Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity

Kawai, Taro; Nomura, Fumiko; Hoshino, Katsuaki; Copeland, Neal G.; Gilbert, Debra J.; Jenkins, Nancy A.; Akira, Shizuo

doi:10.1038/sj.onc.1202701

Cited by 112 publications

(143 citation statements)

References 47 publications

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“…Yet, within the DAPk family itself, DRP-1 and ZIP-kinase are also capable of phosphorylating the purified regulatory light chain. 2,3,5,6 In fact, ZIPk phosphorylates the RLC on Thr18 and Ser19 in vivo, leading to membrane protrusions that are reminiscent of those observed with DAPk. 37 In addition, introduction of RLC mutated at Thr18 and Ser19 blocked ZIPk-induced protrusions.…”

Section: Discussionmentioning

confidence: 96%

“…1 It is the prototype for a family of death-inducing kinases, which includes DRP-1 and ZIP-kinase (ZIPk). [2][3][4][5][6] In addition to the conserved catalytic module, DAPk harbors multiple functional domains, including eight ankyrin repeats, a cytoskeletal interacting region, and a C-terminal death domain. 1 DAPk activity is necessary for the induction of cell death by ceramide, matrix detachment, oncogene expression, TNF-a, Fas, TGF-b, and IFN-g, and overexpression leads to pronounced death-associated cellular changes, which include membrane blebbing, cell rounding, and the formation of autophagic vesicles.…”

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confidence: 99%

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DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation

2004

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DAP-kinase (DAPk) is a Ser/Thr kinase that regulates cytoplasmic changes associated with programmed cell death. It is shown here that a GFP-DAPk fusion, which partially localized to actin stress fibers, induced extensive membrane protrusions. This phenotype correlated with changes in myosin-II distribution and with increased phosphorylation of the myosin-II regulatory light chain (RLC). A mutant lacking the cytoskeletal-interacting region (GFP-DAPkDCyto) displayed diffuse cytoplasmic localization, and induced peripheral membrane blebbing, instead of the extensive protrusions. In contrast, deletion of the ankyrin repeats led to mislocalization of the kinase to focal contacts, where it failed to elicit any changes in cell morphology. While both wild-type DAPk and DAPkDCyto induced RLC phosphorylation independently of the Rho-activated kinase ROCK, only the wild type led to increases in stress-fiber associated phospho-RLC. Thus, the precise intracellular localization of DAPk is critical for exposure to its substrates, including the RLC, which mediate varying morphologic changes.

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Section: Discussionmentioning

confidence: 96%

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confidence: 99%

DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation

2004

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“…As DAPK2 shares B80% of homology to DAPK1 in the kinase domain but has no discernible death domain 12 (Supplementary Figure S1), we hypothesised that depending on the cellular content and expression levels of DAPK2 this kinase would work either as a pro-or antiapoptotic protein.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, evidence for a proapoptotic role is largely based on its ability to induce apoptosis-like cell morphology upon overexpression. [12][13][14] We thus hypothesised that endogenous DAPK2 may under some circumstances have antiapoptotic properties and provide cancer cells with prosurvival cues.…”

