DAPK1 explained

Death-associated protein kinase 1 is an enzyme that in humans is encoded by the DAPK1 gene.^[1]

Function

Death-associated protein kinase 1 is a positive mediator of gamma-interferon induced programmed cell death. DAPK1 encodes a structurally unique 160-kD calmodulin dependent serine-threonine kinase that carries 8 ankyrin repeats and 2 putative P-loop consensus sites. It is a tumor suppressor candidate.^[2]

In melanocytic cells DAPK1 gene expression may be regulated by MITF.^[3]

As a drug target

Depletion of DAPK1 results in inhibition of tumor cell count and volume growth in cellular and animal models of triple receptor-negative breast cancer, from individuals with p53-mutant cancers.^[4] This has not been demonstrated in actual patients.

Further reading

• Deiss LP, 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 & Development . 9 . 1 . 15–30 . Jan 1995 . 7828849 . 10.1101/gad.9.1.15 . free .
• Inbal B, Shani G, Cohen O, Kissil JL, Kimchi A . Death-associated protein kinase-related protein 1, a novel serine/threonine kinase involved in apoptosis . Molecular and Cellular Biology . 20 . 3 . 1044–54 . Feb 2000 . 10629061 . 85221 . 10.1128/MCB.20.3.1044-1054.2000 .
• Jin Y, Blue EK, Dixon S, Hou L, Wysolmerski RB, Gallagher PJ . Identification of a new form of death-associated protein kinase that promotes cell survival . The Journal of Biological Chemistry . 276 . 43 . 39667–78 . Oct 2001 . 11485996 . 2823794 . 10.1074/jbc.M101886200 . free .
• Shohat G, Spivak-Kroizman T, Cohen O, Bialik S, Shani G, Berrisi H, Eisenstein M, Kimchi A . The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism . The Journal of Biological Chemistry . 276 . 50 . 47460–7 . Dec 2001 . 11579085 . 10.1074/jbc.M105133200 . free .
• Soria JC, Rodriguez M, Liu DD, Lee JJ, Hong WK, Mao L . Aberrant promoter methylation of multiple genes in bronchial brush samples from former cigarette smokers . Cancer Research . 62 . 2 . 351–5 . Jan 2002 . 11809677 .
• Larramendy ML, Niini T, Elonen E, Nagy B, Ollila J, Vihinen M, Knuutila S . Overexpression of translocation-associated fusion genes of FGFRI, MYC, NPMI, and DEK, but absence of the translocations in acute myeloid leukemia. A microarray analysis . Haematologica . 87 . 6 . 569–77 . Jun 2002 . 12031912 .
• Hasegawa M, Nelson HH, Peters E, Ringstrom E, Posner M, Kelsey KT . Patterns of gene promoter methylation in squamous cell cancer of the head and neck . Oncogene . 21 . 27 . 4231–6 . Jun 2002 . 12082610 . 10.1038/sj.onc.1205528 . 24566542 .
• Jin Y, Blue EK, Dixon S, Shao Z, Gallagher PJ . 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 . The Journal of Biological Chemistry . 277 . 49 . 46980–6 . Dec 2002 . 12351649 . 2824503 . 10.1074/jbc.M208585200 . free .
• Wang WJ, Kuo JC, Yao CC, Chen RH . DAP-kinase induces apoptosis by suppressing integrin activity and disrupting matrix survival signals . The Journal of Cell Biology . 159 . 1 . 169–79 . Oct 2002 . 12370243 . 2173490 . 10.1083/jcb.200204050 .
• Nakatsuka S, Takakuwa T, Tomita Y, Hoshida Y, Nishiu M, Yamaguchi M, Nishii K, Yang WI, Aozasa K . Hypermethylation of death-associated protein (DAP) kinase CpG island is frequent not only in B-cell but also in T- and natural killer (NK)/T-cell malignancies . Cancer Science . 94 . 1 . 87–91 . Jan 2003 . 12708480 . 10.1111/j.1349-7006.2003.tb01357.x . 11818957 . free . 11160098 .
• Tian JH, Das S, Sheng ZH . Ca2+-dependent phosphorylation of syntaxin-1A by the death-associated protein (DAP) kinase regulates its interaction with Munc18 . The Journal of Biological Chemistry . 278 . 28 . 26265–74 . Jul 2003 . 12730201 . 10.1074/jbc.M300492200 . free .
• Gonzalez-Gomez P, Bello MJ, Alonso ME, Lomas J, Arjona D, Amiñoso C, De Campos JM, Isla A, Gutierrez M, Rey JA . Frequent death-associated protein-kinase promoter hypermethylation in brain metastases of solid tumors . Oncology Reports . 10 . 4 . 1031–3 . 2004 . 12792765 . 10.3892/or.10.4.1031 .
• Matsumoto H, Nagao M, Ogawa S, Kanehiro H, Hisanaga M, Ko S, Ikeda N, Fujii H, Koyama F, Mukogawa T, Nakajima Y . Prognostic significance of death-associated protein-kinase expression in hepatocellular carcinomas . Anticancer Research . 23 . 2B . 1333–41 . 2003 . 12820391 .
• Henshall DC, Araki T, Schindler CK, Shinoda S, Lan JQ, Simon RP . Expression of death-associated protein kinase and recruitment to the tumor necrosis factor signaling pathway following brief seizures . Journal of Neurochemistry . 86 . 5 . 1260–70 . Sep 2003 . 12911633 . 10.1046/j.1471-4159.2003.01934.x . 21971958 . free .
• Voso MT, Scardocci A, Guidi F, Zini G, Di Mario A, Pagano L, Hohaus S, Leone G . Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes . Blood . 103 . 2 . 698–700 . Jan 2004 . 14504087 . 10.1182/blood-2003-07-2249 . free .
• Jin Y, Gallagher PJ . Antisense depletion of death-associated protein kinase promotes apoptosis . The Journal of Biological Chemistry . 278 . 51 . 51587–93 . Dec 2003 . 14530257 . 2823796 . 10.1074/jbc.M309165200 . free .
• Kim WS, Son HJ, Park JO, Song SY, Park C . Promoter methylation and down-regulation of DAPK is associated with gastric atrophy . International Journal of Molecular Medicine . 12 . 6 . 827–30 . Dec 2003 . 14612952 . 10.3892/ijmm.12.6.827 .
• Bai T, Tanaka T, Yukawa K, Maeda M, Umesaki N . Reduced expression of death-associated protein kinase in human uterine and ovarian carcinoma cells . Oncology Reports . 11 . 3 . 661–5 . Mar 2004 . 14767518 . 10.3892/or.11.3.661 .

Notes and References

1. Feinstein E, Druck T, Kastury K, Berissi H, Goodart SA, 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 . 1 . 305–7 . Sep 1995 . 8530096 . 10.1006/geno.1995.1255 .
2. Web site: Entrez Gene: DAPK1 death-associated protein kinase 1.
3. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E . Novel MITF targets identified using a two-step DNA microarray strategy . Pigment Cell & Melanoma Research . 21 . 6 . 665–76 . Dec 2008 . 19067971 . 10.1111/j.1755-148X.2008.00505.x . 24698373 . free .
4. Zhao J, Zhao D, Poage GM, Mazumdar A, Zhang Y, Hill JL, Hartman ZC, Savage MI, Mills GB, Brown PH . Death-associated protein kinase 1 promotes growth of p53-mutant cancers . The Journal of Clinical Investigation . 125 . 7 . 2707–20 . Jul 2015 . 26075823 . 10.1172/JCI70805 . 4563671.