MAP4K4 Activation Mediates Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Cell Reports, Journal Year: 2019, Volume and Issue: 26(5), P. 1143 - 1156.e5

Published: Jan. 1, 2019

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neurons (MNs). To date, its underlying mechanisms have yet to be clarified completely, there are no truly effective treatments. Here, we show that MAP4K4, MAP kinase family member, regulates MN death, with suppression not only promoting survival but preventing neurite degeneration decreasing mutant SOD1 levels through autophagy activation. Moreover, report MAP4K4 signaling specifically modulates viability via phosphorylated JNK3 activation of the canonical c-Jun apoptotic pathway. Finally, feasibility as drug target by using an available MAP4K4-specific inhibitor, which improves ESC and/or iPSC-derived MNs cultured from mouse spinal cords. In summary, our studies highlight MAP4K4-initiated cascade induces degeneration, shedding light on mechanism providing druggable for ALS therapeutics.

Language: Английский

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A 5′-tRNA halve, tiRNA-Gly promotes cell proliferation and migration via binding to RBM17 and inducing alternative splicing in papillary thyroid cancer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2021, Volume and Issue: 40(1)

Published: July 5, 2021

Abstract Background tRNA-derived small noncoding RNAs (sncRNAs) are mainly categorized into tRNA halves (tiRNAs) and fragments (tRFs). Biological functions of tiRNAs in human solid tumor attracting more attention, but researches concerning the mechanisms tiRNAs-mediated tumorigenesis rarely. The direct regulatory relationship between splicing-related proteins remain elusive. Methods Papillary thyroid carcinoma (PTC) associated were screened by deep sequencing validated qRT-PCR Northern Blot PTC tissues. biological function assessed cell counting kit, transwells subcutaneous transplantation nude mice. For mechanistic study, pull-down, RNA immunoprecipitation, Western Blot, Immunofluorescence, Immunohistochemical staining performed. Results Herein, we have identified a 33 nt tiRNA-Gly significantly increases papillary cancer based on tRFs & sequencing. ectopic expression promotes proliferation migration, whereas down-regulation exhibits reverse effects. Mechanistic investigations reveal directly bind UHM domain RNA-binding protein RBM17. interaction with could translocate RBM17 from cytoplasm nucleus. In addition, via inhibiting its degradation ubiquitin/proteasome-dependent way. Moreover, level high-expressing tissues is upregulated. vivo mouse model shows that suppression decreases expression. Importantly, can induce exon 16 splicing MAP4K4 mRNA leading to phosphorylation downstream signaling pathway, which dependent. Conclusions Our study firstly illustrates display oncogenic effect RBM17-mediated alternative splicing. This fully novel broadens our understanding molecular mechanism fragment cells binding play role

Language: Английский

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Genetic risk factors for severe and fatigue dominant long COVID and commonalities with ME/CFS identified by combinatorial analysis

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Nov. 1, 2023

Long COVID is a debilitating chronic condition that has affected over 100 million people globally. It characterized by diverse array of symptoms, including fatigue, cognitive dysfunction and respiratory problems. Studies have so far largely failed to identify genetic associations, the mechanisms behind disease, or any common pathophysiology with other conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present similar symptoms.We used combinatorial analysis approach combinations variants significantly associated development long examine biological underpinning its various symptoms. We compared two subpopulations patients from Sano Genetics' GOLD study cohort, focusing on severe dominant phenotypes. evaluated signatures previously identified in an ME/CFS population against this understand similarities disorders may be triggered prior viral infection. Finally, we also output known associations diseases, range metabolic neurological disorders, overlap pathophysiological mechanisms.Combinatorial 73 genes were highly at least one populations included analysis. Of these, 9 acute COVID-19, 14 differentially expressed transcriptomic patients. A pathway enrichment revealed pathways most mainly aligned cardiometabolic diseases. Expanded genotype suggests specific SNX9 genotypes are significant contributor risk protection infection, but gene-disease relationship context dependent mediated interactions KLF15 RYR3. Comparison uniquely Severe Fatigue Dominant differences between enriched each subgroup. The unique immune myeloid differentiation macrophage foam cells. Genes subgroup MAPK/JNK signaling. ME/CFS, several involved circadian rhythm regulation insulin regulation. Overall, 39 SNPs can linked recent patient UK Biobank. Among COVID, 42 potentially tractable for novel drug discovery approaches, 13 these already targeted drugs clinical pipelines. From example, TLR4 antagonists repurposing candidates potential protect term impairment pathology caused SARS-CoV-2. currently evaluating targets use treating and/or ME/CFS.This demonstrates power analytics stratifying heterogeneous complex diseases do not simple monogenic etiologies. These results build upon findings analyses COVID-19 expect access additional independent, larger datasets will further improve disease insights validate treatment options COVID.

Language: Английский

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Molecular Insights of MAP4K4 Signaling in Inflammatory and Malignant Diseases

Cancers, Journal Year: 2023, Volume and Issue: 15(8), P. 2272 - 2272

Published: April 13, 2023

Mitogen-activated protein kinase (MAPK) cascades are crucial in extracellular signal transduction to cellular responses. The classical three-tiered MAPK include signaling through MAP (MAP3K) that activates a (MAP2K), which turn induces activation and downstream upstream activators of MAP3K often small guanosine-5′-triphosphate (GTP)-binding proteins, but some pathways, can be activated by another kinase, is known as (MAP4K). MAP4K4 one the widely studied MAP4K members, play significant role inflammatory, cardiovascular, malignant diseases. plays an essential cell proliferation, transformation, invasiveness, adhesiveness, inflammation, stress responses, migration. Overexpression frequently reported many cancers, including glioblastoma, colon, prostate, pancreatic cancers. Besides its mainstay pro-survival various malignancies, has been implicated cancer-associated cachexia. In present review, we discuss functional malignant/non-malignant diseases cachexia possible use targeted therapy.

