Babu Geetha R, Jin Wei, Norman Lourdes, Waterfield Michael, Chang Mikyoung, Wu Xuefeng, Zhang Minying, Sun Shao-Cong
Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey Medical Center, P.O. Box 850, Hershey, PA 17033, USA.
Biochim Biophys Acta. 2006 Feb;1763(2):174-81. doi: 10.1016/j.bbamcr.2005.12.010. Epub 2006 Jan 13.
The oncoprotein kinase Tpl2 plays an essential role in macrophage activation by the bacterial component lipopolysaccharide (LPS). In response to LPS stimulation, Tpl2 phosphorylates a downstream kinase, MEK1, leading to the activation of ERK signaling pathway. Recent studies demonstrate that the NF-kappaB1 precursor protein p105 functions as an inhibitor of Tpl2 and that the LPS-stimulated Tpl2 activation requires p105 degradation. However, how p105 inhibits the signaling function of Tpl2 is not completely understood. We show here that p105 does not inhibit the intrinsic kinase activity of Tpl2. When complexed with p105, Tpl2 remains catalytically active and uses p105 as a substrate. However, the p105-bound Tpl2 is unable to phosphorylate its physiological target, MEK1. These findings suggest that p105 functions as a competitive inhibitor of Tpl2 that blocks its access by MEK1.
癌蛋白激酶Tpl2在细菌成分脂多糖（LPS）激活巨噬细胞的过程中发挥着重要作用。响应LPS刺激时，Tpl2会磷酸化下游激酶MEK1，从而导致ERK信号通路的激活。最近的研究表明，NF-κB1前体蛋白p105作为Tpl2的抑制剂发挥作用，并且LPS刺激下Tpl2的激活需要p105的降解。然而，p105如何抑制Tpl2的信号功能尚未完全明确。我们在此表明，p105并不抑制Tpl2的内在激酶活性。当与p105形成复合物时，Tpl2仍具有催化活性，并将p105用作底物。然而，与p105结合的Tpl2无法磷酸化其生理靶点MEK1。这些发现表明，p105作为Tpl2的竞争性抑制剂发挥作用，阻止MEK1接近Tpl2。
