Deletion of the kinase domain from death-associated protein kinase enhances spatial memory in mice

Yukawa, Kazunori; Tanaka, Tetsuji; Bai, Tong; Li, Li; Tsubota, Yuji; Owada-Makabe, Kyoko; Maeda, Masanobu; Hoshino, Katsuaki; Akira, Shizuo; Iso, Hiroyuki

doi:10.3892/ijmm.17.5.869

Cited by 18 publications

(20 citation statements)

References 37 publications

(65 reference statements)

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“…Treatment of animals with bioavailable DAPK inhibitors results in a selective upregulation in the hippocampus of the synaptosomal scaffold protein PSD-95 (4), a marker for synaptic integrity that participates in the control of synaptic transmission and plasticity (6). Consistent with a role of DAPK in synaptic plasticity, experiments in mice showed that deletion of 74 amino acids from the catalytic domain of this kinase causes superior spatial learning compared to wild-type animals (7). These findings suggest a role for DAPK in synaptic integrity and function, but a potential DAPK substrate that is involved in such regulation has not been reported.…”

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confidence: 99%

Death-Associated Protein Kinase Phosphorylates Mammalian Ribosomal Protein S6 and Reduces Protein Synthesis

et al. 2006

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Death associated protein kinase (DAPK) is a pro-apoptotic, calcium/calmodulin regulated protein kinase that is a drug discovery target for neurodegenerative disorders. Despite the potential profound physiological role of DAPK in neuronal function and pathophysiology, the endogenous substrate(s) of this kinase and the mechanisms via which DAPK elicits its biological action remain largely unknown. We report here that the mammalian 40S ribosomal protein S6 is a DAPK substrate. Results from immunoprecipitation experiments are consistent with endogenous DAPK being associated with endogenous S6 in rat brain. When S6 is a component of the 40S ribosomal subunit complex, DAPK selectively phosphorylates it at serine 235, one of the five sites in S6 that are phosphorylated by the S6 kinase family of proteins. The amino acid sequence flanking serine 235 matches the established pattern for DAPK peptide and protein substrates. Kinetic analyses using purified 40S subunits revealed a K m value of 9 μM, consistent with S6 being a potential physiological substrate of DAPK. This enzyme-substrate relationship has functional significance. DAPK suppresses translation in rabbit reticulocyte lysate and treatment of neuroblastoma cells with a stimulator of DAPK reduces protein synthesis. In both cases, suppression of translation correlates with increased phosphorylation of S6 at serine 235. These results demonstrate that DAPK is an S6 kinase and provide evidence for a novel role of DAPK in regulation of translation. KeywordsApoptosis; synaptic plasticity; translational control; protein synthesis; DAPK; ribosomal protein S6; S6 kinase Death associated protein kinase (DAPK) is a calcium and calmodulin (CaM)-regulated serine/threonine protein kinase implicated in the pathophysiology characteristic of diverse † A.M.S. and A

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confidence: 99%

Death-Associated Protein Kinase Phosphorylates Mammalian Ribosomal Protein S6 and Reduces Protein Synthesis

et al. 2006

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“…9 Furthermore, mice with a deletion in DAPK kinase domain exhibit an enhanced spatial memory. 30 Although these studies implicate a potential impact of DAPK on AD, our finding that DAPK enhances MARK-induced tau phosphorylation and tau toxicity provides a molecular linkage of DAPK to tauopathy-related neurodegenerative disorders, such as AD. Thus, besides promoting acute neuronal cell death, elevated DAPK expression caused by genetic variation or environmental stress 1,[7][8][9] might increase the risk of AD through aberrant MARK activation.…”

