The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.
The JNKK2-JNK1 Fusion Protein Acts As a Constitutively Active c-Jun Kinase That Stimulates c-Jun Transcription Activity
Open accessAbstract
c-Jun N-terminal protein kinase (JNK), a member of the mitogen-activated protein (MAP) kinase family, regulates gene expression in response to various extracellular stimuli. JNK is activated by JNK-activating kinase (JNKK1 and JNKK2), a subfamily of the dual specificity MAP kinase kinase (MEK) family, through phosphorylation on threonine (Thr) 183 and tyrosine (Tyr) 185 residues. The physiological functions of the JNK pathway, however, are not completely understood. A major obstacle is the lack of specific and activated kinase components that can stimulate the JNK pathway in the absence of any stimulus. Here we show that fusion of JNK1 to its upstream activator JNKK2 resulted in its constitutive activation. In HeLa cells, the JNKK2-JNK1 fusion protein showed significant JNK activity, which was comparable with that of JNK1 activated by many stimuli and activators, including EGF, TNF-alpha, anisomycin, UV irradiation, MEKK1, and small GTP binding proteins Rac1 and Cdc42Hs. Immunoblotting analysis indicated that JNK1 was phosphorylated by JNKK2 in the fusion protein on both Thr(183) and Tyr(185) residues. Like JNKK2, the JNKK2-JNK1 fusion protein was highly specific for the JNK pathway and did not activate either p38 or ERK2. Transient transfection assays demonstrated that the JNKK2-JNK1 fusion protein was sufficient to stimulate c-Jun transcriptional activity in the absence of any stimulus. Immunofluorescence analysis revealed that the JNKK2-JNK1 fusion protein was predominantly located in the nucleus of transfected HeLa cells. These results indicate that the JNKK2-JNK1 fusion protein is a constitutively active Jun kinase, which will facilitate the investigation of the physiological roles of the JNK pathway.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“While these mutations do not yield constitutive activity (Zheng et al., 1999), they induce a different conformer for the A-loop, allowing us to ask how changing the A-loop conformer impacts the catalytic and peptide-binding sites.”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Zheng et al., 1999
Citations
Cites
A protein kinase involved in the regulation of inflammatory cytokine biosynthesis
Lee, J. C., Laydon, J. T., McDonnell, P., Gallagher, T. F., Kumar, S., Green, D., McNulty, D. E., Blumenthal, M. J., Keys, J., vatter, S. W. L., et al. (1994) · Nature · doi:10.1038/372739a0 · Cited by 3,266
Dérijard, B., Hibi, M., Wu, I.-H., Barrett, T., Su, B., Deng, T., Karin, M., & Davis, R. J. (1994) · Cell · doi:10.1016/0092-8674(94)90380-8 · Cited by 3,188
A synthetic inhibitor of the mitogen-activated protein kinase cascade.
Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., & Saltiel, A. R. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.17.7686 · Cited by 2,679
The stress-activated protein kinase subfamily of c-Jun kinases
Kyriakis, J. M., Banerjee, P. T., Nikolakaki, E., Dai, T., Rubie, E. A., Ahmad, M. F., Avruch, J., & Woodgett, J. R. (1994) · Nature · doi:10.1038/369156a0 · Cited by 2,601
The Regulation of AP-1 Activity by Mitogen-activated Protein Kinases
Karin, M. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.28.16483 · Cited by 2,423
Ichijo, H., Nishida, E., Irie, K., ten Dijke, P., Saitoh, M., Moriguchi, T., Takagi, M., Matsumoto, K., Miyazono, K., & Gotoh, Y. (1997) · Science · doi:10.1126/science.275.5296.90 · Cited by 2,310
Cowley, S. A. (1994) · Cell · doi:10.1016/0092-8674(94)90133-3 · Cited by 1,959
Hibi, M., Lin, A., Smeal, T., Minden, A., & Karin, M. (1993) · Genes & Development · doi:10.1101/gad.7.11.2135 · Cited by 1,886
