Abstract
The transcription factor NF-κB is composed of homodimeric andheterodimeric complexes of Rel/NF-κB-family polypeptides, which include Rel-A, c-Rel, Rel-B, NF-κB1/p50 and NF-κB2/p52 (ref. 1). The NF-κB1 gene encodes a larger precursor protein, p105, from which p50 is produced constitutively by proteasome-mediated removal of the p105 carboxy terminus2,3,4,5. The p105 precursor also acts as an NFκB-inhibitory protein, retaining associated p50, c-Rel and Rel-A proteins in the cytoplasm through its carboxy terminus6,7. Following cell stimulation by agonists, p105 is proteolysed more rapidly and released Rel subunits translocate into the nucleus8,9,10. Here we show that TPL-2 (ref. 11), which ishomologous to MAP-kinase-kinase kinases in its catalytic domain12, forms a complex with the carboxy terminus of p105. TPL-2 was originally identified, in a carboxy-terminal-deleted form, as an oncoprotein in rats11 and is more than 90% identical to the human oncoprotein COT13. Expression of TPL-2 results in phosphorylation and increased degradation of p105 while maintaining p50production. This releases associated Rel subunits or p50–Rel heterodimers to generate active nuclear NF-κB. Furthermore, kinase-inactive TPL-2 blocks the degradation of p105 induced by tumour-necrosis factor-α. TPL-2 is therefore a component of a new signalling pathway that controls proteolysis of NF-κB1 p105.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ghosh, S., May, M. J. & Kopp, E. B. NF-κB and Rel proteins: evolutionary conserved mediators of immune responses. Annu. Rev. Immunol. 16, 225–260 (1998).
Ghosh, S. et al. Cloning of the p50 DNA binding subunit of NF-κB: homology to rel and dorsal. Cell 62, 1019–1029 (1990).
Kieran, M. et al. The DNA binding subunit of NF-κB is identical to factor KBF1 and homologous to the rel oncogene product. Cell 62, 1007–1018 (1990).
Palombella, V. J., Rando, O. J., Goldberg, A. L. & Maniatis, T. The ubiquitin-proteasome pathway is required for processing the NF-κB 1 precursor protein and activation of NF-κB. Cell 78, 773–785 (1994).
Lin, L., DeMartino, G. N. & Greene, W. C. Cotranslational biogenesis of NF-κB p50 by the 26S proteasome. Cell 92, 819– 828 (1998).
Rice, N. R., MacKichan, M. L. & Israel, A. The precursor of NF-κB p50 has IκB-like functions. Cell 71, 243– 253 (1992).
Mercurio, F., DiDonato, J. A., Rosette, C. & Karin, M. p105 and p98 precursor proteins play an active role in NF-κB-mediated signal transduction. Genes Dev. 7, 705– 718 (1993).
Donald, R., Ballard, D. W. & Hawiger, J. Proteolytic processing of NF-κB/IκB in human monocytes. J.Biol. Chem. 270, 9– 12 (1995).
MacKichan, M. L., Logeat, F. & Israel, A. Phosphorylation of p105 PEST sequences via a redox-insensitive pathway up-regulates processing to p50 NF-κB. J. Biol. Chem. 271, 6084–6091 ( 1996).
Mellits, K. H., Hay, R. T. & Goodbourn, S. Proteolytic degradation of MAD3 (IκBα) and enhanced processing of the NF-κB precursor p105 are obligatory steps in the activation of NF-κB. Nucleic Acids Res. 21, 5059–5066 (1993).
Patriotis, C., Makris, A., Bear, S. E. & Tsichlis, P. N. Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T cell lymphomas and in T cell activation. Proc. Natl Acad. Sci. USA 90, 2251–2255 (1993).
Salmeron, A. et al. Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J. 15, 817–826 (1996).
Aoki, M. et al. The human cot proto-oncogene encodes two protein serine/threonine kinases with different transforming activities by alternative initiation of translation. J. Biol. Chem. 268, 22723– 22732 (1993).
Fromont-Racine, M., Rain, J. -C. & Legrain, P. Toward a functional analysis of the yeast genome through exhaustive two-hybrid analysis. Nature Genet. 16, 277–282 (1997).
Malinin, N. L., Boldin, M. P., Kovalenko, A. V. & Wallach, D. MAP 3K-related kinase involved in NF-κB induction by TNF, CD95 and IL-1. Nature 385, 540–544 (1997).
