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DAPK1 (death-associated protein kinase 1)

Written2009-02Regine Schneider-Stock, Albert Roessner, Khouloud Bajbouj
Department of Pathology, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany

(Note : for Links provided by Atlas : click)


Other aliasDAPK
DAP Kinase 1
LocusID (NCBI) 1612
Atlas_Id 417
Location 9q21.33  [Link to chromosome band 9q21]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
DAPK1 (9q21.33) / AGTPBP1 (9q21.33)DAPK1 (9q21.33) / DAPK1 (9q21.33)DAPK1 (9q21.33) / GRIA3 (Xq25)
DAPK1 (9q21.33) / MAMDC2 (9q21.12)DAPK1 (9q21.33) / NRBP1 (2p23.3)DAPK1 (9q21.33) / RBM5 (3p21.31)
TGDS (13q32.1) / DAPK1 (9q21.33)


Description 160kDa, 1430 amino acids.
DAPKβ has an additional unique carboxyl-terminal 12- amino acid extension.
Transcription 2 alternative transcripts.


  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).

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 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 Lung cancer
    Note DAPK hypermethylation was not detectable in normal lung specimens but in 39% of invasive adenocarcinoma (Licchesi et al., 2008).
    Entity Non small cell lung cancer
    Note DAPK hypermethylation was evident in 50% of resected primary nonsmall cell lung cancers (Wang et al., 2008).
    Entity Gastric cancer
    Note DAPK methylation might predict the prognosis and response to chemotherapy in gastric cancer (Kato et al., 2008).
    Entity Barrett's adenocarcinoma
    Note DAPK inactivation by promoter hypermethylation as an early event in Barrett's carcinogenesis (Kuester et al., 2007).
    Entity Colon cancer
    Note DAPK inactivation by promoter hypermethylation as an early event in colorectal carcinogenesis (Mittag et al., 2006).
    Entity Cervical cancer
    Note DAPK hypermethylation was found more frequently in cervical squamous cell carcinoma than in cervical adenocarcinoma (Kang et al., 2006).
    Entity Brain disorders:
    Entity Ischemia
    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 Alzheimer's disease
    Note Two SNPs in the DAPK1 gene are associated with late-onset Alzheimer's disease (Li et al., 2006).


