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Dual leucine zipper kinase

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https://www.readbyqxmd.com/read/28993483/the-ste20-family-kinases-map4k4-mink1-and-tnik-converge-to-regulate-stress-induced-jnk-signaling-in-neurons
#1
Martin Larhammar, Sarah Huntwork-Rodriguez, York Rudhard, Arundhati Sengupta-Ghosh, Joseph W Lewcock
The c-Jun-N-terminal Kinase (JNK) signaling pathway regulates nervous system development, axon regeneration, and neuronal degeneration following acute injury or in chronic neurodegenerative disease. Dual Leucine Zipper Kinase (DLK) is required for stress-induced JNK signaling in neurons, yet the factors that initiate DLK/JNK pathway activity remain poorly defined. In the present study, we identify the Ste20 kinases MAP4K4, TNIK, and MINK1 as upstream regulators of DLK/JNK signaling in neurons. Using a trophic factor withdrawal-based model of neurodegeneration in both male and female embryonic mouse dorsal root ganglion neurons, we show that MAP4K4, TNIK, and MINK1 act redundantly to regulate DLK activation and downstream JNK dependent phosphorylation of c-Jun in response to stress...
October 9, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28929759/selective-inhibitors-of-dual-leucine-zipper-kinase-dlk-map3k12-with-activity-in-a-model-of-alzheimer-s-disease
#2
Snahel Patel, William J Meilandt, Rebecca I Erickson, Jinhua Chen, Gauri Deshmukh, Anthony A Estrada, Reina N Fuji, Paul Gibbons, Amy Gustafson, Seth F Harris, Jose Imperio, Wendy Liu, Xingrong Liu, Yichin Liu, Joseph P Lyssikatos, Changyou Ma, Jianping Yin, Joseph W Lewcock, Michael Siu
Significant data exists to suggest that dual leucine zipper kinase (DLK, MAP3K12) is a conserved regulator of neuronal degeneration following neuronal injury and in chronic neurodegenerative disease. Consequently, there is considerable interest in the identification of DLK inhibitors with a profile compatible with development for these indications. Herein, we use structure-based drug design combined with a focus on CNS drug-like properties to generate compounds with superior kinase selectivity and metabolic stability as compared to previously disclosed DLK inhibitors...
October 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28885866/caspase-inhibitors-a-review-of-recently-patented-compounds-2013-2015
#3
Hyemin Lee, Eun Ah Shin, Jae Hee Lee, Deoksoo Ahn, Chang Geun Kim, Ju-Ha Kim, Sung-Hoon Kim
Although many caspase inhibitors have been patented, caspase inhibitors have not entered the market due to their toxicity and poor pharmacokinetic profile. Areas covered: In this article, we review patents (2013-2015) for peptide and non-peptide caspase inhibitors and their compositions. Expert opinion: Noteworthy patents include a peptidic caspase-2 inhibitor for nasal administration and a peptidomimetic caspase-6 inhibitor that can be administered via several routes for the treatment of neurodegenerative diseases...
September 8, 2017: Expert Opinion on Therapeutic Patents
https://www.readbyqxmd.com/read/28814543/loss-of-dual-leucine-zipper-kinase-signaling-is-protective-in-animal-models-of-neurodegenerative-disease
#4
Claire E Le Pichon, William J Meilandt, Sara Dominguez, Hilda Solanoy, Han Lin, Hai Ngu, Alvin Gogineni, Arundhati Sengupta Ghosh, Zhiyu Jiang, Seung-Hye Lee, Janice Maloney, Vineela D Gandham, Christine D Pozniak, Bei Wang, Sebum Lee, Michael Siu, Snahel Patel, Zora Modrusan, Xingrong Liu, York Rudhard, Miriam Baca, Amy Gustafson, Josh Kaminker, Richard A D Carano, Eric J Huang, Oded Foreman, Robby Weimer, Kimberly Scearce-Levie, Joseph W Lewcock
Hallmarks of chronic neurodegenerative disease include progressive synaptic loss and neuronal cell death, yet the cellular pathways that underlie these processes remain largely undefined. We provide evidence that dual leucine zipper kinase (DLK) is an essential regulator of the progressive neurodegeneration that occurs in amyotrophic lateral sclerosis and Alzheimer's disease. We demonstrate that DLK/c-Jun N-terminal kinase signaling was increased in mouse models and human patients with these disorders and that genetic deletion of DLK protected against axon degeneration, neuronal loss, and functional decline in vivo...
