Death-Associated Protein Kinase 1 as a Promising Drug Target in Cancer and Alzheimer’s Disease

Author(s): Dongmei Chen, Xiao Z. Zhou*, Tae H. Lee*

Journal Name: Recent Patents on Anti-Cancer Drug Discovery

Volume 14 , Issue 2 , 2019

Become EABM
Become Reviewer
Call for Editor


Background: Death-Associated Protein Kinase 1 (DAPK1) plays an important role in apoptosis, tumor suppression and neurodegeneration including Alzheimer’s Disease (AD).

Objective: This review will describe the diverse roles of DAPK1 in the development of cancer and AD, and the current status of drug development targeting DAPK1-based therapies.

Methods: Reports of DAPK1 regulation, function and substrates were analyzed using genetic DAPK1 manipulation and chemical DAPK1 modulators.

Results: DAPK1 expression and activity are deregulated in cancer and AD. It is down-regulated and/or inactivated by multiple mechanisms in many human cancers, and elicits a protective effect to counteract numerous death stimuli in cancer, including activation of the master regulator Pin1. Moreover, loss of DAPK1 expression has correlated strongly with tumor recurrence and metastasis, suggesting that lack of sufficient functional DAPK1 might contribute to cancer. In contrast, DAPK1 is highly expressed in the brains of most human AD patients and has been identified as one of the genetic factors affecting susceptibility to late-onset AD. The absence of DAPK1 promotes efficient learning and better memory in mice and prevents the development of AD by acting on many key proteins including Pin1 and its downstream targets tau and APP. Recent patents show that DAPK1 modulation might be used to treat both cancer and AD.

Conclusion: DAPK1 plays a critical role in diverse physiological processes and importantly, its deregulation is implicated in the pathogenesis of either cancer or AD. Therefore, manipulating DAPK1 activity and/or expression may be a promising therapeutic option for cancer or AD.

Keywords: Alzheimer's Disease (AD), apoptosis, cancer, Death-Associated Protein Kinase 1 (DAPK1), kinase modulator, phosphorylation, therapeutic target.

Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001; 411(6835): 355-65.
Pawson T, Scott JD. Protein phosphorylation in signaling: 50 Years and counting. Trends Biochem Sci 2005; 30(6): 286-90.
Lee TH, Pastorino L, Lu KP. Peptidyl-prolyl cis-trans isomerase Pin1 in ageing, cancer and Alzheimer disease. Expert Rev Mol Med 2011; 13e21
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011; 144(5): 646-74.
Fujita Y, Yamashita T. Role of DAPK in neuronal cell death. Apoptosis 2014; 19(2): 339-45.
Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal cell death in Alzheimer’s disease. J Neurosci 2001; 21(8): 2661-8.
Nagy Z, Esiri MM, Smith AD. The cell division cycle and the pathophysiology of Alzheimer’s disease. Neuroscience 1998; 87(4): 731-9.
Raina AK, Monteiro MJ, McShea A, Smith MA. The role of cell cycle-mediated events in Alzheimer’s disease. Int J Exp Pathol 1999; 80(2): 71-6.
Gandy SE, Caporaso GL, Buxbaum JD, De Cruz Silva O, Iverfeldt K, Nordstedt C, et al. Protein phosphorylation regulates relative utilization of processing pathways for Alzheimer beta/A4 amyloid precursor protein. Ann N Y Acad Sci 1993; 695: 117-21.
Preuss U, Doring F, Illenberger S, Mandelkow EM. Cell cycle-dependent phosphorylation and microtubule binding of tau protein stably transfected into Chinese hamster ovary cells. Mol Biol Cell 1995; 6(10): 1397-410.
Musicco M, Adorni F, Di Santo S, Prinelli F, Pettenati C, Caltagirone C, et al. Inverse occurrence of cancer and Alzheimer disease: A population-based incidence study. Neurology 2013; 81(4): 322-8.
Ou SM, Lee YJ, Hu YW, Liu CJ, Chen TJ, Fuh JL, et al. Does Alzheimer’s disease protect against cancers? A nationwide population-based study. Neuroepidemiology 2013; 40(1): 42-9.
Roe CM, Behrens MI, Xiong C, Miller JP, Morris JC. Alzheimer disease and cancer. Neurology 2005; 64(5): 895-8.
Bialik S, Kimchi A. The death-associated protein kinases: Structure, function, and beyond. Annu Rev Biochem 2006; 75: 189-210.
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 Dev 1995; 9(1): 15-30.
Shiloh R, Bialik S, Kimchi A. The DAPK family: A structure-function analysis. Apoptosis 2014; 19(2): 286-97.
Levin-Salomon V, Bialik S, Kimchi A. DAP-kinase and autophagy. Apoptosis 2014; 19(2): 346-56.
Chen HY, Lee YR, Chen RH. The functions and regulations of DAPK in cancer metastasis. Apoptosis 2014; 19(2): 364-70.
Lai MZ, Chen RH. Regulation of inflammation by DAPK. Apoptosis 2014; 19(2): 357-63.
Michie AM, McCaig AM, Nakagawa R, Vukovic M. Death-associated protein kinase (DAPK) and signal transduction: Regulation in cancer. FEBS J 2010; 277(1): 74-80.
Kim BM, You M-H, Chen C-H, Lee S, Hong Y, Hong Y, et al. Death-associated protein kinase 1 plays a critical role in aberrant tau protein regulation and function. Cell Death Dis 2014; 5e1237
Kim BM, You MH, Chen CH, Suh J, Tanzi RE, Lee TH. Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein. Hum Mol Genet 2016; 25(12): 2498-513.
Li Y, Grupe A, Rowland C, Nowotny P, Kauwe JS, Smemo S, et al. DAPK1 variants are associated with Alzheimer’s disease and allele-specific expression. Hum Mol Genet 2006; 15(17): 2560-8.
Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol 2008; 65(1): 45-53.
Laumet G, Chouraki V, Grenier-Boley B, Legry V, Heath S, Zelenika D, et al. Systematic analysis of candidate genes for Alzheimer’s disease in a French, genome-wide association study. J Alzheimers Dis 2010; 20(4): 1181-8.
Gaj P, Paziewska A, Bik W, Dabrowska M, Baranowska-Bik A, Styczynska M, et al. Identification of a late onset Alzheimer’s disease candidate risk variant at 9q21.33 in Polish patients. J Alzheimers Dis 2012; 32(1): 157-68.
Kristensen LS, Asmar F, Dimopoulos K, Nygaard MK, Aslan D, Hansen JW, et al. Hypermethylation of DAPK1 is an independent prognostic factor predicting survival in diffuse large B-cell lymphoma. Oncotarget 2014; 5(20): 9798-810.
Behrens MI, Lendon C, Roe CM. A common biological mechanism in cancer and Alzheimer’s disease? Curr Alzheimer Res 2009; 6(3): 196-204.
Huang Y, Chen L, Guo L, Hupp TR, Lin Y. Evaluating DAPK as a therapeutic target. Apoptosis 2014; 19(2): 371-86.
Xu L, Li B, Jia J. DAPK1: A Novel pathology and treatment target for Alzheimer’s Disease. Mol Neurobiol 2018.
