DAPK1 (death-associated protein kinase 1)

2009-02-01   Regine Schneider-Stock , Albert Roessner , Khouloud Bajbouj 

Department of Pathology, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany

Identity

HGNC
LOCATION
9q21.33
LOCUSID
ALIAS
DAPK,ROCO3
FUSION GENES

DNA/RNA

Description

160kDa, 1430 amino acids.
DAPKβ has an additional unique carboxyl-terminal 12- amino acid extension.

Transcription

2 alternative transcripts.

Proteins

Atlas Image
Schematic diagram of DAP-kinase protein structure. The 160 kDa actin microfilament-associated Ca2+/calmodulin (CaM)-regulated Serine/Threonine kinase bears a multiple domain structure. The catalytic and the calmodulin regulatory domains determine substrate specificity and regulation of kinase catalytic activity, respectively. The non-catalytic association domains, involved in subcellular localization or interactions with other proteins, include the 8 ankyrin repeats, two nucleotide-binding P-loops, a cytoskeleton-binding region, and a death domain. Phosphorylation by RSK at Ser289 triggers a suppression of DAPK proapoptotic function (Anjum et al., 2005). The autophosphorylation site was mapped to Ser308 within the CaM-regulatory domain (Shohat et al., 2002). ERK phosphorylates DAPK at Ser735, which stimulates DAPK-mediated apoptosis (Chen et al., 2005).

Description

LAR and Src have been identified as a DAPK regulator through their reciprocal modification of DAPK Y491/492 residues.

Function

Apoptosis
DAPK-mediated cell death is characterized by two main characteristics: formation of autophagic vesicles and membrane blebbing (Shohat et al., 2002).

Migration
DAPK is involved in stabilization of stress fibers through phosphorylation of MLC which occurs prior the onset of apoptosis (Kuo et al., 2003).

Signal transduction
DAP kinase is up-regulated by hyperproliferative signals, and operates upstream of p19-ARF and p53 to induce apoptosis. Whereas the inactivation or loss of DAP kinase significantly reduces the p53 responses to c-Myc or E2F-1, it does not completely eliminate them, indicating that DAP kinase is not an exclusive player upstream of p19ARF/p53 (Raveh et al., 2001). Recent studies showed several mechanisms influencing DAPK activity. These include RSK dependent inactivation of DAPK1 (Anjum et al., 2005) and ERK-dependent activation of the proapoptotic function of DAPK (Chen et al., 2005). Death-promoting effects of DAPK are counteracted by Bcl2 (Cohen et al., 1997).
It was shown that the apoptosis regulatory activities mediated by DAPK are controlled both by phosphorylation status and protein stability.

Phosphorylation sites
There are three well characterized phosphorylation sites on DAPK protein;
1) the phosphorylation by RSK at Ser289, which triggers a suppression of DAPK pro-apoptotic function (Anjum et al., 2005),
2) the autophosphorylation site, which was mapped to Ser308 within the CaM-regulatory domain (Shohat et al., 2002), and
3) ERK-phosphorylation of DAPK at Ser735, which stimulates DAPK-mediated apoptosis by switching off the ERK-C/EBP-beta pathway (Chen et al., 2005). Src phosphorylates DAPK at Y491/492, which induces DAPK intra-/intermolecular interaction and inactivation (Wang et al., 2007).

Interaction partners
Cathepsin B can directly interact with DAPK, forming a stable immune complex (Lin et al., 2007). It has been found that inhibition of HSP90 results in degradation of active dephosphorylated DAPK via the ubiquitin proteasome pathway. DAPK can also form heterocomplexes composed of HSP90 and CHIP or DIP1/Mib1, indicating that the heightened surveillance and modulation of DAPK activities is critical to accurate regulation of apoptosis and cellular homeostasis (Zhang et al., 2007). An interaction between UNC5C (UNC5H3) and DAPK1 was demonstrated (Llambi et al., 2005), whereby this interaction was shown to be dependent on both UNC5H2 lipid raft localization and palmitoylation (Maisse et al., 2008). An interaction between DAPK1 promoter and transcription factors ATF2 and c-jun was demonstrated in cisplatin-treated human breast cancer cells (Hayakawa et al., 2004). Amino acid starvation of cells induced a stable immune complex between microtubule-associated protein MAP1B and DAPK-1 (Harrison et al., 2008) highlighting a new mechanism for authophagy and membrane blebbing. There was found an interaction between DAPK and TSC2 proteins in response to growth factor stimulation that links the DAPK and mTORC1 signaling pathways affecting cell survival, autophagy, and apoptosis (Stevens et al., 2009).