August 16, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/28641113/enhanced-functional-genomic-screening-identifies-novel-mediators-of-dual-leucine-zipper-kinase-dependent-injury-signaling-in-neurons
#5
Derek S Welsbie, Katherine L Mitchell, Vinod Jaskula-Ranga, Valentin M Sluch, Zhiyong Yang, Jessica Kim, Eugen Buehler, Amit Patel, Scott E Martin, Ping-Wu Zhang, Yan Ge, Yukan Duan, John Fuller, Byung-Jin Kim, Eman Hamed, Xitiz Chamling, Lei Lei, Iain D C Fraser, Ze'ev A Ronai, Cynthia A Berlinicke, Donald J Zack
Dual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs...
June 21, 2017: Neuron
https://www.readbyqxmd.com/read/28593342/the-role-of-dual-leucine-zipper-kinase-dlk-in-%C3%AE-cell-apoptosis-a-potential-target-for-the-prevention-and-treatment-of-type-2-diabetes-commentary-to-b%C3%A3-rchers-et-al-tnf-%C3%AE-induced-dlk-activation-contributes-to-apoptosis-in-the-%C3%AE-cell-line-hit
#6
EDITORIAL
https://www.readbyqxmd.com/read/28550372/tnf%C3%AE-induced-dlk-activation-contributes-to-apoptosis-in-the-beta-cell-line-hit
#7
Svenja Börchers, Rohollah Babaei, Catarina Klimpel, Jorge Duque Escobar, Sabine Schröder, Roland Blume, Muhammad Nasir Hayat Malik, Elke Oetjen
Reduction in beta-cell mass and function contributes to the pathogenesis of diabetes mellitus type 2. The proinflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1β have been implicated in the pathogenesis of this disease. Overexpression of the dual leucine zipper kinase (DLK) inhibits beta-cell function and induces apoptosis in the beta-cell line HIT. In the present study, it was investigated whether TNFα or IL-1β stimulates DLK enzymatic activity. Immunoblot analysis, transient transfection with luciferase reporter gene assays, and immunofluorescence were used...
August 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28440222/dual-leucine-zipper-kinase-dependent-perk-activation-contributes-to-neuronal-degeneration-following-insult
#8
Martin Larhammar, Sarah Huntwork-Rodriguez, Zhiyu Jiang, Hilda Solanoy, Arundhati Sengupta Ghosh, Bei Wang, Joshua S Kaminker, Kevin Huang, Jeffrey Eastham-Anderson, Michael Siu, Zora Modrusan, Madeline M Farley, Marc Tessier-Lavigne, Joseph W Lewcock, Trent A Watkins
The PKR-like endoplasmic reticulum kinase (PERK) arm of the Integrated Stress Response (ISR) is implicated in neurodegenerative disease, although the regulators and consequences of PERK activation following neuronal injury are poorly understood. Here we show that PERK signaling is a component of the mouse MAP kinase neuronal stress response controlled by the Dual Leucine Zipper Kinase (DLK) and contributes to DLK-mediated neurodegeneration. We find that DLK-activating insults ranging from nerve injury to neurotrophin deprivation result in both c-Jun N-terminal Kinase (JNK) signaling and the PERK- and ISR-dependent upregulation of the Activating Transcription Factor 4 (ATF4)...
April 25, 2017: ELife
https://www.readbyqxmd.com/read/28396258/dlk-silencing-attenuated-neuron-apoptosis-through-jip3-ma2k7-jnk-pathway-in-early-brain-injury-after-sah-in-rats
#9
Cheng Yin, Guang-Fu Huang, Xiao-Chuan Sun, Zongduo Guo, John H Zhang
OBJECTIVE: Dual leucine zipper kinase (DLK/MA3K12) has been reported involved in apoptosis and neuronal degeneration during neural development and traumatic brain injury. This study was designed to investigate the role of DLK with its adaptor protein JNK interacting protein-3 (JIP3), and its downstream MA2K7/JNK signaling pathway in early brain injury (EBI) after subarachnoid hemorrhage (SAH) in a rat model. DESIGN: Controlled in vivo laboratory study. SETTING: Animal research laboratory...
July 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28111074/apoe2-apoe3-and-apoe4-differentially-stimulate-app-transcription-and-a%C3%AE-secretion
#10
Yu-Wen Alvin Huang, Bo Zhou, Marius Wernig, Thomas C Südhof
Human apolipoprotein E (ApoE) apolipoprotein is primarily expressed in three isoforms (ApoE2, ApoE3, and ApoE4) that differ only by two residues. ApoE4 constitutes the most important genetic risk factor for Alzheimer's disease (AD), ApoE3 is neutral, and ApoE2 is protective. How ApoE isoforms influence AD pathogenesis, however, remains unclear. Using ES-cell-derived human neurons, we show that ApoE secreted by glia stimulates neuronal Aβ production with an ApoE4 > ApoE3 > ApoE2 potency rank order. We demonstrate that ApoE binding to ApoE receptors activates dual leucine-zipper kinase (DLK), a MAP-kinase kinase kinase that then activates MKK7 and ERK1/2 MAP kinases...
