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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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Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene
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Regulation and inhibition of MAP kinases
Kaoud, T. S. (2012) · Texas ScholarWorks (Texas Digital Library)
Haas, M. J. (2008) · Science-Business eXchange · doi:10.1038/scibx.2008.940
Orejana, L. (2014) · Deposito Adademico Digital Universidad De Navarra (University of Navarra)
Tran, H. (2011) · Open Scholarship Institutional Repository (Washington University in St. Louis) · doi:10.7936/k7gb223z
Figuera-Losada, M., & LoGrasso, P. V. (2012)
Effectors—Sonic Hedgehog and p38 Mitogen-Activated Protein Kinase
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Sassano, A., Iacono, M. L., Antico, G., Jordan, A., Shahab Uddin, M. S., Calogero, R., & Platanias, L. C. (2023) · doi:10.1158/1535-7163.c.6532071
Non-ATP Site Inhibitors and Bi-dentate Inhibitors
De, S. K. (2024) · Springer eBooks · doi:10.1007/978-3-031-75682-5_4
Chinnathambi, S., Dubey, T., & Rangappa, N. (2025) · Advances in protein chemistry and structural biology · doi:10.1016/bs.apcsb.2025.08.009
BindingDB Entry 50031494: Small molecule JNK (c-Jun N-terminal kinase) inhibitors.
BindingDB (2010) · UC San Diego · doi:10.7270/q2ks6rp5
BindingDB (2014) · UC San Diego · doi:10.7270/q25719pn
BindingDB Entry 2917: Identification of a new JNK inhibitor targeting the JNK-JIP interaction site.
BindingDB (2008) · UC San Diego · doi:10.7270/q22n50k9
BindingDB (2010) · UC San Diego · doi:10.7270/q2n29wr7
Bogoyevitch, Barr, R. K., Hopkins, R. M., Watt, P. M., Boehm, I., Chan, A., & Arthur, P. G. (2003) · Cellular & Molecular Biology Letters
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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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