Known substrates
DAPK phosphorylates the myosin II regulatory light chain (Jin et al., 2001) and tropomyosin in response to ERK activation by hydrogen peroxide leading to stress fiber formation (Houle et al., 2007). Furthermore, Syntaxin is a DAP kinase substrate and provides a novel signal transduction pathway by which syntaxin function could be regulated in response to intracellular [Ca2+] and synaptic activity (Tian et al., 2003). Also one of the common DAPK substrate is p19ARF (Raveh et al., 2001). Shani el al. (2004) and Mukhopadhyay et al. (2008) showed that ZIPK serves as a substrate for DAPK. It has been reported that the mammalian 40S ribosomal protein S6 is a DAPK substrate (Schumacher et al., 2006).

Homology

Member of the Death-associated protein kinase family (Shohat et al., 2002):
  • DRP-1/DAPK2 (Death-Related Protein 1)
  • DAPK3/ZIPK/DLK (Zipper Interacting Protein Kinase/DAP Like Kinase)
  • DRAK1/DRAK2 (DAPk-Related Apoptosis inducing protein Kinases 1 and 2)

  • Mutations

    Germinal

    A novel mutation (N1347S) in the death domain of DAPK-1 alters the oligomeric structure of the death domain, de-stabilizes DAPK-1 binding to ERK, and prevents ERK:DAPK-1-dependent apoptosis (Stevens et al., 2007).

    Implicated in

    Entity name
    Cancers in general:
    Note
    DAPK is a tumor suppressor gene. Promoter hypermethylation and homozygous deletion of DAPK1 are the major alternative mechanisms of DAPK protein loss in cancers (Kawaguchi et al., 2004).
    Entity name
    Lung cancer
    Note
    DAPK hypermethylation was not detectable in normal lung specimens but in 39% of invasive adenocarcinoma (Licchesi et al., 2008).
    Entity name
    Non small cell lung cancer
    Note
    DAPK hypermethylation was evident in 50% of resected primary nonsmall cell lung cancers (Wang et al., 2008).
    Entity name
    Gastric cancer
    Note
    DAPK methylation might predict the prognosis and response to chemotherapy in gastric cancer (Kato et al., 2008).
    Entity name
    Barretts adenocarcinoma
    Note
    DAPK inactivation by promoter hypermethylation as an early event in Barretts carcinogenesis (Kuester et al., 2007).
    Entity name
    Colon cancer
    Note
    DAPK inactivation by promoter hypermethylation as an early event in colorectal carcinogenesis (Mittag et al., 2006).
    Entity name
    Cervical cancer
    Note
    DAPK hypermethylation was found more frequently in cervical squamous cell carcinoma than in cervical adenocarcinoma (Kang et al., 2006).
    Entity name
    Brain disorders:
    Note
    DAPK1 regulates exocytosis of neurotransmitter release by phosphorylation of syntaxin-1 (Tian et al., 2003) and protecting neurons during development or recovery from hypoxic-ischemic injury (Schumacher et al., 2002).
    DAPK is inactive in normal brain tissues, where it is found in its phosphorylated state and becomes rapidly and persistently dephosphorylated and activated in response to ischemia in vivo (Shamloo et al., 2005).
    Entity name
    Alzheimers disease
    Note
    Two SNPs in the DAPK1 gene are associated with late-onset Alzheimers disease (Li et al., 2006).

