Alternative titles; symbols
HGNC Approved Gene Symbol: DAPK1
Cytogenetic location: 9q21.33 Genomic coordinates (GRCh38): 9:87,497,228-87,708,634 (from NCBI)
Death-associated protein kinase (DAPK1) and DAP (600954) are positive mediators of the programmed cell death induced by gamma-interferon (IFNG; 147570). The inactivation of these genes by antisense RNA expression reduced the susceptibility of HeLa cells to IFNG-induced apoptosis. DAP is expressed as a single 2.4-kb mRNA that codes for a basic proline-rich 15-kD protein. DAPK is transcribed into a single 6.3-kb mRNA encoded for a structurally unique 160-kD calmodulin (114180)-dependent serine-threonine kinase that carries 8 ankyrin repeats and 2 putative P-loop consensus sites (Deiss et al., 1995).
Inbal et al. (1997) found that mouse lung carcinoma clones characterized by highly aggressive metastatic behavior did not express Dapk. Restoration of Dapk to physiologic levels in Lewis carcinoma cells suppressed their ability to form lung metastases and delayed local tumor growth. In situ TUNEL staining of tumor sections revealed that Dapk expression raised the incidence of apoptosis in vivo. Dapk transfectants also showed increased sensitivity in vitro to apoptotic stimuli. Inbal et al. (1997) concluded that loss of DAPK expression provides a link between suppression of apoptosis and metastasis.
Raveh et al. (2001) showed that Dapk1 counteracts oncogene-induced transformation of mouse primary embryonic fibroblasts (MEFs) by activating p53 (191170) in a p19ARF (600160)-dependent manner. Furthermore, they demonstrated that Dapk1 is involved in an intrinsic p53-dependent apoptotic checkpoint that is turned on by oncogenes at the initial stages of transformation. Expression of Myc (190080) or E2f1 (189971) induced an upregulation of Dapk1, along with p19Arf and p53, in wildtype, but not Dapk1-deficient, MEFs. Raveh et al. (2001) concluded that DAPK1 is involved in an early apoptotic checkpoint designed to eliminate premalignant cells from cancer development.
Jang et al. (2002) determined that the human DAP-kinase promoter is activated by TGFB (see 190180) through the action of SMAD2 (601366), SMAD3 (603109), and SMAD4 (600993). Overexpression of DAP-kinase triggers apoptosis in the absence of TGFB, whereas inhibition of DAP-kinase activity protects cells from TGFB-induced apoptosis, blocks TGFB-induced release of cytochrome c from mitochondria, and prevents TGFB-induced dissipation of the mitochondrial membrane potential. Jang et al. (2002) concluded that DAP-kinase mediates TGFB-dependent apoptosis by linking SMADs to mitochondrial-based pro-apoptotic events.
Simpson et al. (2002) examined 32 sporadic pituitary tumors for expression of the DAP kinase protein and transcript. In addition, they examined the methylation and deletion status of the DAP kinase CpG island as possible mechanisms for inactivation of the DAPK1 gene. In 11 of 32 (34%) tumors, DAP kinase expression was undetectable by Western blot and/or RT-PCR analysis. Loss of DAP kinase expression was significantly (P = 0.004) associated with invasive tumors (10 of 17; 59%) compared to their noninvasive (1 of 15; 7%) counterparts. Of 11 tumors that failed to express DAP kinase, 5 (45%) showed de novo methylation of the CpG island contained within the promoter region, while 4 (36%) had evidence of homozygous deletion of this region.
Tada et al. (2002) examined the frequency of aberrant promoter hypermethylation of 7 genes in 55 superficial bladder cancers (109800) and 5 normal urothelial epithelia by methylation-specific PCR. Patients with superficial bladder cancer had been followed prospectively by cystoscopy. The results indicated that hypermethylation of DAPK1 is a strong indicator of high recurrence rate (P less than 0.001; hazards ratio, 7.01). This suggested that such hypermethylation may be a useful prognostic marker for disease recurrence in superficial bladder cancers.
Jin et al. (2002) found that Dip1 (608677) immunoprecipitated with Dapk from COS cell lysates; Dip1 interacted with the ankyrin repeats in Dapk. HeLa cells transiently expressing mouse Dip1 or only the Dip1 RING finger motifs showed DNA fragmentation characteristic of apoptotic changes. Overexpression of Dip1 abolished the antiapoptotic effect of Dapk expression. Dip1 regulated the cellular levels of Dapk through its E3 ubiquitin ligase activity, which promoted ubiquitination of Dapk in vitro and in vivo.
