c-Jun N-terminal kinase binding domain-dependent phosphorylation of mitogen-activated protein kinase kinase 4 and mitogen-activated protein kinase kinase 7 and balancing cross-talk between c-Jun N-terminal kinase and extracellular signal-regulated kinase pathways in cortical neurons

M Repici, L Mare, A Colombo, C Ploia, A Sclip, C Bonny, P Nicod, M Salmona, T Borsello

Research output: Contribution to journalArticle

Abstract

The c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK) activated by stress-signals and involved in many different diseases. Previous results proved the powerful effect of the cell permeable peptide inhibitor d-JNKI1 (d-retro-inverso form of c-Jun N-terminal kinase-inhibitor) against neuronal death in CNS diseases, but the precise features of this neuroprotection remain unclear. We here performed cell-free and in vitro experiments for a deeper characterization of d-JNKI1 features in physiological conditions. This peptide works by preventing JNK interaction with its c-Jun N-terminal kinase-binding domain (JBD) dependent targets. We here focused on the two JNK upstream MAPKKs, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), because they contain a JBD homology domain. We proved that d-JNKI1 prevents MKK4 and MKK7 activity in cell-free and in vitro experiments: these MAPKK could be considered not only activators but also substrates of JNK. This means that d-JNKI1 can interrupt downstream but also upstream events along the JNK cascade, highlighting a new remarkable feature of this peptide. We also showed the lack of any direct effect of the peptide on p38, MEK1, and extracellular signal-regulated kinase (ERK) in cell free, while in rat primary cortical neurons JNK inhibition activates the MEK1-ERK-Ets1/c-Fos cascade. JNK inhibition induces a compensatory effect and leads to ERK activation via MEK1, resulting in an activation of the survival pathway-(MEK1/ERK) as a consequence of the death pathway-(JNK) inhibition. This study should hold as an important step to clarify the strong neuroprotective effect of d-JNKI1.

Original languageEnglish
Pages (from-to)94-103
Number of pages10
JournalNeuroscience
Volume159
Issue number1
DOIs
Publication statusPublished - 3 Mar 2009

Fingerprint

MAP Kinase Kinase 4
MAP Kinase Kinase Kinases
JNK Mitogen-Activated Protein Kinases
Extracellular Signal-Regulated MAP Kinases
Phosphotransferases
Phosphorylation
Neurons
Peptides
Mitogen-Activated Protein Kinase Kinases
Central Nervous System Diseases
Neuroprotective Agents
MAP kinase kinase kinase 7
Mitogen-Activated Protein Kinases

Keywords

  • Activating Transcription Factor 2/metabolism
  • Amino Acid Sequence
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Cerebral Cortex/cytology
  • Dose-Response Relationship, Drug
  • Enzyme Activation/drug effects
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases/metabolism
  • L-Lactate Dehydrogenase/metabolism
  • MAP Kinase Kinase 4/metabolism
  • MAP Kinase Kinase 7/metabolism
  • Neurons/metabolism
  • Peptides/pharmacology
  • Phosphorylation
  • Protein Binding/physiology
  • Protein Interaction Domains and Motifs
  • Rats
  • Signal Transduction/drug effects
  • ets-Domain Protein Elk-1/metabolism

Cite this

@article{bce59d1d733348569f5857c2bae6074e,
title = "c-Jun N-terminal kinase binding domain-dependent phosphorylation of mitogen-activated protein kinase kinase 4 and mitogen-activated protein kinase kinase 7 and balancing cross-talk between c-Jun N-terminal kinase and extracellular signal-regulated kinase pathways in cortical neurons",
abstract = "The c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK) activated by stress-signals and involved in many different diseases. Previous results proved the powerful effect of the cell permeable peptide inhibitor d-JNKI1 (d-retro-inverso form of c-Jun N-terminal kinase-inhibitor) against neuronal death in CNS diseases, but the precise features of this neuroprotection remain unclear. We here performed cell-free and in vitro experiments for a deeper characterization of d-JNKI1 features in physiological conditions. This peptide works by preventing JNK interaction with its c-Jun N-terminal kinase-binding domain (JBD) dependent targets. We here focused on the two JNK upstream MAPKKs, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), because they contain a JBD homology domain. We proved that d-JNKI1 prevents MKK4 and MKK7 activity in cell-free and in vitro experiments: these MAPKK could be considered not only activators but also substrates of JNK. This means that d-JNKI1 can interrupt downstream but also upstream events along the JNK cascade, highlighting a new remarkable feature of this peptide. We also showed the lack of any direct effect of the peptide on p38, MEK1, and extracellular signal-regulated kinase (ERK) in cell free, while in rat primary cortical neurons JNK inhibition activates the MEK1-ERK-Ets1/c-Fos cascade. JNK inhibition induces a compensatory effect and leads to ERK activation via MEK1, resulting in an activation of the survival pathway-(MEK1/ERK) as a consequence of the death pathway-(JNK) inhibition. This study should hold as an important step to clarify the strong neuroprotective effect of d-JNKI1.",
keywords = "Activating Transcription Factor 2/metabolism, Amino Acid Sequence, Analysis of Variance, Animals, Animals, Newborn, Cerebral Cortex/cytology, Dose-Response Relationship, Drug, Enzyme Activation/drug effects, Extracellular Signal-Regulated MAP Kinases, JNK Mitogen-Activated Protein Kinases/metabolism, L-Lactate Dehydrogenase/metabolism, MAP Kinase Kinase 4/metabolism, MAP Kinase Kinase 7/metabolism, Neurons/metabolism, Peptides/pharmacology, Phosphorylation, Protein Binding/physiology, Protein Interaction Domains and Motifs, Rats, Signal Transduction/drug effects, ets-Domain Protein Elk-1/metabolism",
author = "M Repici and L Mare and A Colombo and C Ploia and A Sclip and C Bonny and P Nicod and M Salmona and T Borsello",
year = "2009",
month = "3",
day = "3",
doi = "10.1016/j.neuroscience.2008.11.049",
language = "English",
volume = "159",
pages = "94--103",
journal = "Neuroscience",
issn = "0306-4522",
publisher = "Elsevier",
number = "1",

