摘要
混合的系 kinase (MLK3 ) 3 是被肿瘤坏死因素激活的激活 mitogen 的蛋白质 kinase kinase kinase -- 伪(TNF- 伪) 并且明确地在 TNF- 伪刺激上激活 c6 月 N 终端 kinase (JNK ) 。TNF- 伪由激活 MLK3 的机制不被知道。TNF 联系受体的因素(TRAF ) 是被招募到 TNF 受体的细胞质的结束并且调停的改编者分子,包括 JNK 的激活下游的发信号。这里,我们报导 MLK3 与 TRAF2, TRAF5 和 TRAF6 联系;然而,仅仅 TRAF2 能显著地导致 MLK3 的 kinase 活动。到 TRAF 领域并且为到它的 C 终端一半(氨基酸 511-847 ) 的 MLK3 的 TRAF2 地图的相互作用领域。与对方一起的内长的 TRAF2 和响应以一种时间依赖者方式的 TNF- 伪处理的 MLK3 伙伴。在 MLK3 和 TRAF2 之间的协会调停有绑在 MLK3 的 TRAF2 删除异种的 MLK3 激活和竞争以一种剂量依赖者方式稀释 MLK3 kinase 活动,在 TNF- 伪处理上。而且 MLK3 的下游的目标, JNK 被 TNF- 伪以一种 TRAF2 依赖的方式激活。因此,我们在 TRAF2 和 MLK3 之间的直接相互作用为 TNF- 伪 - 被要求的数据表演导致了 MLK3 和它的下游的目标的激活, JNK。
Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase that is activated by tumor necrosis factor-α (TNF-α) and specifically activates c-Jun N-terminal kinase (JNK) on TNF-a stimulation. The mecha- nism by which TNF-α activates MLK3 is still not known. TNF receptor-associated factors (TRAFs) are adapter molecules that are recruited to cytoplasmic end of TNF receptor and mediate the downstream signaling, including activation of JNK. Here, we report that MLK3 associates with TRAF2, TRAF5 and TRAF6; however only TRAF2 can significantly induce the kinase activity of MLK3. The interaction domain of TRAF2 maps to the TRAF domain and for MLK3 to its C-terminal half (amino acids 511-847). Endogenous TRAF2 and MLK3 associate with each other in response to TNF-α treatment in a time-dependent manner. The association between MLK3 and TRAF2 mediates MLK3 activation and competition with the TRAF2 deletion mutant that binds to MLK3 attenuates MLK3 kinase activity in a dose-dependent manner, on TNF-α treatment. Furthermore the downstream target of MLK3, JNK was activated by TNF-α in a TRAF2-dependent manner. Hence, our data show that the direct interaction between TRAF2 and MLK3 is required for TNF-α-induced activation of MLK3 and its downstream target, JNK.