• ROCO gene family
• brown algae
• exon shuffling
• immunity
• phylogenetics

• cancer stem cell (CSC)
• death-associated protein kinase 1 (DAPK1)
• epithelial to mesenchymal transition (EMT)
• papillary thyroid carcinoma (PTC)

• 2024 KonKuk University

• KLHLs
• Kelch domain
• PPI inhibitors
• PROTAC
• TPD

• Humans
• Cullin Proteins/metabolism
• Ubiquitination
• Ubiquitin-Protein Ligases/metabolism

• Breast cancer
• Death-associated protein kinase 1 (DAPK1)
• Mouse double minute 2 (MDM2)
• Tumor suppressor
• Tumorigenesis
• p53

• Animals
• Female
• Humans
• Mice
• Breast Neoplasms/drug therapy
• Cell Line, Tumor
• Death-Associated Protein Kinases/metabolism
• Phosphorylation
• Protein Stability
• Proto-Oncogene Proteins c-mdm2/metabolism
• Tumor Suppressor Protein p53/metabolism

• 81970993 National Natural Science Foundation of China
• 82271449 National Natural Science Foundation of China

• Bone mesenchymal stem cell
• DAPK1
• Extracellular vesicles
• Inflammation factors
• THP-1 macrophages
• miR-191

• 3' Untranslated Regions
• Culture Media, Conditioned/pharmacology
• Death-Associated Protein Kinases/genetics
• Extracellular Vesicles/genetics
• Gene Expression Regulation/drug effects
• Humans
• Inflammation/etiology
• Inflammation/genetics
• Lipopolysaccharides/toxicity
• Macrophage Activation/genetics
• Macrophage Activation/physiology
• Mesenchymal Stem Cells/cytology
• MicroRNAs/genetics
• MicroRNAs/pharmacology
• Promoter Regions, Genetic
• THP-1 Cells

• DNA methylation
• biomarkers
• cell-free circulating tumor DNA
• circulating melanoma cells
• liquid biopsy
• melanoma
• tumor extracellular vesicles

• GR-2016-02361019 Italian Ministry of Health

• DEAD-box helicase 20
• death-associated protein kinase
• hepatocellular carcinoma
• invasion
• migration
• proteasome degradation

• Carcinogenesis/pathology
• Carcinoma, Hepatocellular/pathology
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• DEAD Box Protein 20/metabolism
• Death-Associated Protein Kinases/metabolism
• HEK293 Cells
• Humans
• Liver Neoplasms/pathology
• Neoplasm Invasiveness/pathology
• Up-Regulation

• WKJ2016-2-27 the United Fujian Provincial Health and Education Project Tackling the Key Research
• 2016YFE0121900 the International S&T Cooperation Program of China
• IRTL1702 the Scientific Research Innovation Team Construction Program of Fujian Normal University

• CUX1
• PanNET
• apoptosis
• chemotherapy
• neuroendocrine
• pancreas
• recurrence

• Ewing sarcoma
• chondrosarcoma
• genomics
• osteosarcoma
• personalized therapy

• Apoptosis
• Cell death pathway
• Ferroptosis
• Ischemic stroke
• Necroptosis
• Pyroptosis

• Alzheimer’s disease
• Pin1
• SUMOylation
• cancer
• oxidation
• phosphorylation
• post-translational modification
• ubiquitination

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

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.

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

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 suscepti-bility 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 tar-gets tau and APP. Recent patents show that DAPK1 modulation might be used to treat both cancer and AD.

DAPK1 plays a critical role in diverse physiological processes and importantly, its deregula-tion 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.