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TY - JOUR

T1 - c-Jun N-terminal kinase binding domain-dependent phosphorylation of mitogen-activated protein kinase kinase 4 and mitogen-activated protein kinase kinase 7 and balancing cross-talk between c-Jun N-terminal kinase and extracellular signal-regulated kinase pathways in cortical neurons

AU - Repici, M

AU - Mare, L

AU - Colombo, A

AU - Ploia, C

AU - Sclip, A

AU - Bonny, C

AU - Nicod, P

AU - Salmona, M

AU - Borsello, T

PY - 2009/3/3

Y1 - 2009/3/3

N2 - The c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK) activated by stress-signals and involved in many different diseases. Previous results proved the powerful effect of the cell permeable peptide inhibitor d-JNKI1 (d-retro-inverso form of c-Jun N-terminal kinase-inhibitor) against neuronal death in CNS diseases, but the precise features of this neuroprotection remain unclear. We here performed cell-free and in vitro experiments for a deeper characterization of d-JNKI1 features in physiological conditions. This peptide works by preventing JNK interaction with its c-Jun N-terminal kinase-binding domain (JBD) dependent targets. We here focused on the two JNK upstream MAPKKs, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), because they contain a JBD homology domain. We proved that d-JNKI1 prevents MKK4 and MKK7 activity in cell-free and in vitro experiments: these MAPKK could be considered not only activators but also substrates of JNK. This means that d-JNKI1 can interrupt downstream but also upstream events along the JNK cascade, highlighting a new remarkable feature of this peptide. We also showed the lack of any direct effect of the peptide on p38, MEK1, and extracellular signal-regulated kinase (ERK) in cell free, while in rat primary cortical neurons JNK inhibition activates the MEK1-ERK-Ets1/c-Fos cascade. JNK inhibition induces a compensatory effect and leads to ERK activation via MEK1, resulting in an activation of the survival pathway-(MEK1/ERK) as a consequence of the death pathway-(JNK) inhibition. This study should hold as an important step to clarify the strong neuroprotective effect of d-JNKI1.

AB - The c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK) activated by stress-signals and involved in many different diseases. Previous results proved the powerful effect of the cell permeable peptide inhibitor d-JNKI1 (d-retro-inverso form of c-Jun N-terminal kinase-inhibitor) against neuronal death in CNS diseases, but the precise features of this neuroprotection remain unclear. We here performed cell-free and in vitro experiments for a deeper characterization of d-JNKI1 features in physiological conditions. This peptide works by preventing JNK interaction with its c-Jun N-terminal kinase-binding domain (JBD) dependent targets. We here focused on the two JNK upstream MAPKKs, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), because they contain a JBD homology domain. We proved that d-JNKI1 prevents MKK4 and MKK7 activity in cell-free and in vitro experiments: these MAPKK could be considered not only activators but also substrates of JNK. This means that d-JNKI1 can interrupt downstream but also upstream events along the JNK cascade, highlighting a new remarkable feature of this peptide. We also showed the lack of any direct effect of the peptide on p38, MEK1, and extracellular signal-regulated kinase (ERK) in cell free, while in rat primary cortical neurons JNK inhibition activates the MEK1-ERK-Ets1/c-Fos cascade. JNK inhibition induces a compensatory effect and leads to ERK activation via MEK1, resulting in an activation of the survival pathway-(MEK1/ERK) as a consequence of the death pathway-(JNK) inhibition. This study should hold as an important step to clarify the strong neuroprotective effect of d-JNKI1.

KW - Activating Transcription Factor 2/metabolism

KW - Amino Acid Sequence

KW - Analysis of Variance

KW - Animals

KW - Animals, Newborn

KW - Cerebral Cortex/cytology

KW - Dose-Response Relationship, Drug

KW - Enzyme Activation/drug effects

KW - Extracellular Signal-Regulated MAP Kinases

KW - JNK Mitogen-Activated Protein Kinases/metabolism

KW - L-Lactate Dehydrogenase/metabolism

KW - MAP Kinase Kinase 4/metabolism

KW - MAP Kinase Kinase 7/metabolism

KW - Neurons/metabolism

KW - Peptides/pharmacology

KW - Phosphorylation

KW - Protein Binding/physiology

KW - Protein Interaction Domains and Motifs

KW - Rats

KW - Signal Transduction/drug effects

KW - ets-Domain Protein Elk-1/metabolism

UR - https://www.sciencedirect.com/science/article/pii/S0306452208017557?via%3Dihub

U2 - 10.1016/j.neuroscience.2008.11.049

DO - 10.1016/j.neuroscience.2008.11.049

M3 - Article

C2 - 19135136

VL - 159

SP - 94

EP - 103

JO - Neuroscience

JF - Neuroscience

SN - 0306-4522

IS - 1

ER -