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 . The NF-κB1 gene encodes a larger precursor protein, p105, from which p50 is produced constitutively by proteasome-mediated removal of the p105 carboxy terminus^,,,. 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 terminus,. Following cell stimulation by agonists, p105 is proteolysed more rapidly and released Rel subunits translocate into the nucleus^,,. Here we show that TPL-2 , which ishomologous to MAP-kinase-kinase kinases in its catalytic domain, 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 and is more than 90% identical to the human oncoprotein COT. 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.