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Identification of the Critical Features of a Small Peptide Inhibitor of JNK Activity
Open accessAbstract
The c-Jun N-terminal kinases (JNKs) are a subfamily of the mitogen-activated protein kinases (MAPKs). Although progress in evaluating the functions of other MAPKs has been facilitated by the characterization of specific inhibitors, no JNK-directed inhibitor is commercially available. We have identified a 21-amino acid peptide inhibitor of activated JNKs, based on amino acids 143-163 of the JNK-binding domain (JBD) of the JNK scaffolding protein, JNK-interacting protein-1 (JIP-1). This peptide, I-JIP (Inhibitor of JNK-based on JIP-1), inhibited JNK activity in vitro toward recombinant c-Jun, Elk, and ATF2 up to 90%. A truncated I-JIP (TI-JIP), the C-terminal 11 amino acids of I-JIP, directly interacted with recombinant JNKs but not its substrates as shown by surface plasmon resonance analysis. Scanning alanine replacement within truncated I-JIP identified 4 residues (Arg-156, Pro-157, Leu-160, or Leu-162) as independently critical for inhibition. JBD peptide sequences from JIP-2 and JIP-3 shared these critical residues and accordingly were effective JNK inhibitors. In contrast, peptides based on the JBDs of ATF2 and c-Jun inhibited JNK activity by <40%, which agreed with their lack of homology to the critical Arg-156 and Pro-157. These studies thus define a small peptide inhibitor sequence of JNKs based on the JIP proteins.
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“This peptide, pepJIP1 (a peptide version of JIP1), inhibited JNK activity in vitro toward recombinant c-jun, Elk, and ATF2 up to 90% with significant selectivity of no inhibition of the related Erk and p38 MAPKs.”
From Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125 (2004) · cites this paper as Barr et al , 2002
In the citing paper
“the binding between JNK and pepJIP1 is not dependent on the kinase activity of JNK (Barr et al , 2002)”
From Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125 (2004) · cites this paper as Barr et al , 2002
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A protein kinase involved in the regulation of inflammatory cytokine biosynthesis
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SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase
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Signal Transduction through MAP Kinase Cascades
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Selective interaction of JNK protein kinase isoforms with transcription factors.
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Organization and regulation of mitogen-activated protein kinase signaling pathways
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Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene
Yang, D. D., Kuan, C.-Y., Whitmarsh, A. J., Rinócn, M., Zheng, T. S., Davis, R. J., RAKIC, P. T., & Flavell, R. A. (1997) · Nature · doi:10.1038/39899 · Cited by 1,230
Research works printed but not linked: 1
- Elion, 1998, Nature, 281, 1625
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Self-citationJNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships
Zeke, A., Misheva, M., Reményi, A., & Bogoyevitch, M. A. (2016) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00043-14 · Cited by 552
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Metadata
- Authors
- Barr, R. K., Kendrick, T. S., & Bogoyevitch, M. A.
- Affiliations
- The University of Western Australia (AU)
- Corresponding author
- Bogoyevitch, Marie A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-03
- Volume
- 277
- Issue
- 13
- Pages
- 10987-10997
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2035262124
- Cited by
- 211
- References
- 45
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 3 · 2018: 4 · 2017: 6 · 2016: 12 · 2015: 2 · 2014: 2 · 2013: 13 · 2012: 9
- FWCI
- 4.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Funders
- National Heart Foundation of Australia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- JNK, c-Jun N-terminal kinase, peptide inhibitors, JIP1, MAPK inhibitors, c-Jun, elk, ATF2, critical residues, alanine scanning, protein-protein interaction, kinase inhibition
- MeSH terms
- Amino Acid Sequence, Animals, DNA-Binding Proteins, Enzyme Inhibitors, Kinetics, Molecular Sequence Data, Peptides, Phosphorylation, Proto-Oncogene Proteins, Recombinant Proteins, Substrate Specificity, Transcription Factors, Cyclic AMP Response Element-Binding Protein, Sequence Homology, Amino Acid, COS Cells, Surface Plasmon Resonance, Mitogen-Activated Protein Kinases, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, ets-Domain Protein Elk-1, Activating Transcription Factor 2
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