activity by unblocking substrate access when bound to Ca2+/CaM. Autophosphorylation of S308 decreases DAPK2 activity. The C-terminal dimerization domain allows for homodimerization. (Kawai T et al., 1999; Inbal B et al., 2000)

Description

DAPK2 encodes a 42 KDa protein kinase (Inbal B., 2000) that belongs to the serine/threonine protein family of five proapoptotic proteins with tumor suppressor activity. DAPK2 is soluble and cytosolic (Inbal B., 2000). It contains highly-conserved N-terminal kinase catalytic domain, followed by a conserved calcium/calmodulin regulatory binding domain and a C-terminal homodimerization domain encompassing the last 40 aminoacids, predicted to form two helices, which has no sequence homology to known protein sequences.
Autophosphorylation restrains the apoptotic activity of DAPK2 kinase by controlling dimerization and calmodulin binding (Shani G et al., 2001).
DAPK2 is a monomer in its activated state and a homodimer when inhibited by autophosphorylation at Ser-308 (Shani G et al., 2001). The dimers of DAPK2 are formed through the association of two opposed catalytic domains (Patel AK et al., 2001). DAPK2 is negatively regulated by the autoinhibitory CaM-binding domain and this inhibition is removed by the binding of Ca2+/CaM (Inbal B et al., 2000). That is, DAPK2 is activated by CaM in response to Ca2+ stimuli, and regulated by a double locking mechanism. DAPK2 is dephosphorylated at Ser-308 in response to activated Fas and TNF-alpha receptors.
UniProtKB: Q9UIK4
Atlas Image
Translation (370 aa)

Expression

Widespread expression. Strong expression in heart, lung and skeletal muscle, but also expressed in colon, breast, spleen tissue and leukocytes (Kawai T et al., 1999; Inbal B et al., 2000). In mouse, DAPK2 is strongly and specifically expressed in interstitial cells of the kidney cortex (Guay JA et al., 2014).

Localisation

Cytoplasm (Inbal B et al., 2000), cytoplasmic vesicles, inside autophagic vesicles (Inbal B et al., 2002).

Function

DAPK2 is a regulator of apoptosis, autophagy and inflammation (Geering B 2015).

Apoptosis
DAPK2 overexpression induces cell apoptosis in 50 to 60% (Inbal B et al., 2000). Depletion of the C-terminal tail of DAPK2 abolishes its apoptotic activity, while further truncation of the CaM-regulatory domain strongly enhances its apoptotic effect (Inbal B et al., 2000).
DAPK2 is a modulator of TRAIL signaling and TRAIL-induced apoptosis. Genetic ablation of DAPK2 causes phosphorylation of NF-KB and its transcriptional activity in several cancer cell lines, leading to the induction of several proapoptotic proteins (TNFRSF10A (DR4) and TNFRSF10B (DR5)) (Schlegel CR et al., 2014).

Autophagy
DAPK2 modulates MTOR activity by directly interacting and phosphorylating mTORC1. This way it suppresses mTOR activity to promote autophagy induction and autophagy levels under stress and steady-state conditions (Ber Y et al., 2015).
Expression of DAPK2 in its activated form triggers autophagy in a caspase independent way. DAPK2 mediates the formation of autophagic vesicles during apoptosis (Inbal B et al., 2002). Expression of dominant negative mutant of DAPK2 reduces autophagy (Inbal B et al., 2002).

Protein serine/threonine kinase activity
In vitro kinase assays, using myosin light chain (MLC) as substrate, have shown both MLC phosphorylation and DAPK2 autophosphorylation (Kawai T et al., 1999; Inbal B et al., 2000). DAPK2 functions in vitro as a kinase that is capable of phosphorylating itself and an external substrate (Kawai T et al., 1999; Inbal B et al., 2000).

Calmodulin binding
The addition of Ca2+/CaM to in vitro kinase assays using myosin light chain (MLC) as substrate, lead to an increased amount of phosphorylated MLC, suggesting that DPK2 is regulated by binding to CaM (Kawai T et al., 1999; Inbal B et al., 2000). DPAK2 is negatively regulated by the autoinhibitory CaM-binding domain and this inhibition is removed by the binding of Ca2+/CaM (Inbal B et al., 2000).
Truncation of the CaM-regulatory region of DAPK2 enhances the apoptotic effect (Inbal B et al., 2000). Oxidative stress regulation
DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function. Depletion of DAPK2 leads to an increased production of mitochondrial superoxide anions and increased oxidative stress (Schlegel CR et al., 2015).