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

Calmodulin (CaM) is the principal Ca²⁺ sensor protein in all eukaryotic cells, that upon binding to target proteins transduces signals encoded by global or subcellular-specific changes of Ca²⁺ concentration within the cell. The Ca²⁺/CaM complex as well as Ca²⁺-free CaM modulate the activity of a vast number of enzymes, channels, signaling, adaptor and structural proteins, and hence the functionality of implicated signaling pathways, which control multiple cellular functions. A basic and important cellular function controlled by CaM in various ways is cell motility. Here we discuss the role of CaM-dependent systems involved in cell migration, tumor cell invasiveness, and metastasis development. Emphasis is given to phosphorylation/dephosphorylation events catalyzed by myosin light-chain kinase, CaM-dependent kinase-II, as well as other CaM-dependent kinases, and the CaM-dependent phosphatase calcineurin. In addition, the role of the CaM-regulated small GTPases Rac1 and Cdc42 (cell division cycle protein 42) as well as CaM-binding adaptor/scaffold proteins such as Grb7 (growth factor receptor bound protein 7), IQGAP (IQ motif containing GTPase activating protein) and AKAP12 (A kinase anchoring protein 12) will be reviewed. CaM-regulated mechanisms in cancer cells responsible for their greater migratory capacity compared to non-malignant cells, invasion of adjacent normal tissues and their systemic dissemination will be discussed, including closely linked processes such as the epithelial–mesenchymal transition and the activation of metalloproteases. This review covers as well the role of CaM in establishing metastatic foci in distant organs. Finally, the use of CaM antagonists and other blocking techniques to downregulate CaM-dependent systems aimed at preventing cancer cell invasiveness and metastasis development will be outlined.

• calcium signaling
• calmodulin
• calmodulin antagonists
• cell migration
• metastasis
• tumor cell invasiveness

• Animals
• Calcium Signaling
• Calmodulin/metabolism
• Cell Movement
• Humans
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplasm Proteins/metabolism
• Neoplasms/metabolism
• Neoplasms/pathology

• Cancer targeted
• Gene therapy
• Metastasis
• PEDF-DNA
• iRGD

Colorectal cancer (CRC) is one of the leading cancer-related causes of death worldwide. Despite the improvement of surgical and chemotherapeutic treatments, as of yet, the disease has not been overcome due to metastasis to distant organs. Hence, it is of great relevance to understand the mechanisms responsible for metastasis initiation and progression and to identify novel metastatic markers for a higher chance of preventing the metastatic disease. The Death-associated protein kinase 1 (DAPK1), recently, has been shown to be a potential candidate for regulating metastasis in CRC. Hence, the aim of the study was to investigate the impact of DAPK1 protein on CRC aggressiveness. Using CRISPR/Cas9 technology, we generated DAPK1-deficient HCT116 monoclonal cell lines and characterized their knockout phenotype in vitro and in vivo. We show that loss of DAPK1 implemented changes in growth pattern and enhanced tumor budding in vivo in the chorioallantoic membrane (CAM) model. Further, we observed more tumor cell dissemination into chicken embryo organs and increased invasion capacity using rat brain 3D in vitro model. The novel identified DAPK1-loss gene expression signature showed a stroma typical pattern and was associated with a gained ability for remodeling the extracellular matrix. Finally, we suggest the DAPK1-ERK1 signaling axis being involved in metastatic progression of CRC. Our results highlight DAPK1 as an anti-metastatic player in CRC and suggest DAPK1 as a potential predictive biomarker for this cancer type.

• Apoptosis
• Autophagy
• DAPK-1
• Preeclampsia

Regulated neuronal cell death plays an essential role in biological processes in normal physiology, including the development of the nervous system. However, the deregulation of neuronal apoptosis by various factors leads to neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease (AD). Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca²⁺/CaM)-dependent serine/threonine (Ser/Thr) protein kinase that activates death signaling and regulates apoptotic neuronal cell death. Although DAPK1 is tightly regulated under physiological conditions, DAPK1 deregulation in the brain contributes to the development of neurological disorders. In this review, we describe the molecular mechanisms of DAPK1 regulation in neurons under various stresses. We also discuss the role of DAPK1 signaling in the phosphorylation-dependent and phosphorylation-independent regulation of its downstream targets in neuronal cell death. Moreover, we focus on the major impact of DAPK1 deregulation on the progression of neurodegenerative diseases and the development of drugs targeting DAPK1 for the treatment of diseases. Therefore, this review summarizes the DAPK1 phosphorylation signaling pathways in various neurodegenerative diseases.