Self-citationCobb, M. H., & Goldsmith, E. J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.25.14843 · Cited by 1,718
Independent Human MAP-Kinase Signal Transduction Pathways Defined by MEK and MKK Isoforms
Dérijard, B., Raingeaud, J., Barrett, T., Wu, I.-H., Han, J., Ulevitch, R. J., & Davis, R. J. (1995) · Science · doi:10.1126/science.7839144 · Cited by 1,555
Transformation of Mammalian Cells by Constitutively Active MAP Kinase Kinase
Mansour, S. J., Matten, W. T., Hermann, A. S., Candia, J. M., Rong, S., Fukasawa, K., Woude, G. F. V., & Ahn, N. G. (1994) · Science · doi:10.1126/science.8052857 · Cited by 1,355
Identification of a Member of the MAPKKK Family as a Potential Mediator of TGF-β Signal Transduction
Yamaguchi, T., Shirakabe, K., Shibuyà, H., Irie, K., Oishi, I., Ueno, N., Taniguchi, T., Nishida, E., & Matsumoto, K. (1995) · Science · doi:10.1126/science.270.5244.2008 · Cited by 1,344
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
Nuclear Localization and Regulation of erk- and rsk-Encoded Protein Kinases
Chen, R., Sarnecki, C., & Blenis, J. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.3.915 · Cited by 1,099
Differential Activation of ERK and JNK Mitogen-Activated Protein Kinases by Raf-1 and MEKK
Minden, A., Lin, A., McMahon, M., Lange, C. A., Dérijard, B., Davis, R. J., Johnson, G. L., & Karin, M. (1994) · Science · doi:10.1126/science.7992057 · Cited by 1,069
Self-citationRole of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun
Sánchez, I., Hughes, R. T., Mayer, B. J., Yee, K. O., Woodgett, J. R., Avruch, J., Kyriakls, J. M., & Zon, L. I. (1994) · Nature · doi:10.1038/372794a0 · Cited by 970
A Divergence in the MAP Kinase Regulatory Network Defined by MEK Kinase and Raf
Lange-Carter, C. A., Pleiman, C. M., Gardner, A. M., Blumer, K. J., & Johnson, G. L. (1993) · Science · doi:10.1126/science.8385802 · Cited by 827
Identification of a Dual Specificity Kinase That Activates the Jun Kinases and p38-Mpk2
Lin, A., Minden, A., Martinetto, H., Claret, F.-X., Lange, C. A., Mercurio, F., Johnson, G. L., & Karin, M. (1995) · Science · doi:10.1126/science.7716521 · Cited by 763
Self-citationActivation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1
Yan, M., Dai, T., Deak, J. C., Kyriakis, J. M., Zon, L. I., Woodgett, J. R., & Templeton, D. J. (1994) · Nature · doi:10.1038/372798a0 · Cited by 705
Phosphorylation of the MAP Kinase ERK2 Promotes Its Homodimerization and Nuclear Translocation
Khokhlatchev, A. V., Canagarajah, B. J., Wilsbacher, J. L., Robinson, M. J., Atkinson, M. A., Goldsmith, E. J., & Cobb, M. H. (1998) · Cell · doi:10.1016/s0092-8674(00)81189-7 · Cited by 675
A Cytoplasmic Inhibitor of the JNK Signal Transduction Pathway
Dickens, M., Rogers, J. S., Cavanagh, J., Raitano, A., Xia, Z., Halpern, J. R., Greenberg, M. E., Sawyers, C. L., & Davis, R. J. (1997) · Science · doi:10.1126/science.277.5326.693 · Cited by 675
Lenormand, P., Sardet, C., Pagès, G., L’Allemain, G., Brunet, A., & Pouysségur, J. (1993) · The Journal of Cell Biology · doi:10.1083/jcb.122.5.1079 · Cited by 660
Defective T Cell Differentiation in the Absence of Jnk1
Dong, C., Yang, D. D., Wysk, M., Whitmarsh, A. J., Davis, R. J., & Flavell, R. A. (1998) · Science · doi:10.1126/science.282.5396.2092 · Cited by 579
Identification of the sites in MAP kinase kinase‐1 phosphorylated by p74raf‐1.
Alessi, D. R., Saito, Y., Campbell, D. G., Cohen, P., Sithanandam, G., Rapp, U. R., Ashworth, A., Marshall, C. J., & Cowley, S. A. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06424.x · Cited by 562
Induction of c‐fos expression through JNK‐mediated TCF/Elk‐1 phosphorylation.