Singh P, Ravanan P, Talwar P. Death associated protein kinase 1 (DAPK1): A Regulator of apoptosis and autophagy. Front Mol Neurosci 2016; 9: 46-52.
Tereshko V, Teplova M, Brunzelle J, Watterson DM, Egli M. Crystal structures of the catalytic domain of human protein kinase associated with apoptosis and tumor suppression. Nat Struct Biol 2001; 8(10): 899-907.
Zimmermann M, Atmanene C, Xu Q, Fouillen L, Van Dorsselaer A, Bonnet D, et al. Homodimerization of the death-associated protein kinase catalytic domain: Development of a new small molecule fluorescent reporter. PLoS One 2010; 5(11)e14120
Velentza AV, Schumacher AM, Weiss C, Egli M, Watterson DM. A protein kinase associated with apoptosis and tumor suppression: Structure, activity, and discovery of peptide substrates. J Biol Chem 2001; 276(42): 38956-65.
Cohen O, Feinstein E, Kimchi A. DAP-kinase is a Ca2+/calmodulin-dependent, cytoskeletal-associated protein kinase, with cell death-inducing functions that depend on its catalytic activity. EMBO J 1997; 16(5): 998-1008.
Shohat G, Spivak-Kroizman T, Cohen O, Bialik S, Shani G, Berrisi H, et al. The pro-apoptotic function of death-associated protein kinase is controlled by a unique inhibitory autophosphorylation-based mechanism. J Biol Chem 2001; 276(50): 47460-7.
Shani G, Henis-Korenblit S, Jona G, Gileadi O, Eisenstein M, Ziv T, et al. Autophosphorylation restrains the apoptotic activity of DRP-1 kinase by controlling dimerization and calmodulin binding. EMBO J 2001; 20(5): 1099-113.
Carlessi R, Levin-Salomon V, Ciprut S, Bialik S, Berissi H, Albeck S, et al. GTP binding to the ROC domain of DAP-kinase regulates its function through intramolecular signalling. EMBO Rep 2011; 12(9): 917-23.
Gozuacik D, Bialik S, Raveh T, Mitou G, Shohat G, Sabanay H, et al. DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. Cell Death Differ 2008; 15(12): 1875-86.
Guenebeaud C, Goldschneider D, Castets M, Guix C, Chazot G, Delloye-Bourgeois C, et al. The dependence receptor UNC5H2/B triggers apoptosis via PP2A-mediated dephosphorylation of DAP kinase. Mol Cell 2010; 40(6): 863-76.
Tu W, Xu X, Peng L, Zhong X, Zhang W, Soundarapandian MM, et al. DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell 2010; 140(2): 222-34.
Bialik S, Bresnick AR, Kimchi A. DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation. Cell Death Differ 2004; 11(6): 631-44.
Raveh T, Berissi H, Eisenstein M, Spivak T, Kimchi A. A functional genetic screen identifies regions at the C-terminal tail and death-domain of death-associated protein kinase that are critical for its proapoptotic activity. Proc Natl Acad Sci USA 2000; 97(4): 1572-7.
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. J Biol Chem 2002; 277(49): 46980-6.
Lee TH, Chen C-H, Suizu F, Huang P, Schiene-Fischer C, Daum S, et al. Death associated protein kinase phosphorylates Pin1 and inhibits its prolyl isomerase activity and cellular function. Mol Cell 2011: In press.
Bialik S, Kimchi A. Pin-pointing a new DAP kinase function: The peptidyl-proly isomerase Pin1 is negatively regulated by DAP kinase-mediated phosphorylation. Mol Cell 2011; 42(2): 139-41.
You MH, Kim BM, Chen CH, Begley MJ, Cantley LC, Lee TH. Death-associated protein kinase 1 phosphorylates NDRG2 and induces neuronal cell death. Cell Death Differ 2017; 24(2): 238-50.
Bialik S, Kimchi A. The DAP-kinase interactome. Apoptosis 2014; 19(2): 316-28.
Chen CH, Wang WJ, Kuo JC, Tsai HC, Lin JR, Chang ZF, et al. Bidirectional signals transduced by DAPK-ERK interaction promote the apoptotic effect of DAPK. EMBO J 2005; 24(2): 294-304.
Llambi F, Lourenco FC, Gozuacik D, Guix C, Pays L, Del Rio G, et al. The dependence receptor UNC5H2 mediates apoptosis through DAP-kinase. EMBO J 2005; 24(6): 1192-201.
Lee YR, Yuan WC, Ho HC, Chen CH, Shih HM, Chen RH. The Cullin 3 substrate adaptor KLHL20 mediates DAPK ubiquitination to control interferon responses. EMBO J 2010; 29(10): 1748-61.
Wu PR, Tsai PI, Chen GC, Chou HJ, Huang YP, Chen YH, et al. DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity. Cell Death Differ 2011; 18(9): 1507-20.
Mor I, Carlessi R, Ast T, Feinstein E, Kimchi A. Death-associated protein kinase increases glycolytic rate through binding and activation of pyruvate kinase. Oncogene 2012; 31(6): 683-93.
