Death-associated protein kinase: A molecule with functional antagonistic duality and a potential role in inflammatory bowel disease (Review)

Steinmann, Sara; Scheibe, Kristina; Erlenbach-Wuensch, Katharina; Neufert, Clemens; Schneider‐Stock, Regine

doi:10.3892/ijo.2015.2998

Cited by 21 publications

(24 citation statements)

References 103 publications

(142 reference statements)

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“…The death‐associated protein kinase (DAPK) family is one of the important families of STKs that regulate several biological functions in the human cells. A few research groups have reviewed DAPK1‐related subjects mostly focusing on the structure, regulation, and biological roles . In this review, our objective is to give an updated comprehensive overview about the structure, regulation, and biological roles of DAPKs and provide, for the first time, a comprehensive review on the strategies used to modulate the activity of this kinase family with small molecules from a medicinal chemistry perspective and evaluate their therapeutic outcomes.…”

Section: Introductionmentioning

confidence: 99%

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag

Roh

2018

Medicinal Research Reviews

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Serine/threonine kinases (STKs) represent the majority of discovered kinases to date even though a few Food and Drug Administration approved STKs inhibitors are reported. The third millennium came with the discovery of an important group of STKs that reshaped our understanding of several biological signaling pathways. This family was named death-associated protein kinase family (DAPK family). DAPKs comprise five members (DAPK1, DAPK2, DAPK3, DRAK1, and DRAK2) and belong to the calcium/calmodulin-dependent kinases domain. As time goes on, the list of biological functions of this family is constantly updated. The most extensively studied member is DAPK1 (based on the publications number and Protein Data Bank reported crystal structures) that plays fundamental biological roles depending on the cellular context. DAPK1 regulates apoptosis, autophagy, contributes to the pathogenesis of Alzheimer's disease, acts as a tumor suppressor, inhibits metastasis, mediates the body responses to viral infections, and regulates the synaptic plasticity and depression. For their biological roles, several DAPKs' modulators have been reported for treatment of many diseases as well as acting as probe compounds to facilitate the understanding of the biological functions elicited by this family. Despite that, the number of reported modulators is still limited and more research needs to be conducted on the discovery of novel strategies to activate or inhibit this family. In this report, we aim at drawing more attention to this family by reviewing the recent updates regarding the structure, biological roles, and regulation of this family. In addition, the small-molecule modulators of this family are reviewed in details with their potential therapeutic outcomes evaluated to help medicinal chemists develop more potent and selective possible drug candidates.

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Section: Introductionmentioning

confidence: 99%

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag

Roh

2018

Medicinal Research Reviews

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“…The scarce literature on DAPK expression in inflammatory cells implicates T cells and macrophages as the main source (15). Alternative splicing creates various DAPK1 isoforms.…”

Section: Resultsmentioning

confidence: 99%

“…The operational downstream pathways (caspase-and p53-dependent vs. -independent apoptosis; ref. 1) and cell biologic outcomes [i.e., apoptosis (1, 10) versus autophagic preservation (1) vs autophagic cell death (12,13) vs. necroptosis (14)] appear cell context specific and to be dictated by the nature of the upstream stressor and the executing DAPK family member (1,2,15).…”

Section: Introductionmentioning

confidence: 99%

“…Strategies employ gene therapy, development of functional DAPK activators, or demethylating agents to reestablish DAPK expression (19,20). This also extents (reversely) to DAPK inhibitors in autoinflammatory disease and graft rejection (15,(20)(21)(22). We explored here if reinstating DAPK activity would perturb the high apoptotic threshold in DAKP-deficient neoplastic B cells that are burdened by incurring (oncogenic) stress.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Recombinant Anti-CD22 Immunokinase Delivers Proapoptotic Activity of Death-Associated Protein Kinase (DAPK) and Mediates Cytotoxicity in Neoplastic B Cells

Lilienthal

Lohmann

Crispatzu

et al. 2016

Molecular Cancer Therapeutics

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The serine/threonine death-associated protein kinases (DAPK) provide pro-death signals in response to (oncogenic) cellular stresses. Lost DAPK expression due to (epi)genetic silencing is found in a broad spectrum of cancers. Within B-cell lymphomas, deficiency of the prototypic family member DAPK1 represents a predisposing or early tumorigenic lesion and high-frequency promoter methylation marks more aggressive diseases. On the basis of protein studies and meta-analyzed gene expression profiling data, we show here that within the low-level context of B-lymphocytic DAPK, particularly CLL cells have lost DAPK1 expression. To target this potential vulnerability, we conceptualized B-cell-specific cytotoxic reconstitution of the DAPK1 tumor suppressor in the format of an immunokinase. After rounds of selections for its most potent cytolytic moiety and optimal ligand part, a DK1KD-SGIII fusion protein containing a constitutive DAPK1 mutant, DK1KD, linked to the scFv SGIII against the B-cell-exclusive endocytic glyco-receptor CD22 was created. Its high purity and large-scale recombinant production provided a stable, selectively binding, and efficiently internalizing construct with preserved robust catalytic activity. DK1KD-SGIII specifically and efficiently killed CD22-positive cells of lymphoma lines and primary CLL samples, sparing healthy donor-or CLL patient-derived non-B cells. The mode of cell death was predominantly PARP-mediated and caspase-dependent conventional apoptosis as well as triggering of an autophagic program. The notoriously high apoptotic threshold of CLL could be overcome by DK1KD-SGIII in vitro also in cases with poor prognostic features, such as therapy resistance. The manufacturing feasibility of the novel CD22-targeting DAPK immunokinase and its selective antileukemic efficiency encourage intensified studies towards specific clinical application. Mol Cancer Ther; 15(5);

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“…14-3-3-proteins inhibit DAPK2 activity and its apoptotic effects (Yuasa K et al, 2015). DAPK2 also interacts with RAD1, MAPK1 and MLC1 (Steinmann S et al, 2015).…”

Section: Regulation Of Erythropoiesismentioning

confidence: 99%

DAPK2 (death-associated protein kinase 2)

Pinto¹,

Máximo²

2018

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Death-associated protein kinase: A molecule with functional antagonistic duality and a potential role in inflammatory bowel disease (Review)

Cited by 21 publications

References 103 publications

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

A Novel Recombinant Anti-CD22 Immunokinase Delivers Proapoptotic Activity of Death-Associated Protein Kinase (DAPK) and Mediates Cytotoxicity in Neoplastic B Cells

DAPK2 (death-associated protein kinase 2)

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