• Alzheimer’s disease (AD)
• death-associated protein kinase 1 (DAPK1)
• ischemic stroke
• neuronal cell death
• phosphorylation

• UNC5D
• expression
• metastasis
• methylation
• prostate cancer

• Animals
• Cell Line, Tumor
• DNA Methylation
• Death-Associated Protein Kinases/genetics
• Death-Associated Protein Kinases/metabolism
• Disease Models, Animal
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Gene Silencing
• Heterografts
• Humans
• Immunohistochemistry
• Male
• Neoplasm Metastasis
• Neoplasm Staging
• Promoter Regions, Genetic
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology
• Receptors, Cell Surface/genetics
• Receptors, Cell Surface/metabolism

• 81201653 National Natural Science Foundation of China
• 81402174 National Natural Science Foundation of China
• 81502519 National Natural Science Foundation of China
• 2014KYM04 Research Project of Tianjin Medical University
• 16JCYBJC26000 Natural Science Foundation of Tianjin

• Breast cancer
• DAPK1
• hypermethylation
• immunohistochemistry
• MSP

• Intramolecular mechanism
• LRRK2
• Roc
• Small GTPase

• Genetic biomarkers
• osteosarcoma
• prognosis
• tailored treatments
• toxicity

• DAPK
• ERK
• JNK
• MAPK
• p38

• Animals
• Apoptosis/drug effects
• Death-Associated Protein Kinases/antagonists & inhibitors
• Death-Associated Protein Kinases/metabolism
• Humans
• MAP Kinase Signaling System
• Molecular Targeted Therapy/methods
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use

• death-associated protein kinase
• diagnosis
• methylation
• nasopharyngeal carcinoma

• cisatracurium
• colorectal cancer
• invasion
• migration
• p53

• cochlea
• guinea pigs
• interferon
• organs of Corti
• scanning electron microscopy

Breast cancer (BC) is the second leading cause of cancer-related death in American women and more than 90% of BC-related death is caused by metastatic BC (MBC). This review stresses the limited success of traditional therapies as well as the use of nanomedicine for treating MBC. Understanding the biological barriers of MBC that nanoparticle in vivo trafficking must overcome could provide valuable new insights for translating nanomedicine from the bench side to the bedside. A view about nanomedicine applied in BC therapy has been summarized with their present status, which is gaining attention in the clinically-applied landscape. The progressions of drug/gene delivery systems, especially the status of their preclinical or clinical trials, are also discussed. Here we highlight that the treatment of metastasis, in addition to the extensively described inhibition of primary tumor growth, is an indispensable requirement for nanomedicine. Along with more innovations in material chemistry and more progressions in biology, nanomedicine will constantly supply more exciting new approaches for targeted drug/gene delivery against MBC.

• breast cancer
• metastasis
• nanomaterials
• nanomedicine

• DAPK1
• LRRK1
• LRRK2
• MASL1/MAFHAS1
• ROCO proteins
• protein microarrays
• protein networks

• GTP-Binding Proteins/metabolism
• Humans
• Protein Array Analysis
• Protein Interaction Maps
• Protein Serine-Threonine Kinases/metabolism

• Z99 AG999999 Intramural NIH HHS
• BB/M017222/1 Biotechnology and Biological Sciences Research Council
• MR/N026004/1 Medical Research Council
• F-1002 Parkinson's UK
• MR/L010933/1 Medical Research Council

• cancer
• diagnostics
• metastasis
• nanomedicine
• peptide delivery

• apoptosis inducers
• cancer immunotherapy
• death-associated protein kinases (DAPk)
• humanised cytolytic fusion proteins (hCFPs)

• DAPK1
• IHC
• Liver cancer
• Prognosis
• Survival

Defining new therapeutic strategies to overcome therapy resistance due to tumor heterogeneity in colon cancer is challenging. One option is to explore the molecular profile of aggressive disseminating tumor cells. The cytoskeleton-associated Death-associated protein kinase (DAPK) is involved in the cross talk between tumor and immune cells at the invasion front of colorectal cancer. Here dedifferentiated tumor cells histologically defined as tumor budding are associated with a high risk of metastasis and poor prognosis. Analyzing samples from 144 colorectal cancer patients we investigated immunhistochemical DAPK expression in different tumor regions such as center, invasion front, and buds. Functional consequences for tumor aggressiveness were studied in a panel of colon tumor cell lines using different migration, wound healing, and invasion assays. DAPK levels were experimentally modified by siRNA transfection and overexpression as well as inhibitor treatments. We found that DAPK expression was reduced towards the invasion front and was nearly absent in tumor buds. Applying the ECIS system with HCT116 and HCT116 stable lentiviral DAPK knock down cells (HCTshDAPK) we identified an important role for DAPK in decreasing the migratory capacity whereas proliferation was not affected. Furthermore, the migration pattern differed with HCTshDAPK cells showing a cluster-like migration of tumor cell groups. DAPK inhibitor treatment revealed that the migration rate was independent of DAPK's catalytic activity. Modulation of DAPK expression level in SW480 and DLD1 colorectal cancer cells significantly influenced wound closure rate. DAPK seems to be a major player that influences the migratory capability of disseminating tumor cells and possibly affects the dynamic interface between pro- and anti-survival factors at the invasion front of colorectal cancer. This interesting and new finding requires further evaluation.