Stevens C, Lin Y, Harrison B, Burch L, Ridgway RA, Sansom O, et al. 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. J Biol Chem 2009; 284(1): 334-44.
Fodale V, Pierobon M, Liotta L, Petricoin E. Mechanism of cell adaptation: When and how do cancer cells develop chemoresistance? Cancer J 2011; 17(2): 89-95.
Morris LG, Chan TA. Therapeutic targeting of tumor suppressor genes. Cancer 2015; 121(9): 1357-68.
Bialik S, Kimchi A. DAP-kinase as a target for drug design in cancer and diseases associated with accelerated cell death. Semin Cancer Biol 2004; 14(4): 283-94.
Gozuacik D, Kimchi A. DAPk protein family and cancer. Autophagy 2006; 2(2): 74-9.
Benderska N, Schneider-Stock R. Transcription control of DAPK. Apoptosis 2014; 19(2): 298-305.
Tang X, Khuri FR, Lee JJ, Kemp BL, Liu D, Hong WK, et al. Hypermethylation of the death-associated protein (DAP) kinase promoter and aggressiveness in stage I non-small-cell lung cancer. J Natl Cancer Inst 2000; 92(18): 1511-6.
Kim DH, Nelson HH, Wiencke JK, Christiani DC, Wain JC, Mark EJ, et al. Promoter methylation of DAP-kinase: Association with advanced stage in non-small cell lung cancer. Oncogene 2001; 20(14): 1765-70.
Harden SV, Tokumaru Y, Westra WH, Goodman S, Ahrendt SA, Yang SC, et al. Gene promoter hypermethylation in tumors and lymph nodes of stage I lung cancer patients. Clin Cancer Res 2003; 9(4): 1370-5.
Hu SL, Kong XY, Cheng ZD, Sun YB, Shen G, Xu WP, et al. Promoter methylation of p16, Runx3, DAPK and CHFR genes is frequent in gastric carcinoma. Tumori 2010; 96(5): 726-33.
Chan AW, Chan MW, Lee TL, Ng EK, Leung WK, Lau JY, et al. Promoter hypermethylation of death-associated protein-kinase gene associated with advance stage gastric cancer. Oncol Rep 2005; 13(5): 937-41.
Sanchez-Cespedes M, Esteller M, Wu L, Nawroz-Danish H, Yoo GH, Koch WM, et al. Gene promoter hypermethylation in tumors and serum of head and neck cancer patients. Cancer Res 2000; 60(4): 892-5.
Levy D, Plu-Bureau G, Decroix Y, Hugol D, Rostene W, Kimchi A, et al. Death-associated protein kinase loss of expression is a new marker for breast cancer prognosis. Clin Cancer Res 004; 10(9): 3124-30.
Brabender J, Arbab D, Huan X, Vallbohmer D, Grimminger P, Ling F, et al. Death-associated protein kinase (DAPK) promoter methylation and response to neoadjuvant radiochemotherapy in esophageal cancer. Ann Surg Oncol 2009; 16(5): 1378-83.
Inbal B, Cohen O, Polak-Charcon S, Kopolovic J, Vadai E, Eisenbach L, et al. DAP kinase links the control of apoptosis to metastasis. Nature 1997; 390(6656): 180-4.
Raval A, Tanner SM, Byrd JC, Angerman EB, Perko JD, Chen SS, et al. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell 2007; 129(5): 879-90.
Chen HY, Lin YM, Chung HC, Lang YD, Lin CJ, Huang J, et al. miR-103/107 promotes metastasis of colorectal cancer by targeting the metastasis suppressors DAPK and KLF4. Cancer Res 2012; 72(14): 3631-41.
Wang WJ, Kuo JC, Ku W, Lee YR, Lin FC, Chang YL, et al. The tumor suppressor DAPK is reciprocally regulated by tyrosine kinase Src and phosphatase LAR. Mol Cell 2007; 27(5): 701-16.
Anjum R, Roux PP, Ballif BA, Gygi SP, Blenis J. The tumor suppressor DAP kinase is a target of RSK-mediated survival signaling. Curr Biol 2005; 15(19): 1762-7.
Citri A, Harari D, Shohat G, Ramakrishnan P, Gan J, Lavi S, et al. Hsp90 recognizes a common surface on client kinases. J Biol Chem 2006; 281(20): 14361-9.
Zhang L, Nephew KP, Gallagher PJ. Regulation of death-associated protein kinase. Stabilization by HSP90 heterocomplexes. J Biol Chem 2007; 282(16): 11795-804.
Raveh T, Droguett G, Horwitz MS, DePinho RA, Kimchi A. DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation. Nat Cell Biol 2001; 3(1): 1-7.
Wang WJ, Kuo JC, Yao CC, Chen RH. DAP-kinase induces apoptosis by suppressing integrin activity and disrupting matrix survival signals. J Cell Biol 2002; 159(1): 169-79.
Martoriati A, Doumont G, Alcalay M, Bellefroid E, Pelicci PG, Marine JC. DAPK1, encoding an activator of a p19ARF-p53-mediated apoptotic checkpoint, is a transcription target of p53. Oncogene 2005; 24(8): 1461-6.
Zhao J, Zhao D, Poage GM, Mazumdar A, Zhang Y, Hill JL, et al. Death-associated protein kinase 1 promotes growth of p53-mutant cancers. J Clin Invest 2015; 125(7): 2707-20.