May, M. J. & Ghosh, S. Signal transduction through NF-κB. Immunol. Today 19, 80– 88 (1998).
Henkel, T. et al. Intramolecular masking of the nuclear location signal and dimerization domain in the precursor for the p50 NF-κB subunit. Cell 68, 1121–1133 ( 1992).
Watanabe, N., Iwamura, T., Shinoda, T. & Fujita, T. Regulation of NF-κB1 proteins by the candidate oncoprotein BCL-3: generation of NF-κB homodimers from the cytoplasmic pool of p50-p105 and nuclear translocation. EMBO J. 16, 3609–3620 ( 1997).
Blank, V., Kourilsky, P. & Israel, A. Cytoplasmic retention, DNA binding and processing of the NF-κB p50 precursor are controlled by a small region in its C-terminus. EMBO J. 10, 4159–4167 (1991).
Lin, L. & Ghosh, S. Aglycine-rich region in NF-κB p105 functions as a processing signal for the generation of the p50 subunit. Mol. Cell. Biol. 16, 2248– 2254 (1996).
Zandi, E., Rothwarf, D. M., Delhase, M., Hayakawa, M. & Karin, M. The IκB kinase complex (IKK) contains two kinase subunits, IKK-α and IKK-β, necessary for IκB phosphorylation and NF-κB activation. Cell 91 , 243–252 (1997).
Mercurio, F. et al. IKK-1 and IKK-2: cytokine-activated IκB kinases essential for NF-κB activation. Science 278, 860–866 (1997).
Woronicz, J. D., Gao, X., Cao, Z., Rothe, M. & Goeddel, D. V. IκB kinase-β: NF-κB activation and complex formation with IκB kinase-α and NIK. Science 278, 866–869 ( 1997).
Ceci, J. D. et al. TPL-2 is an oncogenic kinase that is activated by carboxy-terminal truncation. Genes Dev. 11, 688– 700 (1997).
Cowley, S., Paterson, H., Kemp, P. & Marshall, C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77, 841–852 (1994).
Fan, C. -M. & Maniatis, T. Generation of p50 subunit of NF-κB by processing of p105 through an ATP-dependent pathway. Nature 354, 395–398 ( 1991).
Kabouridis, P. S., Magee, A. I. & Ley, S. C. S-acylation of LCK protein tyrosine kinase is essential for its signalling function in T lymphocytes. EMBO J. 16, 4983–4998 (1997).
Huby, R. D. J., Iwashima, M., Weiss, A. & Ley, S. C. ZAP-70 protein tyrosine kinase is constitutively targeted to the T cell cortex independently of its SH2 domains. J. Cell. Biol. 137, 1639–1649 (1997).
Alkalay, I. et al. In vivo stimulation of IκB phosphorylation is not sufficient to activate NF-κB. Mol. Cell. Biol. 15, 1294–1301 (1995).
Lenardo, M. J. & Baltimore, D. NF-κB: a pleiotropic mediator of inducible and tissue-specific gene control. Cell 58, 227–229 ( 1989).
Acknowledgements
We thank P. Legrain and the Pasteur Institute for help in setting up the yeast two-hybrid assay and for the liver cDNA library; A. Israel, T. Maniatis, P. Tsichlis, D. Wallach and N.Watanabe for reagents; H. Coope, J. Janzen and T. Johnson for technical assistance; and H.Allen and T. Magee for helpful discussions. This work was supported by the MRC.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Belich, M., Salmerón, A., Johnston, L. et al. TPL-2 kinase regulates the proteolysis of the NF-κB-inhibitory protein NF-κB1 p105. Nature 397, 363–368 (1999). https://doi.org/10.1038/16946
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/16946
This article is cited by
-
NF-κB1 p105 suppresses lung tumorigenesis through the Tpl2 kinase but independently of its NF-κB function
Oncogene (2016)
-
MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas
Nature Communications (2015)
-
The NF-κB1 transcription factor prevents the intrathymic development of CD8 T cells with memory properties
The EMBO Journal (2012)
-
Loss of tumor progression locus 2 (tpl2) enhances tumorigenesis and inflammation in two-stage skin carcinogenesis
Oncogene (2011)
-
The E3 ligase c‐Cbl regulates dendritic cell activation
EMBO reports (2011)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.