    Bibliography

    Pubmed IDLast YearTitleAuthors
    162138242005The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling.Anjum R et al
    156165832005Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK.Chen CH et al
    91189611997DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity.Cohen O et al
    181950172008DAPK-1 binding to a linear peptide motif in MAP1B stimulates autophagy and membrane blebbing.Harrison B et al
    155466132004Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress.Hayakawa J et al
    178953592007DAP kinase mediates the phosphorylation of tropomyosin-1 downstream of the ERK pathway, which regulates the formation of stress fibers in response to oxidative stress.Houle F et al
    114859962001Identification of a new form of death-associated protein kinase that promotes cell survival.Jin Y et al
    163316102006Comparison of DNA hypermethylation patterns in different types of uterine cancer: cervical squamous cell carcinoma, cervical adenocarcinoma and endometrial adenocarcinoma.Kang S et al
    179437302008Methylated TMS1 and DAPK genes predict prognosis and response to chemotherapy in gastric cancer.Kato K et al
    154929952004Death-associated protein kinase (DAP kinase) alteration in soft tissue leiomyosarcoma: Promoter methylation or homozygous deletion is associated with a loss of DAP kinase expression.Kawaguchi K et al
    174014632007Early involvement of death-associated protein kinase promoter hypermethylation in the carcinogenesis of Barrett's esophageal adenocarcinoma and its association with clinical progression.Kuester D et al
    146002632003Uncoordinated regulation of stress fibers and focal adhesions by DAP kinase.Kuo JC et al
    168470122006DAPK1 variants are associated with Alzheimer's disease and allele-specific expression.Li Y et al
    184512182008Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung.Licchesi JD et al
    173249272007Identification of a dominant negative functional domain on DAPK-1 that degrades DAPK-1 protein and stimulates TNFR-1-mediated apoptosis.Lin Y et al
    157293592005The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase.Llambi F et al
    185824602008Lipid raft localization and palmitoylation: identification of two requirements for cell death induction by the tumor suppressors UNC5H.Maisse C et al
    162464862006DAPK promotor methylation is an early event in colorectal carcinogenesis.Mittag F et al
    189958352008DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression.Mukhopadhyay R et al
    111466192001DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation.Raveh T et al
    170875152006Death-associated protein kinase phosphorylates mammalian ribosomal protein S6 and reduces protein synthesis.Schumacher AM et al
    162042522005Death-associated protein kinase is activated by dephosphorylation in response to cerebral ischemia.Shamloo M et al
    153676802004Death-associated protein kinase phosphorylates ZIP kinase, forming a unique kinase hierarchy to activate its cell death functions.Shani G et al
    189740952009Peptide combinatorial libraries identify TSC2 as a death-associated protein kinase (DAPK) death domain-binding protein and reveal a stimulatory role for DAPK in mTORC1 signaling.Stevens C et al
    127302012003Ca2+-dependent phosphorylation of syntaxin-1A by the death-associated protein (DAP) kinase regulates its interaction with Munc18.Tian JH et al
    178039362007The tumor suppressor DAPK is reciprocally regulated by tyrosine kinase Src and phosphatase LAR.Wang WJ et al
    182865312008Multiple gene methylation of nonsmall cell lung cancers evaluated with 3-dimensional microarray.Wang Y et al

    Other Information

    Locus ID:

    NCBI: 1612
    MIM: 600831
    HGNC: 2674
    Ensembl: ENSG00000196730

    Variants:

    dbSNP: 1612
    ClinVar: 1612
    TCGA: ENSG00000196730
    COSMIC: DAPK1

    RNA/Proteins

    Gene IDTranscript IDUniprot
    ENSG00000196730ENST00000358077P53355
    ENSG00000196730ENST00000408954P53355
    ENSG00000196730ENST00000469640P53355
    ENSG00000196730ENST00000472284P53355
    ENSG00000196730ENST00000489291F8WCQ3
    ENSG00000196730ENST00000491893P53355
    ENSG00000196730ENST00000622514P53355

    Expression (GTEx)

    0
    10
    20
    30
    40
    50
    60
    70
    80

    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

    Protein levels (Protein atlas)

    Not detected
    Low
    Medium
    High

    PharmGKB

    Entity IDNameTypeEvidenceAssociationPKPDPMIDs
    PA445062NeoplasmsDiseaseClinicalAnnotationassociatedPD22293537
    PA449748gemcitabineChemicalClinicalAnnotationassociatedPD22293537

    References

    Pubmed IDYearTitleCitations
    191801162009DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy.245
    185198262008Molecular genetics of successful smoking cessation: convergent genome-wide association study results.130
    175401692007Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia.127
    205347412010Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals.108
    193958742009Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL.91
    183492822008DNA methylation in tumor and matched normal tissues from non-small cell lung cancer patients.71
    214971222011Death-associated protein kinase 1 phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function.70
    189958352008DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression.64
    203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
    120826102002Patterns of gene promoter methylation in squamous cell cancer of the head and neck.60

    Citation

    Regine Schneider-Stock ; Albert Roessner ; Khouloud Bajbouj

    DAPK1 (death-associated protein kinase 1)

    Atlas Genet Cytogenet Oncol Haematol. 2009-02-01

    Online version: http://atlasgeneticsoncology.org/gene/417/dapk1