The transcription factor NF-kappa B is composed of homodimeric and heterodi
meric 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 B
1 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, r
etaining 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 nuc
leus(8-10). Here we show that TPL-2 (ref. 11), which is homologous to MAP-k
inase-kinase kinases in its catalytic domain(12), forms a complex with the
carboxy terminus of p105, TPL-2 was originally identified, in a carboxy-ter
minal-deleted form, as an oncoprotein in rats(11) and is more than 90% iden
tical to the human oncoprotein COT13. Expression of TPL-2 results in phosph
orylation and increased degradation of p105 while maintaining p50 productio
n. This releases associated Rel subunits or p50-Rel heterodimers to generat
e active nuclear NF-kappa B. Furthermore, kinase-inactive TPL-2 blocks the
degradation of p105 induced by tumour-necrosis factor-alpha. TPL-2 is there
fore a component of a new signalling pathway that controls proteolysis of N
F-kappa B1 p105.