    The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling.
    Anjum R, Roux PP, Ballif BA, Gygi SP, Blenis J.
    Curr Biol. 2005 Oct 11;15(19):1762-7.
    PMID 16213824
    Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK
    Chen CH, Wang WJ, Kuo JC, Tsai HC, Lin JR, Chang ZF, Chen RH.
    EMBO J. 2005 Jan 26;24(2):294-304. Epub 2004 Dec 16.
    PMID 15616583
    DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity.
    Cohen O, Feinstein E, Kimchi A.
    EMBO J. 1997 Mar 3;16(5):998-1008.
    PMID 9118961
    DAPK-1 binding to a linear peptide motif in MAP1B stimulates autophagy and membrane blebbing.
    Harrison B, Kraus M, Burch L, Stevens C, Craig A, Gordon-Weeks P, Hupp TR.
    J Biol Chem. 2008 Apr 11;283(15):9999-10014. Epub 2008 Jan 14.
    PMID 18195017
    Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress.
    Hayakawa J, Mittal S, Wang Y, Korkmaz KS, Adamson E, English C, Ohmichi M, McClelland M, Mercola D.
    Mol Cell. 2004 Nov 19;16(4):521-35.
    PMID 15546613
    DAP 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, Poirier A, Dumaresq J, Huot J.
    J Cell Sci. 2007 Oct 15;120(Pt 20):3666-77. Epub 2007 Sep 25.
    PMID 17895359
    Identification of a new form of death-associated protein kinase that promotes cell survival.
    Jin Y, Blue EK, Dixon S, Hou L, Wysolmerski RB, Gallagher PJ.
    J Biol Chem. 2001 Oct 26;276(43):39667-78. Epub 2001 Aug 2.
    PMID 11485996
    Comparison of DNA hypermethylation patterns in different types of uterine cancer: cervical squamous cell carcinoma, cervical adenocarcinoma and endometrial adenocarcinoma.
    Kang S, Kim JW, Kang GH, Lee S, Park NH, Song YS, Park SY, Kang SB, Lee HP.
    Int J Cancer. 2006 May 1;118(9):2168-71.
    PMID 16331610
    Methylated TMS1 and DAPK genes predict prognosis and response to chemotherapy in gastric cancer.
    Kato K, Iida S, Uetake H, Takagi Y, Yamashita T, Inokuchi M, Yamada H, Kojima K, Sugihara K.
    Int J Cancer. 2008 Feb 1;122(3):603-8.
    PMID 17943730
    Death-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, Oda Y, Saito T, Yamamoto H, Takahira T, Tamiya S, Iwamoto Y, Tsuneyoshi M.
    Hum Pathol. 2004 Oct;35(10):1266-71.
    PMID 15492995
    Early involvement of death-associated protein kinase promoter hypermethylation in the carcinogenesis of Barrett's esophageal adenocarcinoma and its association with clinical progression.
    Kuester D, Dar AA, Moskaluk CC, Krueger S, Meyer F, Hartig R, Stolte M, Malfertheiner P, Lippert H, Roessner A, El-Rifai W, Schneider-Stock R.
    Neoplasia. 2007 Mar;9(3):236-45.
    PMID 17401463
    Uncoordinated regulation of stress fibers and focal adhesions by DAP kinase.
    Kuo JC, Lin JR, Staddon JM, Hosoya H, Chen RH.
    J Cell Sci. 2003 Dec 1;116(Pt 23):4777-90.
    PMID 14600263
    DAPK1 variants are associated with Alzheimer's disease and allele-specific expression.
    Li Y, Grupe A, Rowland C, Nowotny P, Kauwe JS, Smemo S, Hinrichs A, Tacey K, Toombs TA, Kwok S, Catanese J, White TJ, Maxwell TJ, Hollingworth P, Abraham R, Rubinsztein DC, Brayne C, Wavrant-De Vrieze F, Hardy J, O'Donovan M, Lovestone S, Morris JC, Thal LJ, Owen M, Williams J, Goate A.
    Hum Mol Genet. 2006 Sep 1;15(17):2560-8. Epub 2006 Jul 17.
    PMID 16847012
    Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung.
    Licchesi JD, Westra WH, Hooker CM, Herman JG.
    Clin Cancer Res. 2008 May 1;14(9):2570-8.
    PMID 18451218
    Identification of a dominant negative functional domain on DAPK-1 that degrades DAPK-1 protein and stimulates TNFR-1-mediated apoptosis.
    Lin Y, Stevens C, Hupp T.
    J Biol Chem. 2007 Jun 8;282(23):16792-802. Epub 2007 Feb 26.
    PMID 17324927
    The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase.
    Llambi F, Lourenco FC, Gozuacik D, Guix C, Pays L, Del Rio G, Kimchi A, Mehlen P.
    EMBO J. 2005 Mar 23;24(6):1192-201. Epub 2005 Feb 24.
    PMID 15729359
    Lipid raft localization and palmitoylation: identification of two requirements for cell death induction by the tumor suppressors UNC5H.
    Maisse C, Rossin A, Cahuzac N, Paradisi A, Klein C, Haillot ML, Herincs Z, Mehlen P, Hueber AO.
    Exp Cell Res. 2008 Aug 15;314(14):2544-52. Epub 2008 Jun 7.
    PMID 18582460
    DAPK promotor methylation is an early event in colorectal carcinogenesis.
    Mittag F, Kuester D, Vieth M, Peters B, Stolte B, Roessner A, Schneider-Stock R.
    Cancer Lett. 2006 Aug 18;240(1):69-75. Epub 2005 Oct 24.
    PMID 16246486
    DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression.
    Mukhopadhyay R, Ray PS, Arif A, Brady AK, Kinter M, Fox PL.
    Mol Cell. 2008 Nov 7;32(3):371-82.
    PMID 18995835
    DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation.
    Raveh T, Droguett G, Horwitz MS, DePinho RA, Kimchi A.
    Nat Cell Biol. 2001 Jan;3(1):1-7.
    PMID 11146619
    Death-associated protein kinase phosphorylates mammalian ribosomal protein S6 and reduces protein synthesis.
    Schumacher AM, Velentza AV, Watterson DM, Dresios J.
    Biochemistry. 2006 Nov 14;45(45):13614-21.
    PMID 17087515
    Death-associated protein kinase is activated by dephosphorylation in response to cerebral ischemia.
    Shamloo M, Soriano L, Wieloch T, Nikolich K, Urfer R, Oksenberg D.
    J Biol Chem. 2005 Dec 23;280(51):42290-9. Epub 2005 Oct 3.
    PMID 16204252
    Death-Associated Protein Kinase Phosphorylates ZIP Kinase, Forming a Unique Kinase Hierarchy To Activate Its Cell Death Functions.
    Shani G, Marash L, Gozuacik D, Bialik S, Teitelbaum L, Shohat G, Kimchi A.
    Mol Cell Biol. 2004 Oct;24(19):8611-26.
    PMID 15367680
    Peptide 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, Lin Y, Harrison B, Burch L, Ridgway RA, Sansom O, Hupp T.
    J Biol Chem. 2009 Jan 2;284(1):334-44. Epub 2008 Oct 30.
    PMID 18974095
    Ca2+-dependent phosphorylation of syntaxin-1A by the death-associated protein (DAP) kinase regulates its interaction with Munc18.
    Tian JH, Das S, Sheng ZH.
    J Biol Chem. 2003 Jul 11;278(28):26265-74. Epub 2003 May 2.
    PMID 12730201
    The tumor suppressor DAPK is reciprocally regulated by tyrosine kinase Src and phosphatase LAR.
    Wang WJ, Kuo JC, Ku W, Lee YR, Lin FC, Chang YL, Lin YM, Chen CH, Huang YP, Chiang MJ, Yeh SW, Wu PR, Shen CH, Wu CT, Chen RH.
    Mol Cell. 2007 Sep 7;27(5):701-16.
    PMID 17803936
    Multiple gene methylation of nonsmall cell lung cancers evaluated with 3-dimensional microarray.
    Wang Y, Zhang D, Zheng W, Luo J, Bai Y, Lu Z.
    Cancer. 2008 Mar 15;112(6):1325-36.
    PMID 18286531


    This paper should be referenced as such :
    Schneider-Stock, R ; Roessner, A ; Bajbouj, K
    DAPK1 (death-associated protein kinase 1)
    Atlas Genet Cytogenet Oncol Haematol. 2010;14(1):7-10.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
      Head and Neck: Epidermoid carcinoma
    DAPK1/AGTPBP1 (9q21)
    t(9;13)(q21;q32) TGDS/DAPK1

    External links

    Genomic and cartography
    Gene and transcription
    RefSeq transcript (Entrez)
    RefSeq genomic (Entrez)
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    BioGPS (Tissue expression)1612
    Protein : pattern, domain, 3D structure
    Domain families : Pfam (Sanger)
    Domain families : Pfam (NCBI)
    Protein Interaction databases
    Ontologies - Pathways
    Clinical trials, drugs, therapy
    canSAR (ICR) (select the gene name)
    REVIEW articlesautomatic search in PubMed
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    indexed on : Thu Oct 18 17:33:22 CEST 2018

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