Specific activities of individual c-Jun N-terminal kinases in the brain

Haeusgen, Wiebke; Boehm, Ruwen; Zhao, Yi; Herdegen, Thomas; Waetzig, Vicki

doi:10.1016/j.neuroscience.2009.04.014

Cited by 83 publications

(62 citation statements)

References 111 publications

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“…JUN is a member of the immediate early gene family (23). Its expression product is a vasodilator-stimulated phosphoprotein of the cell nucleus, which functions as an intermediary in the external stimuli response and a marker of activation in nerve cells (25). c-Jun mRNA expression levels may be used as an effective index to judge neuronal function following injury to nerve cells (21).…”

Section: Discussionmentioning

confidence: 99%

MAPK pathway mediates the anti‑oxidative effect of chicoric acid against cerebral ischemia‑reperfusion injury inï¿½vivo

et al. 2017

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Section: Discussionmentioning

confidence: 99%

MAPK pathway mediates the anti‑oxidative effect of chicoric acid against cerebral ischemia‑reperfusion injury inï¿½vivo

et al. 2017

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“…GSK3 (GSK3A) phosphorylates the collapsin response mediator protein-2 (Crmp-2) to promote neurite elongation via microtubule assembly (94). The MAP kinase kinase MKK4 (MAP2K4) and its substrate JNK (MAPK9) have also been involved in the regulation of neurite outgrowth through the phosphorylation of the microtubule binding proteins MAP, MAP1, doublecortin, and SGC10 (95). Although these findings point to a wide array of kinase classes that regulate neuritogenesis, it is likely that they work together in time and space to fine-tune changes in the actin and microtubule cytoskeletons that drive this process.…”

Section: Discussionmentioning

confidence: 99%

Spatial Phosphoprotein Profiling Reveals a Compartmentalized Extracellular Signal-regulated Kinase Switch Governing Neurite Growth and Retraction

Wang

Yang

et al. 2011

Journal of Biological Chemistry

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Brain development and spinal cord regeneration require neurite sprouting and growth cone navigation in response to extension and collapsing factors present in the extracellular environment. These external guidance cues control neurite growth cone extension and retraction processes through intracellular protein phosphorylation of numerous cytoskeletal, adhesion, and polarity complex signaling proteins. However, the complex kinase/substrate signaling networks that mediate neuritogenesis have not been investigated. Here, we compare the neurite phosphoproteome under growth and retraction conditions using neurite purification methodology combined with mass spectrometry. More than 4000 non-redundant phosphorylation sites from 1883 proteins have been annotated and mapped to signaling pathways that control kinase/phosphatase networks, cytoskeleton remodeling, and axon/dendrite specification. Comprehensive informatics and functional studies revealed a compartmentalized ERK activation/deactivation cytoskeletal switch that governs neurite growth and retraction, respectively. Our findings provide the first system-wide analysis of the phosphoprotein signaling networks that enable neurite growth and retraction and reveal an important molecular switch that governs neuritogenesis.Neuritogenesis is a dynamic process involving the extension of long, thin protrusions called neurites that will subsequently differentiate into long axons or an elaborate dendritic arbor (1-4). This highly polarized process occurs through the segmentation from the soma periphery of a microtubule-rich shaft capped with a growth cone, which itself is characterized by an actin-rich lamellipodium with numerous filopodial extensions and integrin-mediated adhesive contacts. Understanding this process is crucial, as it is necessary for proper wiring of the brain and nerve regeneration and has been linked to numerous neurodegenerative diseases.Although cultured neurons randomly form neurites in vitro, in vivo this process is orchestrated by gradients of chemoattractants, extracellular matrix proteins, and collapsing factors that precisely guide neurite initiation and advancement (5, 6). This occurs in a polarized and highly controlled manner and relies on spatially regulated mechanisms for gradient sensing, membrane trafficking, integrin-mediated adhesion, and organization of the actin-microtubule cytoskeleton (5-8). These events are largely orchestrated by numerous surface guidance/repulsion and adhesion receptors that signal to the cell interior through multiple kinase activation and substrate phosphorylation events (7, 9 -17). Protein phosphorylation is a critical posttranslational modification that regulates protein-protein interactions, enzymatic activity, and subcellular localization. The reversible addition of PO 4 3Ϫ to serine, threonine, and tyrosine amino acid residues is mediated by more than 500 kinases and more than 150 phosphatases (18 -20). In many cases, kinases phosphorylate specific amino acids in the context of a consensus recognition sequen...

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“…Elevated ERK1/2 activity was also implicated in the induction of neurological disorders [108], diabetes [109] and other diseases [3]. Dysregulated JNK cascade is involved in neurodegenerative diseases including Alzheimer’s and Parkinson’s [110], amyotrophic lateral sclerosis [111], as well as neurodevelopmental disorders such as lissencephaly [112]. Other pathologies that involve the dysregulation of JNKs include insulin resistance [109] and some cases of inflammation [113].…”

Section: Mapk Cascades In Diseasementioning

confidence: 99%

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

et al. 2018

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The mitogen-activated protein kinase (MAPK) cascades are central signaling pathways that play a central role in the regulation of most stimulated cellular processes including proliferation, differentiation, stress response and apoptosis. Currently 4 such cascades are known, each termed by its downstream MAPK components: the extracellular signal-regulated kinase 1/2 (ERK1/2), cJun-N-terminal kinase (JNK), p38 and ERK5. One of the hallmarks of these cascades is the stimulated nuclear translocation of their MAPK components using distinct mechanisms. ERK1/2 are shuttled into the nucleus by importin7, JNK and p38 by a dimer of importin3 with either importin9 or importin7, and ERK5 by importin-α/β. Dysregulation of these cascades often results in diseases, including cancer and inflammation, as well as developmental and neurological disorders. Much effort has been invested over the years in developing inhibitors to the MAPK cascades to combat these diseases. Although some inhibitors are already in clinical use or clinical trials, their effects are hampered by development of resistance or adverse side-effects. Recently, our group developed 2 myristoylated peptides: EPE peptide, which inhibits the interaction of ERK1/2 with importin7, and PERY peptide, which prevents JNK/p38 interaction with either importin7 or importin9. These peptides block the nuclear translocation of their corresponding kinases, resulting in prevention of several cancers, while the PERY peptide also inhibits inflammation-induced diseases. These peptides provide a proof of concept for the use of the nuclear translocation of MAPKs as therapeutic targets for cancer and/or inflammation.

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Specific activities of individual c-Jun N-terminal kinases in the brain

Cited by 83 publications

References 111 publications

MAPK pathway mediates the anti‑oxidative effect of chicoric acid against cerebral ischemia‑reperfusion injury inï¿½vivo

MAPK pathway mediates the anti‑oxidative effect of chicoric acid against cerebral ischemia‑reperfusion injury inï¿½vivo

Spatial Phosphoprotein Profiling Reveals a Compartmentalized Extracellular Signal-regulated Kinase Switch Governing Neurite Growth and Retraction

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

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