Lu KP, Zhou XZ. The prolyl isomerase PIN1: A pivotal new twist in phosphorylation signalling and disease. Nat Rev Mol Cell Biol 2007; 8: 904-16.
Lu KP. Pinning down cell signaling, cancer and Alzheimer’s disease. Trends Biochem Sci 2004; 29: 200-9.
Lu KP, Finn G, Lee TH, Nicholson LK. Prolyl cis-trans isomerization as a molecular timer. Nat Chem Biol 2007; 3(10): 619-29.
Zhou XZ, Lu KP. The isomerase PIN1 controls numerous cancer-driving pathways and is a unique drug target. Nat Rev Cancer 2016; 16(7): 463-78.
Min SH, Zhou XZ, Lu KP. The role of Pin1 in the development and treatment of cancer. Arch Pharm Res 2016; 39(12): 1609-20.
Ryo A, Nakamura N, Wulf G, Liou YC, Lu KP. Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC. Nat Cell Biol 2001; 3: 793-801.
Ryo A, Suizu F, Yoshida Y, Perrem K, Liou YC, Wulf G, et al. Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell 2003; 12: 1413-26.
Liou YC, Ryo R, Huang HK, Lu PJ, Bronson R, Fujimori F, et al. Loss of Pin1 function in the mouse causes phenotypes resembling cyclin D1-null phenotypes. Proc Natl Acad Sci USA 2002; 99: 1335-40.
Suizu F, Ryo A, Wulf G, Lim J, Lu KP. Pin1 regulates centrosome duplication, and its overexpression induces centrosome amplification, chromosome instability, and oncogenesis. Mol Cell Biol 2006; 26: 1463-79.
Min SH, Lau AW, Lee TH, Inuzuka H, Wei S, Huang P, et al. Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase. Mol Cell 2012; 46(6): 771-83.
Lee TH, Tun-Kyi A, Shi R, Lim J, Soohoo C, Finn G, et al. Essential role of Pin1 in the regulation of TRF1 stability and telomere maintenance. Nat Cell Biol 2009; 11(1): 97-105.
Wulf G, Garg P, Liou YC, Iglehart D, Lu KP. Modeling breast cancer in vivo and ex vivo reveals an essential role of Pin1 in tumorigenesis. EMBO J 2004; 23: 3397-407.
Wulf GM, Liou YC, Ryo A, Lee SW, Lu KP. Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. J Biol Chem 2002; 277: 47976-9.
Kozono S, Lin YM, Seo HS, Pinch B, Lian X, Qiu C, et al. Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells. Nat Commun 2018; 9(1): 3069.
Yang D, Luo W, Wang J, Zheng M, Liao XH, Zhang N, et al. A novel controlled release formulation of the Pin1 inhibitor ATRA to improve liver cancer therapy by simultaneously blocking multiple cancer pathways. J Control Release 2018; 269: 405-22.
Zheng M, Xu H, Liao XH, Chen CP, Zhang AL, Lu W, et al. Inhibition of the prolyl isomerase Pin1 enhances the ability of sorafenib to induce cell death and inhibit tumor growth in hepatocellular carcinoma. Oncotarget 2017; 8(18): 29771-84.
Liao XH, Zhang AL, Zheng M, Li MQ, Chen CP, Xu H, et al. Chemical or genetic Pin1 inhibition exerts potent anticancer activity against hepatocellular carcinoma by blocking multiple cancer-driving pathways. Sci Rep 2017; 7: 43639.
Wei S, Kozono S, Kats L, Nechama M, Li W, Guarnerio J, et al. Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med 2015; 21(5): 457-66.
Luo ML, Gong C, Chen CH, Lee DY, Hu H, Huang P, et al. Prolyl isomerase Pin1 acts downstream of miR200c to promote cancer stem-like cell traits in breast cancer. Cancer Res 2014; 74(13): 3603-16.
Chen CH, Chang CC, Lee TH, Luo M, Huang P, Liao PH, et al. SENP1 deSUMOylates and regulates Pin1 protein activity and cellular function. Cancer Res 2013; 73(13): 3951-62.
Lu KP, Hanes SD, Hunter T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 1996; 380(6574): 544-7.
Ryo A, Liou YC, Wulf G, Nakamura N, Lee SW, Lu KP. Pin1 is an E2F target gene essential for the Neu/Ras-induced transformation of mammary epithelial cells. Mol Cell Biol 2002; 22: 5281-95.
Rippmann JF, Hobbie S, Daiber C, Guilliard B, Bauer M, Birk J, et al. Phosphorylation-dependent proline isomerization catalyzed by Pin1 is essential for tumor cell survival and entry into mitosis. Cell Growth Differ 2000; 11(7): 409-16.
Takahashi K, Akiyama H, Shimazaki K, Uchida C, Akiyama-Okunuki H, Tomita M, et al. Ablation of a peptidyl prolyl isomerase Pin1 from p53-null mice accelerated thymic hyperplasia by increasing the level of the intracellular form of Notch1. Oncogene 2007; 26: 3835-45.
Kuo JC, Lin JR, Staddon JM, Hosoya H, Chen RH. Uncoordinated regulation of stress fibers and focal adhesions by DAP kinase. J Cell Sci 2003; 116(Pt 23): 4777-90.
Ittner LM, Gotz J. Amyloid-beta and tau: A toxic pas de deux in Alzheimer’s disease. Nat Rev Neurosci 2011; 12(2): 65-72.
