The Ste20 Family Kinases MAP4K4, MINK1, and TNIK Converge to Regulate Stress-Induced JNK Signaling in Neurons

Journal of Neuroscience, Journal Year: 2017, Volume and Issue: 37(46), P. 11074 - 11084

Published: Oct. 9, 2017

The c-Jun- N -terminal kinase (JNK) signaling pathway regulates nervous system development, axon regeneration, and neuronal degeneration after acute injury or in chronic neurodegenerative disease. Dual leucine zipper (DLK) is required for stress-induced JNK neurons, yet the factors that initiate DLK/JNK activity remain poorly defined. In present study, we identify Ste20 kinases MAP4K4, misshapen-like 1 (MINK1 MAP4K6) TNIK Traf2- Nck-interacting (TNIK MAP4K7), as upstream regulators of neurons. Using a trophic factor withdrawal-based model neurodegeneration both male female embryonic mouse dorsal root ganglion show MINK1, act redundantly to regulate DLK activation downstream JNK-dependent phosphorylation c-Jun response stress. Targeting TNIK, but not any these individually, sufficient protect neurons potently from degeneration. Pharmacological inhibition MAP4Ks blocks stabilization within axons subsequent retrograde translocation complex nucleus. These results position important pathway. SIGNIFICANCE STATEMENT Neuronal occurs disparate circumstances: during development refine connections, clear damaged pathologically dual (DLK)/c-Jun- represents conserved regulator drives little known about activity. Here, uncover novel role subfamily MAP4 consisting regulating Inhibition protects neurodegeneration, suggesting may represent attractive therapeutic targets.

Language: Английский

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Current Trends in Neurodegeneration: Cross Talks between Oxidative Stress, Cell Death, and Inflammation

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(14), P. 7432 - 7432

Published: July 11, 2021

The human body is highly complex and comprises a variety of living cells extracellular material, which forms tissues, organs, organ systems. Human tend to turn over readily maintain homeostasis in tissues. However, postmitotic nerve exceptionally have an ability regenerate be sustained for the entire life individual, safeguard physiological functioning central nervous system. For efficient CNS, neuronal death essential, but extreme loss neurons diminishes system leads onset neurodegenerative diseases. Neurodegenerative diseases range from acute chronic severe life-altering conditions like Parkinson's disease Alzheimer's disease. Millions individuals worldwide are suffering disorders with little or negligible treatment available, thereby leading decline their quality life. Neuropathological studies identified series factors that explain etiology degradation its progression neurological depends on combination causes disruption neurons, such as environmental, biological, physiological, genetic factors. current review highlights some major pathological responsible degradation, oxidative stress, cell death, neuroinflammation. All these been described detail enhance understanding mechanisms target them management.

Language: Английский

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Axon injury signaling and compartmentalized injury response in glaucoma

Progress in Retinal and Eye Research, Journal Year: 2019, Volume and Issue: 73, P. 100769 - 100769

Published: July 10, 2019

Language: Английский

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An inventory of crosstalk between ubiquitination and other post-translational modifications in orchestrating cellular processes

iScience, Journal Year: 2023, Volume and Issue: 26(5), P. 106276 - 106276

Published: Feb. 26, 2023

Ubiquitination is an important post-translational modification (PTM) that regulates a large spectrum of cellular processes in eukaryotes. Abnormalities ubiquitin signaling underlie numerous human pathologies including cancer and neurodegeneration. Much progress has been made during the last three decades understanding how ligases recognize their substrates ubiquitination orchestrated. Several mechanisms regulation have evolved to prevent promiscuity assembly multi-protein complexes with dedicated subunits specific modifications these enzymes co-factors. Here, we outline another layer complexity involving coordinated access E3 substrates. We provide extensive inventory crosstalk multiple PTMs SUMOylation, phosphorylation, methylation, acetylation, hydroxylation, prolyl isomerization, PARylation, O-GlcNAcylation. discuss molecular by which orchestrate ubiquitination, thus increasing its specificity as well other pathways ensure cell homeostasis.

Language: Английский

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CLDN6 inhibits breast cancer metastasis through WIP-dependent actin cytoskeleton-mediated autophagy

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: March 20, 2023

Abstract Background As a breast cancer suppressor gene, CLDN6 overexpression was found to inhibit metastasis in our previous studies, but the specific mechanism remains unclear. This study aimed clarify role and of inhibiting metastasis. Methods Western blot, immunofluorescence transmission electron microscopy were performed detect autophagy. Wound healing, transwell assays lung mouse models used examine Phalloidin staining immunofluorescent observe actin cytoskeleton. mRNA seq, RT-PCR, western chromatin immunoprecipitation, dual luciferase reporter assay, co-immunoprecipitation define molecular mechanism. The expression levels clinical implication CLDN6, WIP LC3 tissues evaluated using immunohistochemistry. Results We demonstrated that inhibited through autophagy vitro vivo. unraveled novel regulated via WIP-dependent cytoskeleton assembly. Through its PDZ-binding motif, overexpressed interacted with JNK upregulated JNK/c-Jun pathway. C-Jun promoted at transcriptional level. Notably, we observed c-Jun transcriptionally expression, there positive feedback loop between JNK/c-Jun. Finally, correlated each other, significantly associated lymph node patients. Conclusions data provide new insight into inhibitory effects CLDN6-mediated on metastasis, revealed regulating Our findings enrich theoretical basis for as potential biomarker diagnosis therapy.

Language: Английский

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