January 26, 2017: Cell
https://www.readbyqxmd.com/read/28009276/mitochondria-localize-to-injured-axons-to-support-regeneration
#11
Sung Min Han, Huma S Baig, Marc Hammarlund
Axon regeneration is essential to restore the nervous system after axon injury. However, the neuronal cell biology that underlies axon regeneration is incompletely understood. Here we use in vivo, single-neuron analysis to investigate the relationship between nerve injury, mitochondrial localization, and axon regeneration. Mitochondria translocate into injured axons so that average mitochondria density increases after injury. Moreover, single-neuron analysis reveals that axons that fail to increase mitochondria have poor regeneration...
December 21, 2016: Neuron
https://www.readbyqxmd.com/read/27519653/a-role-for-dlk-in-microtubule-reorganization-to-the-cell-periphery-and-in-the-maintenance-of-desmosomal-and-tight-junction-integrity
#12
COMPARATIVE STUDY
Carolyne Simard-Bisson, Julie Bidoggia, Danielle Larouche, Sylvain L Guérin, Richard Blouin, Syu-Ichi Hirai, Lucie Germain
Dual leucine zipper-bearing kinase (DLK) is an inducer of keratinocyte differentiation, a complex process also involving microtubule reorganization to the cell periphery. However, signaling mechanisms involved in this process remain to be elucidated. Here, we demonstrate that DLK enhances and is required for microtubule reorganization to the cell periphery in human cell culture models and in Dlk knockout mouse embryos. In tissue-engineered skins with reduced DLK expression, cortical distribution of two microtubule regulators, LIS1 and HSP27, is impaired as well as desmosomal and tight junction integrity...
January 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/27511108/leucine-zipper-bearing-kinase-promotes-axon-growth-in-mammalian-central-nervous-system-neurons
#13
Meifan Chen, Cédric G Geoffroy, Hetty N Wong, Oliver Tress, Mallorie T Nguyen, Lawrence B Holzman, Yishi Jin, Binhai Zheng
Leucine Zipper-bearing Kinase (LZK/MAP3K13) is a member of the mixed lineage kinase family with high sequence identity to Dual Leucine Zipper Kinase (DLK/MAP3K12). While DLK is established as a key regulator of axonal responses to injury, the role of LZK in mammalian neurons is poorly understood. By gain- and loss-of-function analyses in neuronal cultures, we identify LZK as a novel positive regulator of axon growth. LZK signals specifically through MKK4 and JNKs among MAP2Ks and MAPKs respectively in neuronal cells, with JNK activity positively regulating LZK protein levels...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27468987/dual-leucine-zipper-kinase-regulates-expression-of-axon-guidance-genes-in-mouse-neuronal-cells
#14
Andréanne Blondeau, Jean-François Lucier, Dominick Matteau, Lauralyne Dumont, Sébastien Rodrigue, Pierre-Étienne Jacques, Richard Blouin
BACKGROUND: Recent genetic studies in model organisms, such as Drosophila, C. elegans and mice, have highlighted a critical role for dual leucine zipper kinase (DLK) in neural development and axonal responses to injury. However, exactly how DLK fulfills these functions remains to be determined. Using RNA-seq profiling, we evaluated the global changes in gene expression that are caused by shRNA-mediated knockdown of endogenous DLK in differentiated Neuro-2a neuroblastoma cells. RESULTS: Our analysis led to the identification of numerous up- and down-regulated genes, among which several were found to be associated with system development and axon guidance according to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, respectively...
July 28, 2016: Neural Development
https://www.readbyqxmd.com/read/27402706/wallenda-dlk-protein-levels-are-temporally-downregulated-by-tramtrack69-to-allow-r7-growth-cones-to-become-stationary-boutons
#15
Alexander I Feoktistov, Tory G Herman
Dual leucine zipper kinase (DLK) promotes growth cone motility and must be restrained to ensure normal development. PHR (Pam/Highwire/RPM-1) ubiquitin ligases therefore target DLK for degradation unless axon injury occurs. Overall DLK levels decrease during development, but how DLK levels are regulated within a developing growth cone has not been examined. We analyzed the expression of the fly DLK Wallenda (Wnd) in R7 photoreceptor growth cones as they halt at their targets and become presynaptic boutons. We found that Wnd protein levels are repressed by the PHR protein Highwire (Hiw) during R7 growth cone halting, as has been observed in other systems...