Cavigelli, M., Dolfi, F., Claret, F. X., & Karin, M. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00284.x · Cited by 530
Nakano, H., Shindo, M., Komazawa‐Sakon, S., Nishinaka, S., Mihara, M., Yagita∥, H., & Okumura, K. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.7.3537 · Cited by 518
Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae
Chol, K.-Y., Satterberg, B., Lyons, D. M., & Elion, E. A. (1994) · Cell · doi:10.1016/0092-8674(94)90427-8 · Cited by 502
MP1: A MEK Binding Partner That Enhances Enzymatic Activation of the MAP Kinase Cascade
Schaeffer, H. J., Catling, A. D., Eblen, S. T., Collier, L. S., Krauss, A., & Weber, M. J. (1998) · Science · doi:10.1126/science.281.5383.1668 · Cited by 472
Differentiation of CD4+ T Cells to Th1 Cells Requires MAP Kinase JNK2
Yang, D. D., Conze, D. B., Whitmarsh, A. J., Barrett, T., Davis, R. J., Rincón, M., & Flavell, R. A. (1998) · Immunity · doi:10.1016/s1074-7613(00)80640-8 · Cited by 453
MEKK1 activates both IκB kinase α and IκB kinase β
Lee, F. S., Peters, R., Dang, L. C., & Maniatis, T. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9319 · Cited by 384
Casein kinase II is a negative regulator of c-Jun DNA binding and AP-1 activity
Lin, A., Frost, J. A., Deng, T., Smeal, T., Al-Alawi, N., Kikkawa, U., Hunter, T. R., Brenner, D. A., & Karin, M. (1992) · Cell · doi:10.1016/0092-8674(92)90311-y · Cited by 378
Self-citationMitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH 2 -terminal kinase
Tournier, C., Whitmarsh, A. J., Cavanagh, J., Barrett, T., & Davis, R. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.14.7337 · Cited by 377
Rotation of photoreceptor clusters in the developing drosophila eye requires the nemo gene
Choi, K.-W., & Benzer, S. (1994) · Cell · doi:10.1016/0092-8674(94)90579-7 · Cited by 339
Printen, J. A., & Sprague, G. F. (1994) · Genetics · doi:10.1093/genetics/138.3.609 · Cited by 329
Fukuda, M., Gotoh, I., Gotoh, Y., & Nishida, E. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.33.20024 · Cited by 325
Stress-signalling kinase Sek1 protects thymocytes from apoptosis mediated by CD95 and CD3
Nishina, H., Fischer, K., Radvanyi, L. G., Shahinian, A., Hakem, R., Rubie, E. A., Bernstein, A., Mak, T. W., Woodgett, J. R., & Penninger, J. M. (1997) · Nature · doi:10.1038/385350a0 · Cited by 323
Robinson, M. J., Stippec, S. A., Goldsmith, E. J., White, M. A., & Cobb, M. H. (1998) · Current Biology · doi:10.1016/s0960-9822(07)00485-x · Cited by 311
Sabapathy, K., Hu, Y., Kallunki, T., Schreiber, M., David, J., Jochum, W., Wagner, E. F., & Karin, M. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80065-7 · Cited by 302
Juo, P., Kuo, C. J., Reynolds, S. E., Konz, R. F., Raingeaud, J., Davis, R. J., Biemann, H.-P., & Blenis, J. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.1.24 · Cited by 287
Induction of Apoptosis by SB202190 through Inhibition of p38β Mitogen-activated Protein Kinase
Nemoto, S., Xiang, J., Huang, S., & Lin, A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.26.16415 · Cited by 278
Self-citationYang, D., Tournier, C., Wysk, M., Lu, H., Xu, J., Davis, R. J., & Flavell, R. A. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.7.3004 · Cited by 271
HTLV-I Tax Protein Binds to MEKK1 to Stimulate IκB Kinase Activity and NF-κB Activation
Yin, M.-J., Christerson, L. B., Yamamoto, Y., Kwak, Y.-T., Xu, S., Mercurio, F., Barbosa, M. S., Cobb, M. H., & Gaynor, R. B. (1998) · Cell · doi:10.1016/s0092-8674(00)81447-6 · Cited by 267
A novel SAPK/JNK kinase, MKK7, stimulated by TNFα and cellular stresses
Moriguchi, T., Toyoshima, F., Masuyama, N., Hanafusa, H., Gotoh, Y., & Nishida, E. (1997) · The EMBO Journal · doi:10.1093/emboj/16.23.7045 · Cited by 250
Gerwins, P., Jonathan, L., & Johnson, G. L. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.13.8288 · Cited by 242
Marcus, S., Polverino, A. J., Barr, M. M., & Wigler, M. H. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.16.7762 · Cited by 242
Nemoto, S., Sheng, Z., & Lin, A. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.6.3518 · Cited by 230
Self-citationMolecular Cloning of Mitogen-activated Protein/ERK Kinase Kinases (MEKK) 2 and 3
Blank, J. L., Gerwins, P., Elliott, E. M., Sather, S., & Johnson, G. L. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.10.5361 · Cited by 230
