TPL-2 kinase regulates the proteolysis of the NF-κB-inhibitory protein NF-κB1 p105
- 1 January 1999
- journal article
- letter
- Published by Springer Nature in Nature
- Vol. 397 (6717) , 363-368
- https://doi.org/10.1038/16946
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.Keywords
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