Cellular metabolism
DAPK2 kinase domain in important to maintain mitochondrial integrity and thus metabolism. Depletion of DPAK2 leads to metabolic alterations, decreased rate of oxidative phosphorylation and destabilized mitochondrial membrane potential (Schlegel CR et al., 2015). Membrane blebbing
Interaction of DAPK2 with ACTA1 (α-actin-1) at the plasma membrane leads to massive membrane blebbing (Geering B et al., 2015). Expression of DAPK2 in its activated form triggers membrane blebbing and this process is caspase independent (Inbal B et al., 2002). Dominant negative mutants of DAPK2 reduce membrane blebbing during the p55/TRAF1 (TNF-receptor 1)-induced apoptosis (Inbal B et al., 2002).

Motility
Interaction of DAPK2 with α-actin-1 leads to reduced cellular motility (Geering B et al., 2015).

Intracellular signaling transduction
Depletion of DAPK2 leads to the activation of classical stress-activated kinases, such as ERK, JNK and p38 (Schlegel CR et al., 2015).

Positive regulation of eosinophil and neutrophil chemotaxis, and granulocyte maturation
DPAK2 inhibition blocks recruitment of neutrophils to the site of inflammation in a peritonitis mouse model. DAPK2 functions in a signaling pathway that mediates motility in neutrophils and eosinophils in response to intermediary chemoattractants, but not to end-target chemoattractants (Geering B et al., 2014).
DPAK2 regulates granulocytic motility by controlling cell spreading and polarization (Geering B et al., 2014) and may play a role in granulocyte maturation (Rizzi M et al., 2007).

Regulation of erythropoiesis
Among hematopoietic lineages, DPAK2 is expressed predominantly in erythroid cells. DPAK2 is substantially up-modulated during late erythropoiesis (Fang J et al., 2008). In UT7epo cells, siRNA knock-down of DAPK2 enhanced survival due to cytokine withdrawal, and DAPK2s phosphorylation and kinase activity also were erythropoietin (EPO)-modulated. DAPK2 therefore comprises a new candidate attenuator of stress erythropoiesis (Fang J et al., 2008).

The physiological substrate of DAPK2 is unknown although it is known to phosphorylate the myosin light chain in vitro (Inbal B et al., 2000).

INTERACTION
YWHAB (14-3-3-β) (Yuasa K et al., 2015) and α-actinin-1 are novel DAPK2 binding partners (Geering B et al., 2015). The interaction of DAPK2 with α-actinin-1 is localized to the plasma membrane, resulting in massive membrane blebbing and reduced cellular motility, whereas the interaction of DAPK2 with 14-3-3- β is localized to the cytoplasm, with no impact on blebbing, motility, or viability (Geering B et al 2015). 14-3-3- proteins inhibit DAPK2 activity and its apoptotic effects (Yuasa K et al., 2015).
DAPK2 also interacts with RAD1, MAPK1 and MLC1 (Steinmann S et al., 2015).

Homology

DAPK3/ZIPK/DLK (Death-related protein 1); STK17A (DRAK1/STK17B (DRAK2) (DAPK-related apoptosis inducing protein kinases 1 and 2) (Shobat G et al., 2002)

Mutations

Germinal

No germline or somatic mutations have been described for DAPK2 gene. There are 4 structural variants are described for DPAK2 gene: nsv1567 and nsv1569 leading to loss (PubMed ID 18451855), and nsv1568 and esv1414761 leading to insertions (PubMed IDs 18451855 and 17803354, respectively) (Database of Genomic Variants).

Somatic

Hypermethylation of the promoter region downregulates DAPK2 expression.