Section: Discussionmentioning

confidence: 90%

DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity

Tsai

Chen

et al. 2011

Cell Death Differ

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Death-associated protein kinase (DAPK) is a key player in several modes of neuronal death/injury and has been implicated in the late-onset Alzheimer's disease (AD). DAPK promotes cell death partly through its effect on regulating actin cytoskeletons. In this study, we report that DAPK inhibits microtubule (MT) assembly by activating MARK/PAR-1 family kinases MARK1/2, which destabilize MT by phosphorylating tau and related MAP2/4. DAPK death domain, but not catalytic activity, is responsible for this activation by binding to MARK1/2 spacer region, thereby disrupting an intramolecular interaction that inhibits MARK1/2. Accordingly, DAPK À/À mice brain displays a reduction of tau phosphorylation and DAPK enhances the effect of MARK2 on regulating polarized neurite outgrowth. Using a well-characterized Drosophila model of tauopathy, we show that DAPK exerts an effect in part through MARK Drosophila ortholog PAR-1 to induce rough eye and loss of photoreceptor neurons. Furthermore, DAPK enhances tau toxicity through a PAR-1 phosphorylation-dependent mechanism. Together, our study reveals a novel mechanism of MARK activation, uncovers DAPK functions in modulating MT assembly and neuronal differentiation, and provides a molecular link of DAPK to tau phosphorylation, an event associated with AD pathology.

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“…However, the physiological functions of DAPK in vivo were not fully understood until DAPK-mutant mice were generated. Although a few studies have shown roles for DAPK in the kidney and brain (16)(17)(18)(19), the functions of DAPK in the ovary have not previously been reported. In the present study, we have clarified the tissue distributions and biocharacteristics of DAPK in the murine ovary for the first time.…”

Section: Discussionmentioning

confidence: 99%

“…Using DAPK-mutant mice lacking the 74-amino acid catalytic kinase domain of DAPK, we have revealed that DAPK plays a pro-apoptotic role in renal tubular cell apoptosis in chronic obstructive uropathy and renal ischemiareperfusion injuries (16)(17)(18). Furthermore, DAPK is involved in modulating spatial memory in mice (19). However, there have been no previous studies on the tissue distributions and physiologic functions of DAPK in female reproductive organs.…”

Section: Introductionmentioning

confidence: 94%

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Irinotecan-induced ovarian follicular apoptosis is attenuated by deleting the kinase domain of death-associated protein kinase

Tanaka²,

Yukawa³

et al. 2009

Int J Oncol

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Abstract. Although death-associated protein kinase (DAPK) is a Ca2+ /calmodulin-regulated serine/threonine kinase that plays important roles in various types of apoptotic cell death, there have been no reports of its tissue distributions and functions in female reproductive organs. By comparing C57BL/6 wild-type mice with DAPK-mutant mice lacking the 74-amino acid catalytic kinase domain of DAPK, the cellular distributions and biological functions of DAPK in murine ovaries were investigated. In situ hybridization analyses with sense and antisense riboprobes revealed that DAPK mRNA was selectively and highly expressed in granulosa cells in the ovaries of both types of mice. There were no significant differences in the body weights, ovarian weights and unstimulated ovarian follicular numbers between the wild-type and DAPK-mutant mice. Intraperitoneal injection of CPT-11, an anticancer topoisomerase I inhibitor that causes granulosa cell-specific apoptosis partly through Fas-Fas ligand (FasL) interactions in MCH mice, induced follicular apoptosis in both the wild-type and DAPK-mutant mice. However, the numbers of apoptotic follicles were significantly reduced in the DAPK-mutant mice. The Fas and FasL expression levels in the CPT-11-injected mice did not differ significantly between the wild-type and DAPK-mutant mice. These results indicate that DAPK positively regulates intracellular signaling pathways for CPT-11-induced granulosa cell apoptosis.

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Deletion of the kinase domain from death-associated protein kinase enhances spatial memory in mice

Cited by 18 publications

References 37 publications

Death-Associated Protein Kinase Phosphorylates Mammalian Ribosomal Protein S6 and Reduces Protein Synthesis

Death-Associated Protein Kinase Phosphorylates Mammalian Ribosomal Protein S6 and Reduces Protein Synthesis

DAPK activates MARK1/2 to regulate microtubule assembly, neuronal differentiation, and tau toxicity

Irinotecan-induced ovarian follicular apoptosis is attenuated by deleting the kinase domain of death-associated protein kinase

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