• DAPK
• colorectal cancer
• migration
• tumour budding

• Carcinoma, Squamous Cell/genetics
• DNA Methylation
• Death-Associated Protein Kinases/genetics
• Head and Neck Neoplasms/genetics
• Humans
• Promoter Regions, Genetic

• National Nature Science Foundation of China

• DAPK
• PAK-1
• hepatitis C virus
• mTOR
• peg-IFN-α

• Epigenetic modifications
• Gene expression
• Monoclonal gammopathies
• Pathogenesis
• Tumor suppressor genes

Death-Associated Protein Kinase 1 (DAPK1) belongs to a family of five serine/threonine (Ser/Thr) kinases that possess tumor suppressive function and also mediate a wide range of cellular processes, including apoptosis and autophagy. The loss and gain-of–function of DAPK1 is associated with various cancer and neurodegenerative diseases respectively. In recent years, mechanistic studies have broadened our knowledge of the molecular mechanisms involved in DAPK1-mediated autophagy/apoptosis. In the present review, we have discussed the structural information and various cellular functions of DAPK1 in a comprehensive manner.

• apoptosis
• autophagy
• cancer
• death-associated protein kinase 1
• neurodegenerative disease

Death-associated protein kinase (DAPK) is a tumour suppressor. Here we show that DAPK also inhibits T helper 17 (Th17) and prevents Th17-mediated pathology in a mouse model of autoimmunity. We demonstrate that DAPK specifically downregulates hypoxia-inducible factor 1α (HIF-1α). In contrast to the predominant nuclear localization of HIF-1α in many cell types, HIF-1α is located in both the cytoplasm and nucleus in T cells, allowing for a cytosolic DAPK–HIF-1α interaction. DAPK also binds prolyl hydroxylase domain protein 2 (PHD2) and increases HIF-1α-PHD2 association. DAPK thereby promotes the proline hydroxylation and proteasome degradation of HIF-1α. Consequently, DAPK deficiency leads to excess HIF-1α accumulation, enhanced IL-17 expression and exacerbated experimental autoimmune encephalomyelitis. Additional knockout of HIF-1α restores the normal differentiation of Dapk^−/− Th17 cells and prevents experimental autoimmune encephalomyelitis development. Our results reveal a mechanism involving DAPK-mediated degradation of cytoplasmic HIF-1α, and suggest that raising DAPK levels could be used for treatment of Th17-associated inflammatory diseases.

HIF-1α is critical for Th17 differentiation. Here the authors show that DAPK (Death-Associated Protein Kinase) inhibits Th17 differentiation and immunopathology in a mouse model of multiple sclerosis by promoting HIF1-α binding to its negative regulator PHD2.

Cullin-RING ubiquitin ligases are the largest Ubiquitin ligase family in eukaryotes and are multi-protein complexes. In these complexes, the Cullin protein serves as a scaffold to connect two functional modules of the ligases, the catalytic subunit and substrate-binding subunit. KLHL20 is a substrate-binding subunit of Cullin3 (Cul3) ubiquitin ligase. Recent studies have identified a number of substrates of KLHL20-based ubiquitin ligase. Through ubiquitination of these substrates, KLHL20 elicits diverse cellular functions, some of which are associated with human diseases. Furthermore, the functions, subcellular localizations, and expression of KLHL20 are regulated by several physiological and stressed signals, which allow KLHL20 to preferentially act on certain substrates to response to these signals. Here, we provide a summary of the functions and regulations of KLHL20 in several physiological processes and stress responses and its disease implications.

• Actin cytoskeleton
• Angiogenesis
• Autophagy
• Cancer
• Cul3 ubiquitin ligases
• Hypoxia
• KLHL20
• Ubiquitination