Jack CR Jr, Holtzman DM. Biomarker modeling of Alzheimer’s disease. Neuron 2013; 80(6): 1347-58.
Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 2007; 8(9): 663-72.
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 2002; 297(5580): 353-6.
Lee G, Cowan N, Kirschner M. The primary structure and heterogeneity of tau protein from mouse brain. Science 1988; 239(4837): 285-8.
Lee G, Neve RL, Kosik KS. The microtubule binding domain of tau protein. Neuron 1989; 2(6): 1615-24.
Esmaeli-Azad B, McCarty JH, Feinstein SC. Sense and antisense transfection analysis of tau function: tau influences net microtubule assembly, neurite outgrowth and neuritic stability. J Cell Sci 1994; 107(Pt 4): 869-79.
Stoothoff WH, Johnson GV. Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta 2005; 1739(2-3): 280-97.
Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 1992; 8(1): 159-68.
Matsuo ES, Shin RW, Billingsley ML, Van deVoorde A, O’Connor M, Trojanowski JQ, et al. Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron 1994; 13(4): 989-1002.
Lee VM, Balin BJ, Otvos L Jr, Trojanowski JQ. A68: A major subunit of paired helical filaments and derivatized forms of normal Tau. Science 1991; 251(4994): 675-8.
Selkoe DJ, Yamazaki T, Citron M, Podlisny MB, Koo EH, Teplow DB, et al. The role of APP processing and trafficking pathways in the formation of amyloid beta-protein. Ann N Y Acad Sci 1996; 777: 57-64.
Giasson BI, Lee VM, Trojanowski JQ. Interactions of amyloidogenic proteins. Neuromolecular Med 2003; 4(1-2): 49-58.
Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001; 293(5534): 1487-91.
Gotz J, Chen F, van Dorpe J, Nitsch RM. Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 2001; 293(5534): 1491-5.
Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 2007; 316(5825): 750-4.
Bolmont T, Clavaguera F, Meyer-Luehmann M, Herzig MC, Radde R, Staufenbiel M, et al. Induction of tau pathology by intracerebral infusion of amyloid-beta-containing brain extract and by amyloid-beta deposition in APPx Tau transgenic mice. Am J Pathol 2007; 171(6): 2012-20.
Yukawa K, Tanaka T, Bai T, Li L, Tsubota Y, Owada-Makabe K, et al. Deletion of the kinase domain from death-associated protein kinase enhances spatial memory in mice. Int J Mol Med 2006; 17(5): 869-73.
Shu S, Zhu H, Tang N, Chen W, Li X, Li H, et al. Selective degeneration of entorhinal-CA1 Synapses in Alzheimer’s disease via activation of DAPK1. J Neurosci 2016; 36(42): 10843-52.
Luna-Munoz J, Chavez-Macias L, Garcia-Sierra F, Mena R. Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease. J Alzheimers Dis 2007; 12(4): 365-75.
Lu PJ, Wulf G, Zhou XZ, Davies P, Lu KP. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein. Nature 1999; 399(6738): 784-8.
Liou YC, Sun A, Ryo A, Zhou XZ, Yu ZX, Huang HK, et al. Role of the prolyl isomerase Pin1 in protecting against age-dependent neurodegeneration. Nature 2003; 424(6948): 556-61.
Lim J, Balastik M, Lee TH, Nakamura K, Liou YC, Sun A, et al. Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy. J Clin Invest 2008; 118(5): 1877-89.
Lu PJ, Zhou XZ, Shen M, Lu KP. A function of WW domains as phosphoserine- or phosphothreonine-binding modules. Science 1999; 283: 1325-8.
Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, et al. The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production. Nature 2006; 440: 528-34.
Kondo A, Albayram O, Zhou XZ, Lu KP. Pin1 knockout mice: A model for the study of tau pathology in Alzheimer’s disease. Methods Mol Biol 2017; 1523: 415-25.
Chen CH, Li W, Sultana R, You MH, Kondo A, Shahpasand K, et al. Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer’s disease. Neurobiol Dis 2015; 76: 13-23.
Kondo A, Shahpasand K, Mannix R, Qiu J, Moncaster J, Chen CH, et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 2015; 523(7561): 431-6.
Nakamura K, Greenwood A, Binder L, Bigio EH, Denial S, Nicholson L, et al. Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer’s disease. Cell 2012; 149(1): 232-44.
Pei L, Wang S, Jin H, Bi L, Wei N, Yan H, et al. A Novel mechanism of spine damages in stroke via DAPK1 and tau. Cereb Cortex 2015; 25(11): 4559-71.