Language: Английский

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METTL3-mediated upregulation of FAM135B promotes EMT of esophageal squamous cell carcinoma via regulating the Wnt/β-catenin pathway

AJP Cell Physiology, Journal Year: 2024, Volume and Issue: 327(2), P. C329 - C340

Published: June 17, 2024

Family with sequence similarity 135 member B (FAM135B) is a novel driver gene in esophageal squamous cell carcinoma (ESCC). However, little known regarding its biological functions and mechanisms ESCC. Here, we identified that the high expression of FAM135B was associated lymph node metastasis infiltrating development Elevated promoted ESCC migration invasion vitro lung vivo. Furthermore, epithelial-mesenchymal transition (EMT)-related pathways were enriched samples levels positively regulated EMT markers. Mechanistically, observed interacted intermediate domain TRAF2 NCK-interacting kinase (TNIK), activating Wnt/β-catenin signaling pathway. The facilitation TNIK on reversed by siRNA. In addition, N6-methyladenosine (m6A) modification expression, methyltransferase like 3 (METTL3) acting as substantial m6A writer. pro-EMT effects METTL3 overexpression silencing FAM135B. Collectively, these findings illustrate critical role ABCDE progression provide new insights into upstream downstream

Language: Английский

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Dual Leucine Zipper Kinase Inhibitors for the Treatment of Neurodegeneration

Journal of Medicinal Chemistry, Journal Year: 2018, Volume and Issue: 61(18), P. 8078 - 8087

Published: June 4, 2018

Dual leucine zipper kinase (DLK, MAP3K12) is an essential driver of the neuronal stress response that regulates neurodegeneration in models acute injury and chronic neurodegenerative diseases such as Alzheimer's, Parkinson's, ALS. In this review, we provide overview DLK signaling mechanisms describe selected small molecules have been utilized to inhibit activity vivo. These compounds represent valuable tools for understanding role evaluating potential inhibition a therapeutic strategy prevent degeneration.

Language: Английский

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Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents

Cell chemical biology, Journal Year: 2019, Volume and Issue: 26(12), P. 1703 - 1715.e37

Published: Nov. 3, 2019

Language: Английский

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Palmitoylation couples the kinases DLK and JNK3 to facilitate prodegenerative axon-to-soma signaling

Science Signaling, Journal Year: 2022, Volume and Issue: 15(727)

Published: March 29, 2022

Dual leucine-zipper kinase (DLK; a MAP3K) mediates neuronal responses to diverse injuries and insults through the c-Jun N-terminal (JNK) family of mitogen-activated protein kinases (MAPKs). Here, we identified two ways which DLK is coupled neural-specific isoform JNK3 control prodegenerative signaling. catalyzed positive feedback phosphorylation that further activated locked DLK-JNK3 module in highly active state. Neither homologous MAP3Ks nor MAPK could support this loop. Unlike related JNK1 JNK2 promote axon-to-soma signaling were endogenously palmitoylated. Moreover, palmitoylation targeted both same axonal vesicles, was essential for retrograde response optic nerve crush injury vivo. These findings provide previously unappreciated insights into DLK-JNK relevant neuropathological conditions answer long-standing questions regarding selective roles JNK3.

Language: Английский

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MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage

Oncogene, Journal Year: 2023, Volume and Issue: 42(18), P. 1438 - 1452

Published: March 15, 2023

Peritoneal metastasis is a key feature of advanced ovarian cancer, but the critical protein required for cancer and progression yet to be defined. Thus, an unbiased high throughput in-depth study warranted unmask mechanism. Transcriptomic sequencing paired primary tumors metastases unveiled that MAP4K4, serine/threonine kinase belongs Ste20 family kinases, was highly expressed in metastatic sites. Increased MAP4K4 expression further validated other independent patients, with higher associated poorer survival, level CA125 more FIGO stage. Down regulation inhibited cell adhesion, migration, invasion. Notably, found stabilize N-cadherin. Further results showed mediated phosphorylation ADAM10 at Ser436 suppression N-cadherin cleavage by ADAM10, leading stabilization. Pharmacologic inhibition abrogated peritoneal metastases. Overall, our data reveal as significant promoter metastasis. Targeting may potential therapeutic approach patients.

Language: Английский

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Novel inhibitors of acute, axonal DLK palmitoylation are neuroprotective and avoid the deleterious side effects of cell-wide DLK inhibition

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 24, 2024

Abstract Dual leucine-zipper kinase (DLK) drives acute and chronic forms of neurodegeneration, suggesting that inhibiting DLK signaling could ameliorate diverse neuropathological conditions. However, direct inhibition DLK’s domain in human patients conditional knockout mice both cause unintended side effects, including elevated plasma neurofilament levels, indicative neuronal cytoskeletal disruption. Indeed, we found a inhibitor acutely disrupted the axonal cytoskeleton caused vesicle aggregation cultured dorsal root ganglion (DRG) neurons, further cautioning against this therapeutic strategy. In seeking more precise intervention, retrograde (axon-to-soma) pro-degenerative requires acute, palmitoylation hypothesized modulating post-translational modification might be specifically neuroprotective than cell-wide inhibition. To address possibility, screened >28,000 compounds using high-content imaging assay quantitatively evaluates palmitoylation-dependent subcellular localization. Of 33 hits significantly altered localization non-neuronal cells, several reduced protected DRG neurons from DLK-dependent neurodegeneration. Mechanistically, two most selectively prevent stimulus-dependent pools DLK, process crucial for recruitment to vesicles. contrast, these minimally impact healthy avoid disruption associated with Importantly, our hit also reduce vivo, novel

Language: Английский

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