Short communication on DAPK2, with data on DNA and on the protein encoded.
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).
NCBI: 23604 MIM: 616567 HGNC: 2675 Ensembl: ENSG00000035664
dbSNP: 23604 ClinVar: 23604 TCGA: ENSG00000035664 COSMIC: DAPK2
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/gene-explorer/haematological-explorer/js/template.js