A Cytoplasmic Inhibitor of the JNK Signal Transduction Pathway
Abstract
The c-Jun amino-terminal kinase (JNK) is a member of the stress-activated group of mitogen-activated protein (MAP) kinases that are implicated in the control of cell growth. A murine cytoplasmic protein that binds specifically to JNK [the JNK interacting protein-1 (JIP-1)] was characterized and cloned. JIP-1 caused cytoplasmic retention of JNK and inhibition of JNK-regulated gene expression. In addition, JIP-1 suppressed the effects of the JNK signaling pathway on cellular proliferation, including transformation by the Bcr-Abl oncogene. This analysis identifies JIP-1 as a specific inhibitor of the JNK signal transduction pathway and establishes protein targeting as a mechanism that regulates signaling by stress-activated MAP kinases.
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JIP1 is a scaffolding protein that assembles components of the JNK cascade and regulates JNK signaling.
“JNK-interacting protein-1 (JIP1) was identified as a scaffolding protein of the JNK module in yeast two-hybrid analysis, enhancing the correspondent signaling through the pathway (Whitmarsh et al , 1998).”
From Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125 (2004) · cites this paper as Dickens et al , 1997
The minimal JNK-binding region of JIP1 (pepJIP1) inhibits JNK activity in vitro toward c-jun, Elk, and ATF2 up to 90% with selectivity over Erk and p38.
“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 Dickens et al , 1997
Overexpression of JIP1 or its JNK-binding domain inhibits JNK signaling by retaining JNK in the cytoplasm and blocking its nuclear translocation.
“However, the overexpression of either the domain within JIP1 that binds to JNK, or the full-length protein, potently inhibits JNK signaling in the cell (Dickens et al , 1997).”
From Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125 (2004) · cites this paper as Dickens et al , 1997
Inhibition of JNK1 by pepJIP1 is mainly due to competition with other docking sites of substrates or upstream kinases.
“Inhibition of JNK1 by pepJIP1 is mainly due to the competition of pepJIP1 with other docking sites of the substrates or the upstream kinases (Dickens et al , 1997; Ho et al , 2003).”
From Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125 (2004) · cites this paper as Dickens et al , 1997
JIP-1, JIP-2, and JIP-3 are scaffolding proteins for the JNK signaling pathway.
“Three proteins were found, the c-jun NH2-terminal kinase (JNK)–interacting proteins (JIPs) JIP-1, JIP-2, and JIP-3, which are scaffolding proteins for the JNK signaling pathway.”
From Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules (2001) · cites this paper as Dickens et al. 1997
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References 35 · Cited by 675
- Authors
- Dickens, M., Rogers, J. S., Cavanagh, J., Raitano, A., Xia, Z., Halpern, J. R., Greenberg, M. E., Sawyers, C. L., & Davis, R. J.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Davis, Roger J.
- Venue
- Science
- Published
- 1997-08
- Volume
- 277
- Issue
- 5326
- Pages
- 693-696
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2047604959
- Cited by
- 675
- References
- 35
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 6 · 2023: 8 · 2022: 6 · 2021: 3 · 2020: 5 · 2019: 6 · 2018: 7 · 2017: 14 · 2016: 12 · 2015: 8 · 2014: 13 · 2013: 11 · 2012: 9
- FWCI
- 17.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- National Institutes of Health (5r01ca043855-12)
- National Cancer Institute (CA-65861, CA-43855, R01CA065861)
- 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 › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- JNK, c-Jun N-terminal kinase, JIP1, MAPK signaling, signal transduction inhibition, cytoplasmic retention, cell proliferation, gene expression regulation, protein targeting
- MeSH terms
- Animals, Carrier Proteins, Cell Nucleus, Cell Transformation, Neoplastic, Cells, Cultured, Cloning, Molecular, Cytoplasm, Gene Expression Regulation, Molecular Sequence Data, Phosphorylation, Protein Kinases, Recombinant Fusion Proteins, Transcription Factors, Transfection, Signal Transduction, Transcriptional Activation, Fusion Proteins, bcr-abl, Proto-Oncogene Proteins c-jun, Cyclic AMP Response Element-Binding Protein, Calcium-Calmodulin-Dependent Protein Kinases, COS Cells, Mitogen-Activated Protein Kinases, JNK Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 9, Activating Transcription Factor 2
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