TPL-2 kinase regulates the proteolysis of the NF-κB-inhibitory protein NF-κB1 p105
TPL-2 kinase regulates the proteolysis of the NF-κB-inhibitory protein NF-κB1 p105
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作者：
Belich, MP;Salmerón, A;Ley, SC
转录因子NF-κ B B由Rel/NF-κ B家族多肽的同源二聚体和异源二聚体复合物组成，所述多肽包括Rel-A、c-Rel、Rel-B、NF-κ B1/p50和NF-κ B2/p52（参考文献1）。NF-κ B1基因编码较大的前体蛋白p105，通过蛋白酶体介导的p105羧基末端的去除，从p105组成性地产生p50（2. 5）。p105前体也作为NF κ B抑制蛋白，通过其羧基末端将相关的p50、c-Rel和Rel-A蛋白保留在细胞质中（6，7）。在激动剂刺激细胞后，p105蛋白水解更快，释放的Rel亚基易位到细胞核中（8-10）。在此，我们发现TPL-2（参考文献11）与MAP-激酶-激酶的催化结构域（12）同源，与p105的羧基末端形成复合物。TPL-2最初在大鼠中被鉴定为一种癌蛋白，其羧基末端缺失（11），与人癌蛋白COT 13的同一性超过90%。TPL-2的表达导致p105的磷酸化和增加的降解，同时维持p50的产生。这释放相关的Rel亚基或p50-Rel异二聚体以产生活性核NF-κ B。此外，激酶失活的TPL-2阻断肿瘤坏死因子-α诱导的p105降解。因此，TPL-2是控制NF-κ B1 p105蛋白水解的新信号通路的组分。
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.