In hippocampal tissue from 10 patients with intractable temporal lobe epilepsy (608096), Henshall et al. (2004) found increased DAP kinase expression and phosphorylation compared to controls. In control brains, DAP kinase and DIP1 localized within the mitochondria, whereas in epilepsy brain tissue, levels of both were increased in the cytoplasm and microsomal fractions (endoplasmic reticulum). Coimmunoprecipitation analysis showed increased DAP kinase binding to calmodulin, DIP1, and the Fas-associated protein with death domain (FADD; 602457) in neurons of epilepsy brain tissue compared to controls. Henshall et al. (2004) suggested that DAP kinase is a molecular regulator of neuronal death in epilepsy.
Raval et al. (2007) found that epigenetic silencing of DAPK1 by promoter methylation occurs in almost all cases of sporadic chronic lymphocytic leukemia (CLL; 151400). DAPK1 expression was downregulated by 75% in germline cells due to increased HOXB7 (142962) binding. In blood cells from affected members of a family with CLL (see 612557), promoter methylation resulted in additional loss of DAPK1 expression. Raval et al. (2007) concluded that reduced expression of DAPK1 can result from germline predisposition as well as epigenetic or somatic events causing or contributing to the CLL phenotype.
Mukhopadhyay et al. (2008) noted that phosphorylation of ribosomal protein L13A (RPL13A; 619225) is essential for translational repression of inflammatory genes by the IFN-gamma-activated inhibitor of translation (GAIT) complex. They found that IFN-gamma activated a kinase cascade in which DAPK activated ZIPK (DAPK3; 603289), which then phosphorylated RPL13A at ser77 in human U937 cells. RPL13A phosphorylation by DAPK-ZIPK was not only required for activation of RPL13A and subsequent release from the ribosome, but also for GAIT-mediated translational silencing. GAIT-mediated translational silencing then targeted and repressed DAPK and ZIPK expression to return RPL13A to the nonphosphorylated, inactive form. This negative-feedback circuit restored cells to the basal state, allowing subsequent renewed induction of GAIT target transcripts by repeated stimulation.
Cerebral ischemia can cause overstimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, resulting in neurotoxicity and apoptotic cell death. Tu et al. (2010) found that Dapk1 was responsible for ischemia-induced neuronal death in mice. Dapk1 coprecipitated with the NMDA receptor complex and interacted directly with the NMDA subunit Nr2b (GRIN2B; 138252). Ischemia activated Dapk1, and activated Dapk1 serine phosphorylated Nr2b at extrasynaptic sites, leading to injurious Ca(2+) influx. Knockdown of Dapk1 or blocking the Dapk1-Nr2b interaction protected mice against cerebral ischemic damage.
The apoptosis mediators DAPK and UNC5H2 (UNC5B; 607870) form a dimer via their death domains, and DAPK induces cell death via its serine-threonine kinase activity. Guenebeaud et al. (2010) found that the DAPK/UNC5H2 complex associated with the protein phosphatase-2A (PP2A; see 176915) complex in human cell lines via the PP2A subunit PR65-beta (PPP2R1B; 603113). In the presence of the UNC5H2 ligand netrin-1 (NTN1; 601614), CIP2A (KIAA1524; 610643) was recruited to the complex and repressed the phosphatase activity of PP2A. In this context, DAPK was inactivated by autophosphorylation on ser308. In the absence of netrin-1, a conformational change occurred in UNC5H2 concomitant with exposure of its death domain, release of CIP2A, and DAPK dephosphorylation and activation. Guenebeaud et al. (2010) concluded that PP2A is a mediator of DAPK/UNC5H2-induced apoptosis and that recruitment of CIP2A inhibits this pathway.
Since genes involved in the control of cell death can, when dysregulated, behave as oncogenes or growth suppressor genes, Feinstein et al. (1995) determined the chromosome localization of DAP and DAPK1 as a useful indicator of their possible involvement in neoplasia or other diseases. Analysis of rodent-human somatic cell hybrids indicated that DAP is located on chromosome 5p15.2. (The title of the article by Feinstein et al. (1995) erroneously stated that the gene was mapped to 5p12.2.) The DAPK1 cDNA probe was mapped to 9pter-q34 in rodent/human hybrids and was localized to 9q34.1 by fluorescence in situ hybridization. It was thought to be located centromeric to the ABL locus (189980). Loss of heterozygosity studies in bladder cancer had suggested the presence of a suppressor gene between 9q33 and 9q34.2, for which DAPK may be a candidate.