Huang, S., Jiang, Y., Li, Z., Nishida, E., Mathias, P., Lin, S., Ulevitch, R. J., Nemerow, G. R., & Han, J. (1997) · Immunity · doi:10.1016/s1074-7613(00)80449-5 · Cited by 227
Nemoto, S., DiDonato, J. A., & Lin, A. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.12.7336 · Cited by 224
Self-citationTakekawa, M., Posas, F., & Saito, H. (1997) · The EMBO Journal · doi:10.1093/emboj/16.16.4973 · Cited by 193
Holland, P. M., Suzanne, M., Campbell, J. S., Noselli, S., & Cooper, J. A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.40.24994 · Cited by 182
Hirai, S.-I., Katoh, M., Terada, M., Kyriakis, J. M., Zon, L. I., Rana, A., Avruch, J., & Ohno, S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.24.15167 · Cited by 178
The MKK7 Gene Encodes a Group of c-Jun NH 2 -Terminal Kinase Kinases
Tournier, C., Whitmarsh, A. J., Cavanagh, J., Barrett, T., & Davis, R. J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.2.1569 · Cited by 173
Xu, S., Robbins, D. J., Christerson, L. B., English, J. M., Vanderbilt, C. A., & Cobb, M. H. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.11.5291 · Cited by 134
Lu, X., Nemoto, S., & Lin, A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.40.24751 · Cited by 118
Self-citationWu, Z., Wu, J., Jacinto, E., & Karin, M. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.12.7407 · Cited by 105
Cytoplasmic localization of the mitogen-activated protein kinase activator MEK.
Zheng, C. F., & Guan, K. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32112-9 · Cited by 102
Self-citationYao, Z., Diener, K., Wang, X. S., Zukowski, M. M., Matsumoto, G., Zhou, G., Mo, R., Sasaki, T., Nishina, H., Hui, C.-C., et al. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.51.32378 · Cited by 96
SKK4, a novel activator of stress‐activated protein kinase‐1 (SAPK1/JNK)
Lawler, S. E., Cuenda, A., Goedert, M., & Cohen, P. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)00990-3 · Cited by 50
Yang, J., New, L., Jiang, Y., Han, J., & Su, B. (1998) · Gene · doi:10.1016/s0378-1119(98)00158-9 · Cited by 32
Flagged first, then by citations
Research works printed but not linked: 2
- Minden, 1997, Biochim. Biophys. Acta, 1333, F85
- Chen, 1992, Mol. Cell. Biol., 12, 915
Cited by
Sorted by citations
JNK1-Mediated Phosphorylation of Bcl-2 Regulates Starvation-Induced Autophagy
Wei, Y., Pattingre, S., Sinha, S., Bassik, M., & Levine, B. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.06.001 · Cited by 1,329
Inhibition of JNK activation through NF-κB target genes
Tang, G., Minemoto, Y., Dibling, B., Purcell, N. H., Li, Z., Karin, M., & Lin, A. (2001) · Nature · doi:10.1038/35104568 · Cited by 721
Self-citationChang, L., Kamata, H., Solinas, G., Luo, J.-L., Maeda, S., Venuprasad, K., Liu, Y.-C., & Karin, M. (2006) · Cell · doi:10.1016/j.cell.2006.01.021 · Cited by 706
Ikeda, F., Nishimura, R., Matsubara, T., Tanaka, S., Inoue, J., Reddy, S. V., Hata, K., Yamashita, K., Hiraga, T., Watanabe, T., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200419657 · Cited by 468
Lei, K., Nimnual, A. S., Zong, W., Kennedy, N. J., Flavell, R. A., Thompson, C. B., Bar‐Sagi, D., & Davis, R. J. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.13.4929-4942.2002 · Cited by 463
Metadata
- Authors
- Zheng, C., Xiang, J., Hunter, T., & Lin, A.
- Affiliations
- University of Alabama at Birmingham (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Lin, Anning
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-10
- Volume
- 274
- Issue
- 41
- Pages
- 28966-28971
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2022805818
- Cited by
- 110
- References
- 60
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 4 · 2013: 4 · 2012: 7
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29ca073740-02)
- National Cancer Institute (CA 73740)
- 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
- c-Jun N-terminal kinase, JNK1, constitutive kinase activation, MAPK signaling, JNK phosphorylation, Rac1, Cdc42, MEKK1, nuclear localization
- MeSH terms
- Fluorescent Antibody Technique, Gene Expression Regulation, HeLa Cells, Humans, Nuclear Proteins, Phosphorylation, Protein Kinases, Recombinant Fusion Proteins, Transfection, Signal Transduction, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 7
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