Duan DX, Chai GS, Ni ZF, Hu Y, Luo Y, Cheng XS, et al. Phosphorylation of tau by death-associated protein kinase 1 antagonizes the kinase-induced cell apoptosis. J Alzheimers Dis 2013; 37(4): 795-808.
Pastorino L, Lu KP. Phosphorylation of the amyloid precursor protein (APP): Is this a mechanism in favor or against Alzheimer’s disease? Neurosci Res Commun 2005; 35: 213-31.
Suzuki T, Nakaya T. Regulation of amyloid beta-protein precursor by phosphorylation and protein interactions. J Biol Chem 2008; 283(44): 29633-7.
Lee MS, Kao SC, Lemere CA, Xia W, Tseng HC, Zhou Y, et al. APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol 2003; 163(1): 83-95.
Ma SL, Pastorino L, Zhou XZ, Lu KP. Prolyl isomerase Pin1 promotes amyloid precursor protein (APP) turnover by inhibiting glycogen synthase kinase-3beta (GSK3beta) activity: novel mechanism for Pin1 to protect against Alzheimer disease. J Biol Chem 2012; 287(10): 6969-73.
Craft JM, Watterson DM, Frautschy SA, Van Eldik LJ. Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo. Neurobiol Aging 2004; 25(10): 1283-92.
Farag AK, Roh EJ. Death-associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes. Med Res Rev 2018; 4: 120-9.
Gandesiri M, Chakilam S, Ivanovska J, Benderska N, Ocker M, Di Fazio P, et al. DAPK plays an important role in panobinostat-induced autophagy and commits cells to apoptosis under autophagy deficient conditions. Apoptosis 2012; 17(12): 1300-15.
Zhang H, Chen GG, Zhang Z, Chun S, Leung BC, Lai PB. Induction of autophagy in hepatocellular carcinoma cells by SB203580 requires activation of AMPK and DAPK but not p38 MAPK. Apoptosis 2012; 17(4): 325-34.
Wu J, Hu CP, Gu QH, Li YP, Song M. Trichostatin A sensitizes cisplatin-resistant A549 cells to apoptosis by up-regulating death-associated protein kinase. Acta Pharmacol Sin 2010; 31(1): 93-101.
Luo XJ, Li LL, Deng QP, Yu XF, Yang LF, Luo FJ, et al. Grifolin, a potent antitumour natural product upregulates death-associated protein kinase 1 DAPK1 via p53 in nasopharyngeal carcinoma cells. Eur J Cancer 2011; 47(2): 316-25.
Wu B, Yao H, Wang S, Xu R. DAPK1 modulates a curcumin-induced G2/M arrest and apoptosis by regulating STAT3, NF-kappaB, and caspase-3 activation. Biochem Biophys Res Commun 2013; 434(1): 75-80.
Puto LA, Reed JC. Daxx represses RelB target promoters via DNA methyltransferase recruitment and DNA hypermethylation. Genes Dev 2008; 22(8): 998-1010.
Pulling LC, Grimes MJ, Damiani LA, Juri DE, Do K, Tellez CS, et al. Dual promoter regulation of death-associated protein kinase gene leads to differentially silenced transcripts by methylation in cancer. Carcinogenesis 2009; 30(12): 2023-30.
Satoh A, Toyota M, Itoh F, Kikuchi T, Obata T, Sasaki Y, et al. DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers. Br J Cancer 2002; 86(11): 1817-23.
Toyooka S, Toyooka KO, Miyajima K, Reddy JL, Toyota M, Sathyanarayana UG, et al. Epigenetic down-regulation of death-associated protein kinase in lung cancers. Clin Cancer Res 2003; 9(8): 3034-41.
Chico LK, Van Eldik LJ, Watterson DM. Targeting protein kinases in central nervous system disorders. Nat Rev Drug Discov 2009; 8(11): 892-909.
Velentza AV, Wainwright MS, Zasadzki M, Mirzoeva S, Schumacher AM, Haiech J, et al. An aminopyridazine-based inhibitor of a pro-apoptotic protein kinase attenuates hypoxia-ischemia induced acute brain injury. Bioorg Med Chem Lett 2003; 13(20): 3465-70.
Mirzoeva S, Sawkar A, Zasadzki M, Guo L, Velentza AV, Dunlap V, et al. Discovery of a 3-amino-6-phenyl-pyridazine derivative as a new synthetic antineuroinflammatory compound. J Med Chem 2002; 45(3): 563-6.
Okamoto M, Takayama K, Shimizu T, Ishida K, Takahashi O, Furuya T. Identification of death-associated protein kinases inhibitors using structure-based virtual screening. J Med Chem 2009; 52(22): 7323-7.
Okamoto M, Takayama K, Shimizu T, Muroya A, Furuya T. Structure-activity relationship of novel DAPK inhibitors identified by structure-based virtual screening. Bioorg Med Chem 2010; 18(7): 2728-34.
Fan X, Jin WY, Lu J, Wang J, Wang YT. Rapid and reversible knockdown of endogenous proteins by peptide-directed lysosomal degradation. Nat Neurosci 2014; 17(3): 471-80.
Shamloo M, Soriano L, Wieloch T, Nikolich K, Urfer R, Oksenberg D. Death-associated protein kinase is activated by dephosphorylation in response to cerebral ischemia. J Biol Chem 2005; 280(51): 42290-9.