Deiss, L. P., Feinstein, E., Berissi, H., Cohen, O., Kimchi, A. Identification of a novel serine/threonine kinase and a novel 15-kD protein as potential mediators of the gamma interferon-induced cell death. Genes Dev. 9: 15-30, 1995. [PubMed: 7828849] [Full Text: https://doi.org/10.1101/gad.9.1.15]
Feinstein, E., Druck, T., Kastury, K., Berissi, H., Goodart, S. A., Overhauser, J., Kimchi, A., Huebner, K. Assignment of DAP1 and DAPK: genes that positively mediate programmed cell death triggered by IFN-gamma--to chromosome regions 5p12.2 and 9q34.1, respectively. Genomics 29: 305-307, 1995. [PubMed: 8530096] [Full Text: https://doi.org/10.1006/geno.1995.1255]
Guenebeaud, C., Goldschneider, D., Castets, M., Guix, C., Chazot, G., Delloye-Bourgeois, C., Eisenberg-Lerner, A., Shohat, G., Zhang, M., Laudet, V., Kimchi, A., Bernet, A., Mehlen, P. The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. Molec. Cell 40: 863-876, 2010. [PubMed: 21172653] [Full Text: https://doi.org/10.1016/j.molcel.2010.11.021]
Henshall, D. C., Schindler, C. K., So, N. K., Lan, J.-Q., Meller, R., Simon, R. P. Death-associated protein kinase expression in human temporal lobe epilepsy. Ann. Neurol. 55: 485-494, 2004. [PubMed: 15048887] [Full Text: https://doi.org/10.1002/ana.20001]
Inbal, B., Cohen, O., Polak-Charcon, S., Kopolovic, J., Vadai, E., Eisenbach, L., Kimchi, A. DAP kinase links the control of apoptosis to metastasis. Nature 390: 180-184, 1997. [PubMed: 9367156] [Full Text: https://doi.org/10.1038/36599]
Jang, C.-W., Chen, C.-H., Chen, C.-C., Chen, J., Su, Y.-H., Chen, R.-H. TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. Nature Cell Biol. 4: 51-58, 2002. Note: Erratum: Nature Cell Biol. 4: 328 only, 2002. [PubMed: 11740493] [Full Text: https://doi.org/10.1038/ncb731]
Jin, Y., Blue, E. K., Dixon, S., Shao, Z., Gallagher, P. J. A death-associated protein kinase (DAPK)-interacting protein, DIP-1, is an E3 ubiquitin ligase that promotes tumor necrosis factor-induced apoptosis and regulates the cellular levels of DAPK. J. Biol. Chem. 277: 46980-46986, 2002. [PubMed: 12351649] [Full Text: https://doi.org/10.1074/jbc.M208585200]
Mukhopadhyay, R., Ray, P. S., Arif, A., Brady, A. K., Kinter, M., Fox, P. L. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression. Molec. Cell 32: 371-382, 2008. [PubMed: 18995835] [Full Text: https://doi.org/10.1016/j.molcel.2008.09.019]
Raval, A., Tanner, S. M., Byrd, J. C., Angerman, E. B., Perko, J. D., Chen, S.-S., Hackanson, B., Grever, M. R., Lucas, D. M., Matkovic, J. J., Lin, T. S., Kipps, T. J., and 14 others. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 129: 879-890, 2007. [PubMed: 17540169] [Full Text: https://doi.org/10.1016/j.cell.2007.03.043]
Raveh, T., Droguett, G., Horwitz, M. S., DePinho, R. A., Kimchi, A. DAP kinase activates a p19-ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nature Cell Biol. 3: 1-7, 2001. [PubMed: 11146619] [Full Text: https://doi.org/10.1038/35050500]
Simpson, D. J., Clayton, R. N., Farrell, W. E. Preferential loss of death associated protein kinase expression in invasive pituitary tumours is associated with either CpG island methylation or homozygous deletion. Oncogene 21: 1217-1224, 2002. [PubMed: 11850841] [Full Text: https://doi.org/10.1038/sj.onc.1205195]
Tada, Y., Wada, M., Taguchi, K., Mochida, Y., Kinugawa, N., Tsuneyoshi, M., Naito, S., Kuwano, M. The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers. Cancer Res. 62: 4048-4053, 2002. [PubMed: 12124340]
Tu, W., Xu, X., Peng, L., Zhong, X., Zhang, W., Soundarapandian, M. M., Balel, C., Wang, M., Jia, N., Zhang, W., Lew, F., Chan, S. L., Chen, Y., Lu, Y. DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 140: 222-234, 2010. [PubMed: 20141836] [Full Text: https://doi.org/10.1016/j.cell.2009.12.055]