Article Bibliography

Pubmed IDLast YearTitleAuthors
253610812015DAPK2 is a novel regulator of mTORC1 activity and autophagy.Ber Y et al
185352042008Attenuation of EPO-dependent erythroblast formation by death-associated protein kinase-2.Fang J et al
260555152015Death-associated protein kinase 2: Regulator of apoptosis, autophagy and inflammation.Geering B et al
241634212014DAPK2 positively regulates motility of neutrophils and eosinophils in response to intermediary chemoattractants.Geering B et al
264834152016Identification of Novel Death-Associated Protein Kinase 2 Interaction Partners by Proteomic Screening Coupled with Bimolecular Fluorescence Complementation.Geering B et al
249064432014Death associated protein kinase 2 is expressed in cortical interstitial cells of the mouse kidney.Guay JA et al
240382162014The tumor suppressor gene DAPK2 is induced by the myeloid transcription factors PU.1 and C/EBPα during granulocytic differentiation but repressed by PML-RARα in APL.Humbert M et al
119809202002DAP kinase and DRP-1 mediate membrane blebbing and the formation of autophagic vesicles during programmed cell death.Inbal B et al
106290612000Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis.Inbal B et al
103765251999Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity.Kawai T et al
214976052011Structure of the dimeric autoinhibited conformation of DAPK2, a pro-apoptotic protein kinase.Patel AK et al
173473022007The death-associated protein kinase 2 is up-regulated during normal myeloid differentiation and enhances neutrophil maturation in myeloid leukemic cells.Rizzi M et al
257415962015DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function.Schlegel CR et al
112301332001Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding.Shani G et al
124454582002The DAP-kinase family of proteins: study of a novel group of calcium-regulated death-promoting kinases.Shohat G et al
260385782015DAPK2 Downregulation Associates With Attenuated Adipocyte Autophagic Clearance in Human Obesity.Soussi H et al
259636362015Death-associated protein kinase: A molecule with functional antagonistic duality and a potential role in inflammatory bowel disease (Review).Steinmann S et al
259822742016miR-520h is crucial for DAPK2 regulation and breast cancer progression.Su CM et al
196092352009Targeted restoration of down-regulated DAPK2 tumor suppressor activity induces apoptosis in Hodgkin lymphoma cells.Tur MK et al
260477032015Suppression of death-associated protein kinase 2 by interaction with 14-3-3 proteins.Yuasa K et al

Other Information

Locus ID:

NCBI: 23604
MIM: 616567
HGNC: 2675
Ensembl: ENSG00000035664

Variants:

dbSNP: 23604
ClinVar: 23604
TCGA: ENSG00000035664
COSMIC: DAPK2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000035664ENST00000261891Q9UIK4
ENSG00000035664ENST00000261891A0A024R603
ENSG00000035664ENST00000457488Q9UIK4
ENSG00000035664ENST00000457488A0A024R603
ENSG00000035664ENST00000558064H0YL86
ENSG00000035664ENST00000559007H0YMK1
ENSG00000035664ENST00000559306H0YKW8
ENSG00000035664ENST00000561162H0YLP5

Expression (GTEx)

0
5
10
15
20
25
30
35
40
45

Pathways

PathwaySourceExternal ID
Autophagy - animalKEGGko04140
Bladder cancerKEGGko05219
Autophagy - animalKEGGhsa04140
Pathways in cancerKEGGhsa05200
Bladder cancerKEGGhsa05219
Programmed Cell DeathREACTOMER-HSA-5357801
ApoptosisREACTOMER-HSA-109581
Caspase activation via extrinsic apoptotic signalling pathwayREACTOMER-HSA-5357769
Ligand-independent caspase activation via DCCREACTOMER-HSA-418889

References

Pubmed IDYearTitleCitations
366366402023Exosomal miR-133a-3p Derived from BMSCs Alleviates Cerebral Ischemia-Reperfusion Injury via Targeting DAPK2.3
366366402023Exosomal miR-133a-3p Derived from BMSCs Alleviates Cerebral Ischemia-Reperfusion Injury via Targeting DAPK2.3
342981222021Cigarette smoking induces aberrant N(6)-methyladenosine of DAPK2 to promote non-small cell lung cancer progression by activating NF-κB pathway.14
34413451202114-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites.14
342981222021Cigarette smoking induces aberrant N(6)-methyladenosine of DAPK2 to promote non-small cell lung cancer progression by activating NF-κB pathway.14
34413451202114-3-3 proteins inactivate DAPK2 by promoting its dimerization and protecting key regulatory phosphosites.14
322445002020miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2.7
322445002020miR-1285-3p Controls Colorectal Cancer Proliferation and Escape from Apoptosis through DAPK2.7
302439972019Upregulation of DAPK2 ameliorates oxidative damage and apoptosis of placental cells in hypertensive disorder complicating pregnancy by suppressing human placental microvascular endothelial cell autophagy through the mTOR signaling pathway.5
311160762019Ser289 phosphorylation activates both DAPK1 and DAPK2 but in response to different intracellular signaling pathways.1
302439972019Upregulation of DAPK2 ameliorates oxidative damage and apoptosis of placental cells in hypertensive disorder complicating pregnancy by suppressing human placental microvascular endothelial cell autophagy through the mTOR signaling pathway.5
311160762019Ser289 phosphorylation activates both DAPK1 and DAPK2 but in response to different intracellular signaling pathways.1
297171152018Non-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy.22
297171152018Non-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy.22
259822742016miR-520h is crucial for DAPK2 regulation and breast cancer progression.32

Citation

Mafalda Pinto ; Valdemar Máximo

DAPK2 (death-associated protein kinase 2)

Atlas Genet Cytogenet Oncol Haematol. 2016-04-01

Online version: http://atlasgeneticsoncology.org/gene/40263/css/js/teaching-explorer/