Carlson DA, Franke AS, Weitzel DH, Speer BL, Hughes PF, Hagerty L, et al. Fluorescence linked enzyme chemoproteomic strategy for discovery of a potent and selective DAPK1 and ZIPK inhibitor. ACS Chem Biol 2013; 8(12): 2715-23.
Yokoyama T, Kosaka Y, Mizuguchi M. Structural insight into the interactions between death-associated protein kinase 1 and natural flavonoids. J Med Chem 2015; 58(18): 7400-8.
Albayram O, Kondo A, Mannix R, Smith C, Tsai CY, Li C, et al. Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae. Nat Commun 2017; 8(1): 1000.
Lu KP, Kondo A, Albayram O, Herbert MK, Liu H, Zhou XZ. Potential of the antibody against cis-phosphorylated tau in the early diagnosis, treatment, and prevention of Alzheimer disease and brain injury. JAMA Neurol 2016; 73(11): 1356-62.
Nakamura K, Zhen Zhou X, Ping Lu K. Cis phosphorylated tau as the earliest detectable pathogenic conformation in Alzheimer disease, offering novel diagnostic and therapeutic strategies. Prion 2013; 7(2): 117-20.
Nakamura K, Zhou XZ, Lu KP. Distinct functions of cis and trans phosphorylated tau in Alzheimer’s disease and their therapeutic implications. Curr Mol Med 2013; 13(7): 1098-109.
Albayram O, Herbert MK, Kondo A, Tsai CY, Baxley S, Lian X, et al. Function and regulation of tau conformations in the development and treatment of traumatic brain injury and neurodegeneration. Cell Biosci 2016; 6: 59.
Albayram O, Angeli P, Bernstein E, Baxley S, Gao Z, Lu KP, et al. Targeting prion-like cis phosphorylated tau pathology in neurodegenerative diseases. J Alzheimers Dis Parkinsonism 2018; 8(3): 25-32.
Califano J. Detection of head and neck cancer using hypermethylated gene detection. US20140323321 (2014).
Mansour H, Incitti R, Bajic V. Methylation biomarkers for ovarian cancer. US10041124 (2018).
Brock MV, Baylin SB, Heman JG. DNA methylation markers and methods of use. US20150031022 (2015).
Corvalan A. Non-invasive method for the early detection of stomach cancer. US20130095477 (2013).
Cha T, Chang S, Sun G, Lin C, Tsai Y. Pharmaceutical compositions and methods for treating cancer and biomarkers for drug screening. US9782393 (2017).
Schneider-Stock R, Neufert C. Death-associated protein kinases, inhibitors and activators thereof for use in pharmaceutical compositions and in predictive medicine. EP2767273 (2014).
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. J Biol Chem 2001; 276: 39667-78.
Jin Y, Blue EK, Gallagher PJ. Control of death-associated protein kinase (DAPK) activity by phosphorylation and proteasomal degradation. J Biol Chem 2006; 281: 39033-40.
Kimchi A, Carlessi R. Compositions and methods for treating cancer and neurodegenerative diseases. US9149523 (2015).
Watterson M, Van Eldik L, Haiech J, et al. Pyridazine compounds, compositions and methods. US9527819 (2016).
Hertz NT, Shokat KM, Devita R. Compositions and methods for treating neurodegenerative diseases and cardiomyopathy. US20180072731 (2018).
Shantha TR. Alzheimer's disease treatment with multiple therapeutic agents delivered to the olfactory region through a special delivery catheter and iontophoresis. US20150080785 (2015).
Panitch A, Seal B, Ward B. Kinase inhibitors and uses thereof. US20140342993 (2014).
Yang J, Hsu K, Sung T, et al. Selective inhibitors for protein kinases and pharmaceutical composition and use thereof. US20160096848 (2016).
Wang YT, Lan SX, Jin WJ. Peptide directed protein knockdown. US20150266935 (2015).
Bradner J, Ishoey M, Buckley D, Paulk J, Cohen MA, Zeid R. Targeted protein degradation using a mutant E3 ubiquitin ligase. US20180327419 (2018).
Lin Y, Henderson P, Pettersson S, Satsangi J, Hupp T, Stevens C. Tuberous sclerosis-2 (TSC2) regulates the stability of death-associated protein kinase-1 (DAPK) through a lysosome-dependent degradation pathway. FEBS J 2011; 278(2): 354-70.
Pardridge WM. The blood-brain barrier: Bottleneck in brain drug development. NeuroRx 2005; 2(1): 3-14.
Park MH, Hyun H, Ashitate Y, Wada H, Park G, Lee JH, et al. Prototype nerve-specific near-infrared fluorophores. Theranostics 2014; 4: 823-33.

open access plus

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 02 August, 2019
Page: [144 - 157]
Pages: 14
DOI: 10.2174/1574892814666181218170257

Article Metrics

PDF: 48
HTML: 15