August 15, 2016: Development
https://www.readbyqxmd.com/read/27350865/regulation-of-microtubule-dynamics-in-axon-regeneration-insights-from-c-elegans
#16
REVIEW
Ngang Heok Tang, Andrew D Chisholm
The capacity of an axon to regenerate is regulated by its external environment and by cell-intrinsic factors. Studies in a variety of organisms suggest that alterations in axonal microtubule (MT) dynamics have potent effects on axon regeneration. We review recent findings on the regulation of MT dynamics during axon regeneration, focusing on the nematode Caenorhabditis elegans. In C. elegans the dual leucine zipper kinase (DLK) promotes axon regeneration, whereas the exchange factor for Arf6 (EFA-6) inhibits axon regeneration...
2016: F1000Research
https://www.readbyqxmd.com/read/27268300/an-evolutionarily-conserved-mechanism-for-camp-elicited-axonal-regeneration-involves-direct-activation-of-the-dual-leucine-zipper-kinase-dlk
#17
Yan Hao, Erin Frey, Choya Yoon, Hetty Wong, Douglas Nestorovski, Lawrence B Holzman, Roman J Giger, Aaron DiAntonio, Catherine Collins
A broadly known method to stimulate the growth potential of axons is to elevate intracellular levels of cAMP, however the cellular pathway(s) that mediate this are not known. Here we identify the Dual Leucine-zipper Kinase (DLK, Wnd in Drosophila) as a critical target and effector of cAMP in injured axons. DLK/Wnd is thought to function as an injury 'sensor', as it becomes activated after axonal damage. Our findings in both Drosophila and mammalian neurons indicate that the cAMP effector kinase PKA is a conserved and direct upstream activator of Wnd/DLK...
June 7, 2016: ELife
https://www.readbyqxmd.com/read/27100796/regulation-of-beta-cell-function-and-mass-by-the-dual-leucine-zipper-kinase
#18
REVIEW
Elke Oetjen
Diabetes mellitus is one of the most rapidly increasing diseases worldwide, whereby approximately 90-95% of patients suffer from type 2 diabetes. Considering its micro- and macrovascular complications like blindness and myocardial infarction, a reliable anti-diabetic treatment is needed. Maintaining the function and the mass of the insulin producing beta-cells despite elevated levels of beta-cell-toxic prediabetic signals represents a desirable mechanism of action of anti-diabetic drugs. The dual leucine zipper kinase (DLK) inhibits the action of two transcription factors within the beta-cell, thereby interfering with insulin secretion and production and the conservation of beta-cell mass...
June 2016: Archiv der Pharmazie
https://www.readbyqxmd.com/read/27084696/tozasertib-attenuates-neuronal-apoptosis-via-dlk-jip3-ma2k7-jnk-pathway-in-early-brain-injury-after-sah-in-rats
#19
Cheng Yin, Guang-Fu Huang, Xiao-Chuan Sun, Zongduo Guo, John H Zhang
BACKGROUND AND PURPOSE: Since tozasertib is neuroprotective for injured optic nerve, this study is intended to test whether tozasertib reduces early brain injury after subarachnoid hemorrhage (SAH) in a rat model. METHODS: Two hundred sixteen (216) male Sprague-Dawley rats were randomly subjected to endovascular perforation model of SAH and sham group. SAH grade, neurological score, and brain water content were measured at 24 and 72 h after SAH. Dual leucine zipper kinase (DLK) and its downstream factors, JNK-interacting protein 3 (JIP3), MA2K7, p-JNK/JNK (c-Jun N-terminal kinase), and apoptosis related proteins cleaved caspase-3 (CC-3), Bim, Bcl-2, and cleaved caspase-9 (CC-9) were analyzed by western blot at 24 h after SAH...
September 2016: Neuropharmacology
https://www.readbyqxmd.com/read/27043251/dual-leucine-zipper-kinase-map3k12-modulators-a-patent-review-2010-2015
#20
REVIEW
Elke Oetjen, Thomas Lemcke
INTRODUCTION: The dual leucine zipper kinase (DLK, MAP3K12) is essential for neuronal development and has been shown to mediate axon regeneration. On the other hand, DLK is involved in the pathogenesis of neurodegenerative disease and diabetes mellitus. Several patents have been published claiming to modulate or inhibit DLK by various approaches including ATP competitive inhibitors. In addition, two publications describe SAR of highly selective DLK inhibitors with efficacy in distinct mouse models of neurodegeneration...
May 2016: Expert Opinion on Therapeutic Patents
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