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confidence: 99%

DAPK2 is a novel modulator of TRAIL-induced apoptosis

Stöcker

et al. 2014

Cell Death Differ

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Targeting molecules involved in TRAIL-mediated signalling has been hailed by many as a potential magic bullet to kill cancer cells efficiently, with little side effects on normal cells. Indeed, initial clinical trials showed that antibodies against TRAIL receptors, death receptor (DR)4 and DR5, are well tolerated by cancer patients. Despite efficacy issues in the clinical setting, novel approaches to trigger TRAIL-mediated apoptosis are being developed and its clinical potential is being reappraised. Unfortunately, as observed with other cancer therapies, many patients develop resistance to TRAIL-induced apoptosis and there is thus impetuous for identifying additional resistance mechanisms that may be targetable and usable in combination therapies. Here, we show that the death-associated protein kinase 2 (DAPK2) is a modulator of TRAIL signalling. Genetic ablation of DAPK2 using RNA interference causes phosphorylation of NF-jB and its transcriptional activity in several cancer cell lines. This then leads to the induction of a variety of NF-jB target genes, which include proapoptotic DR4 and DR5. DR4 and DR5 protein expression is correspondingly increased on the cell surface and this leads to the sensitisation of resistant cells to TRAILinduced killing, in a p53-independent manner. As DAPK2 is a kinase, it is imminently druggable, and our data thus offer a novel avenue to overcome TRAIL resistance in the clinic. Despite the effort and resources invested in cancer research, cancer remains a serious public health problem. Most patients are treated surgically, with chemotherapeutic drugs and/or antibodies and small molecule inhibitors. Patients generally respond well to the initial therapy but frequently develop resistance to it. This poses a challenge to their treatment and calls for alternative approaches to be developed. Indeed, much excitement was generated in the mid-1990s when tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) was identified. [1][2][3][4] TRAIL is a death receptor (DR) ligand that signals through DR4 and DR5, two members of the TNF receptor family. 5-7 DR5 has two isoforms that differ by 29 amino acids and which are functionally indistinguishable. 5,8 TRAIL ligation activates primarily the extrinsic apoptotic pathway. The formation of ligand/receptor complexes leads to the assembly of a multiprotein death-inducing signalling complex (DISC), which in the case of TRAIL is typically composed of the adaptor Fasassociated death domain, caspase-8, caspase-10 and/or c-FLIP. These initiator caspases proteolytically cleave effector caspases such as caspase-3, caspase-6 and/or caspase-7 thereby activating them. This leads to the destruction of key cellular components and the appearance of typical features of apoptosis. TRAIL can also activate intrinsic apoptotic pathways via BID and thus involve mitochondria. By virtue of preferentially killing tumour cells, TRAIL is seen by many as a 'magic bullet' against cancer cells. Some cancer cells, however, are resistant, or develop resistanc...

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“…Based on these criteria they were classified altogether as members of a novel subfamily of kinases ± the DAP-kinase related proteins. The most homologous kinase to DAP-kinase is DRP-1 (DAP-kinase Related Protein-1 also named DAPK-2), 33,34 a 42 kDa protein which shows high degree of homology (80% identity at the amino-acid level) to DAP-kinase both in its catalytic domain and its calmodulin-regulatory region, but not to other domains of DAP-kinase. Consistent with the structural homology within the kinase domain, DRP-1 was found to phosphorylate MLC, like DAP-kinase, in a Ca 2+ /CaM-dependent manner.…”

Section: The Novel Family Of Dap-kinase Related Proteinsmentioning

confidence: 99%

DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer

2001

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DAP-kinase is a pro-apoptotic Ca 2+ calmodulin-regulated serine/threonine kinase that participates in a wide array of apoptotic systems initiated by interferon-g, TNF-a, activated Fas, and detachment from extracellular matrix. It was isolated by an unbiased functional approach to gene cloning aimed at hitting central mediators of the apoptotic process. This 160 Kd protein kinase is localized to actin microfilaments and carries interesting modules such as ankyrin repeats and the death domain. The death promoting effects of DAP-kinase depend on its intact catalytic activity, the correct intracellular localization, and on the presence of the death domain. A few mechanisms restrain the killing effects of the protein in healthy cells. The enzyme's active site is negatively controlled by an adjacent CaM regulatory domain whose effect is relieved by binding to Ca 2+ -activated calmodulin. A second mode of autoinhibition engages the serine-rich C-terminal tail, spanning the last 17 amino acids of the protein. A link between DAPkinase and cancer has been established. It was found that the mRNA and protein expression is frequently lost in various human cancer cell lines. Analysis of the methylation status of DAP-kinase's 5' UTR in DNA extracted from fresh tumor samples, showed high incidence of hypermethylation in several human carcinomas and B cell malignancies. The antitumorigenic effect of DAP-kinase was also studied experimentally in mouse model systems where the re-introduction of DAP-kinase into highly metastatic mouse lung carcinoma cells who had lost the protein, strongly reduced their metastatic capacity. Thus, it appears that loss of DAP-kinase confers a selective advantage to cancer cells and may play a causative role in tumor progression. A few novel kinases sharing high homology in their catalytic domains with DAPkinase have been recently identified constituting altogether a novel family of death promoting serine/threonine kinases. Cell Death and Differentiation (2001) 8, 6 ± 15.

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Death-associated protein kinase 2 is a new calcium/calmodulin-dependent protein kinase that signals apoptosis through its catalytic activity

Cited by 112 publications

References 47 publications

DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation

DAP-kinase-mediated morphological changes are localization dependent and involve myosin-II phosphorylation

DAPK2 is a novel modulator of TRAIL-induced apoptosis

DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer

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