The transcription factor NF-kappa B is composed of homodimeric and heterodimeric complexes of Rel/NF-kappa B-family polypeptides, which include Rel-A, c-Rel, Rel-B, NF-kappa B1/p50 and NF-kappa B2/p52 (ref. 1), The NF-kappa B1 gene encodes a larger precursor protein, p105, from which p50 is produced constitutively by proteasome-mediated removal of the p105 carboxy terminus(2.-5). The p105 precursor also acts as an NF kappa B-inhibitory protein, retaining associated p50, c-Rel and Rel-A proteins in the cytoplasm through its carboxy terminus(6,7). Following cell stimulation by agonists, p105 is proteolysed more rapidly and released Rel subunits translocate into the nucleus(8-10). Here we show that TPL-2 (ref. 11), which is homologous to MAP-kinase-kinase kinases in its catalytic domain(12), forms a complex with the carboxy terminus of p105, TPL-2 was originally identified, in a carboxy-terminal-deleted form, as an oncoprotein in rats(11) 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 p50 production. This releases associated Rel subunits or p50-Rel heterodimers to generate active nuclear NF-kappa B. Furthermore, kinase-inactive TPL-2 blocks the degradation of p105 induced by tumour-necrosis factor-alpha. TPL-2 is therefore a component of a new signalling pathway that controls proteolysis of NF-kappa B1 p105.