Cytokine-induced activation of mixed lineage kinase 3 requires TRAF2 and TRAF6.
Cytokine-induced activation of mixed lineage kinase 3 requires TRAF2 and TRAF6.
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DOI：
10.1016/j.cellsig.2009.06.008
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发表时间：
2009-11
影响因子：
4.8
通讯作者：
Chadee DN
中科院分区：
文献类型：
--
作者：
Korchnak AC;Zhan Y;Aguilar MT;Chadee DN
混合谱系激酶3（MLK 3）是一种促分裂原活化蛋白激酶（MAP 3 K），其响应于生长因子、应激和促炎细胞因子肿瘤坏死因子（TNF）而活化多种促分裂原活化蛋白激酶（MAPK）途径。MLK 3是TNF最佳激活应激活化蛋白激酶/c-Jun N-末端激酶（SAPK/JNK）信号传导所必需的，然而，MLK 3被TNF受体募集和激活的机制仍然知之甚少。在这里，我们报告了TNF和白细胞介素-1 β（IL-1β）刺激快速激活MLK 3激酶活性。我们观察到TNF刺激MLK 3和TNF受体相关因子（TRAF）2之间的相互作用，而IL-1β刺激MLK 3和TRAF 6之间的相互作用。TRAF 2或TRAF 6的RNA干扰（RNAi）显著损害TNF对MLK 3的激活，表明TRAF 2和TRAF 6是MLK 3激活所必需的。我们发现，TNF还刺激MLK 3的泛素化，MLK 3可以与赖氨酸48（K48）和赖氨酸63（K63）连接的多聚泛素链缀合。我们的研究结果表明，K48连接的泛素化指导MLK 3蛋白体降解，而K63连接的泛素化是MLK 3激酶活性的重要。这些结果揭示了促炎细胞因子TNF和IL-1β激活MLK 3的新机制。
Mixed Lineage Kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates multiple mitogen activated protein kinase (MAPK) pathways in response to growth factors, stresses and the pro-inflammatory cytokine, tumor necrosis factor (TNF). MLK3 is required for optimal activation of stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) signaling by TNF, however, the mechanism by which MLK3 is recruited and activated by the TNF receptor remains poorly understood. Here we report that both TNF and Interleukin-1β (IL-1β) stimulation rapidly activate MLK3 kinase activity. We observed that TNF stimulates an interaction between MLK3 and TNF receptor associated factor (TRAF) 2 and IL-1β stimulates an interaction between MLK3 and TRAF6. RNA interference (RNAi) of traf2 or traf6 dramatically impairs MLK3 activation by TNF indicating that TRAF2 and TRAF6 are critically required for MLK3 activation. We show that TNF also stimulates ubiquitination of MLK3 and MLK3 can be conjugated with lysine 48 (K48)- and lysine 63 (K63)-linked polyubiquitin chains. Our results suggest that K48-linked ubiquitination directs MLK3 for proteosomal degradation while K63-linked ubiquitination is important for MLK3 kinase activity. These results reveal a novel mechanism for MLK3 activation by the proinflammatory cytokines TNF and IL-1β.
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影响因子：
56.9
作者：
Cao, ZD;Henzel, WJ;Gao, XO
通讯作者：
Gao, XO
DOI：
10.1016/s0167-4889(03)00022-3
发表时间：
2003-04-07
影响因子：
5.1
作者：
Sathyanarayana, P;Barthwal, MK;Rana, A
通讯作者：
Rana, A
DOI：
10.1073/pnas.0404132101
发表时间：
2004-10-26
影响因子：
11.1
作者：
Ea, CK;Sun, L;Chen, ZJJ
通讯作者：
Chen, ZJJ
影响因子：
4.4
作者：
Barbin, G;Roisin, MP;Zalc, B
通讯作者：
Zalc, B
影响因子：
5.3
作者：
Chadee, DN;Yuasa, T;Kyriakis, JM
通讯作者：
Kyriakis, JM