Role of DAPK1 in neuronal cell death, survival and diseases in the nervous system

Abstract

DAPK (death‐associated protein kinase) is a calcium/calmodulin (Ca2+/CaM) regulated serine/threonine kinase. Structurally, it assumes a multi‐domain structure and participates in various apoptotic systems which imply that it may interact with a wide range of intracellular components to exert its action. DAPK plays vital roles in pro‐apoptotic, apoptotic and autophagic pathways. In addition, it plays important roles in many diseases such as cancer, Alzheimer's disease, cerebral ischemia and epilepsy. Although a novel protein, DAPK's various cellular signal transduction pathways proves that it can be a target for a potential future therapeutic effects. Specific role of DAPK in the development and maintenance of the nervous system needs to be further investigated as it is involved in neurodegeneration, traumatic brain injury and neuronal development or recovery from injury. This review summarizes DAPK signaling pathways in autophagy, apoptosis, and stresses the important role it might play in the nervous system.

Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

“…Death-associated protein kinase 1 (DAPK1), as a serine/threonine (Ser/Thr) kinase, plays a critical role in the regulation of stress-induced cell death [6,7]. DAPK1 is a pro-apoptotic gene that stimulates cellular apoptosis in response to multiple internal and external apoptotic stimuli [8,9,10]. This pro-apoptotic Ser/Thr kinase is involved in caspase-dependent (i.e., apoptosis) and caspase-independent cell death processes [6,7,10].…”

“…DAPK1 is a pro-apoptotic gene that stimulates cellular apoptosis in response to multiple internal and external apoptotic stimuli [8,9,10]. This pro-apoptotic Ser/Thr kinase is involved in caspase-dependent (i.e., apoptosis) and caspase-independent cell death processes [6,7,10]. In addition to its role in cell death, DAPK1 has been implicated in the cell cycle, tumorigenesis, tumor metastasis, inflammation, oxidative stress and neurodegeneration [7,11,12].…”

Death-associated Protein Kinase 1 Phosphorylates α-Synuclein at Ser129 and Exacerbates Rotenone-induced Toxic Aggregation of α-Synuclein in Dopaminergic SH-SY5Y Cells

“…DAPK1 is widely known as a tumor suppressor that modulates cell survival and death in a variety of cell systems. Moreover, accumulating evidence has shown that apoptotic neuronal death is regulated by DAPK1, and defective DAPK1 function is associated with NDDs [19,21,22,30]. For example, DAPK1 plays a role in brain stroke by interacting with NMDA receptors [41].…”

“…Overexpression of DAPK1 increases formation of autophagic vesicles during programmed cell death [18]. Recent evidence suggests that DAPK1 regulates cell death in the brain, and that the alteration of kinase activity is closely associated with NDDs [19]. For example, DAPK1 activation induces the phosphorylation of p53 at Ser23 [20], increasing apoptotic neuronal cell death [21,22].…”

The Genetics of Alzheimer’s Disease in the Chinese Population

“…Since this discovery, DAPK1 has attracted extensive attention as a potential risk factor for LOAD. DAPK1, a Ca 2+ /CaM-dependent serine/threonine protein kinase, plays a critical role in death signaling (proapoptotic, apoptotic and autophagic pathways) and the regulation of internal and external stress-induced cell damage, including ischemia and Aβ [124][125][126], which implies that it may have a role in various neuropathologies, such as AD, ischemia, and epilepsy. The critical role of DAPK1 in AD was confirmed at the cellular and animal levels [127,128], and it is currently believed that DAPK1 may be a key player in mediating the pathological process of dementia.…”