A Docking Site in MKK4 Mediates High Affinity Binding to JNK MAPKs and Competes with Similar Docking Sites in JNK Substrates
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Specific docking interactions between MAPKs and their activating MAPK kinases (MKKs or MEKs) are crucial for efficient and accurate signal transmission. Here, we report the identification of a MAPK-docking site, or "D-site," in the N terminus of human MKK4/JNKK1. This docking site conforms to the consensus sequence for known D-sites in other MKKs and contains the first of the two cleavage sites for anthrax lethal factor protease that have been found in the N terminus of MKK4. This docking site was both necessary and sufficient for the high affinity binding of the MAPKs JNK1, JNK2, JNK3, p38 alpha, and p38 beta to MKK4. Mutations that altered conserved residues in this docking site reduced JNK/p38 binding. In addition, a peptide version of this docking site, as well as a peptide version of the JNK-binding site of the JIP-1 scaffold protein, inhibited both MKK4/JNK binding and MKK4-mediated phosphorylation of JNK1. These same peptides also inhibited JNK2-mediated phosphorylation of c-Jun and ATF2, suggesting that transcription factors, MKK4, and the JIP scaffold compete for docking to JNK. Finally, the selectivity of the MKK4, MEK1, and MEK2 D-sites for JNK versus ERK was quantified. The MEK1 and MEK2 D-sites displayed a strong selectivity for their cognate MAPK (ERK2) versus a non-cognate MAPK (JNK). In contrast, the MKK4 D-site exhibited only limited selectivity for JNK versus ERK.
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The structural and biochemical analysis, together with other studies, clarified the minimal sequence requirements for linear motifs to bind the MAPK docking groove.
“Our structural and biochemical analysis in combination with other studies clarified the minimal sequence requirements for linear motifs to bind the MAPK docking groove (42-47).”
From Specificity of Linear Motifs That Bind to a Common Mitogen-Activated Protein Kinase Docking Groove (2012) · cites this paper as [43]
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References 60 · Cited by 108
Research works printed but not linked: 1
- Xia, X. G., Harding, T., Weller, M., Bieneman, A., Uney, J. B., and Schulz, J. B. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 10433-10438
- Authors
- Ho, D. T., Bardwell, A. J., Abdollahi, M., & Bardwell, L.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Bardwell, Lee
- ORCID
- Bardwell, Lee
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 278
- Issue
- 35
- Pages
- 32662-32672
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3017503
- OpenAlex
- W2011659866
- Cited by
- 108
- References
- 60
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 1 · 2015: 4 · 2014: 3 · 2013: 7 · 2012: 2
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- University of California, Irvine
- National Institute of General Medical Sciences (GM-60366, R01GM060366)
- U.S. National Library of Medicine (LM-07443, T15LM007443)
- 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
- MKK4, JNK MAPK, JNK1 phosphorylation, c-Jun phosphorylation, ATF2 phosphorylation, MAPK signaling
- MeSH terms
- Amino Acid Sequence, Binding Sites, Codon, Dose-Response Relationship, Drug, Glutathione Transferase, Humans, Kinetics, Molecular Sequence Data, Peptides, Phosphorylation, Plasmids, Protein Binding, Protein-Tyrosine Kinases, Recombinant Fusion Proteins, Transcription, Genetic, Protein Biosynthesis, Conserved Sequence, Protein Structure, Tertiary, DNA Primers, Mitogen-Activated Protein Kinase 1, Amino Acid Motifs, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinase 9, Mitogen-Activated Protein Kinase 10, Mitogen-Activated Protein Kinase 11, MAP Kinase Kinase 4
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