Tumor necrosis factor (TNF)-induced germinal center kinase-related (GCKR) and stress-activated protein-kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2)
Tumor necrosis factor (TNF)-induced germinal center kinase-related (GCKR) and stress-activated protein-kinase (SAPK) activation depends upon the E2/E3 complex Ubc13-Uev1A/TNF receptor-associated factor 2 (TRAF2)
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DOI：
10.1074/jbc.m211796200
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发表时间：
2003-04-25
影响因子：
4.8
通讯作者：
Kehrl, JH
中科院分区：
文献类型：
--
作者：
Shi, CS;Kehrl, JH
肿瘤坏死因子（TNF）诱导的凋亡信号调节激酶1 （ASK1.）和生发中心激酶（GCKs）的激活以及随后的应激活化蛋白激酶（SAPKs和c-Jun nh2末端激酶）的激活需要TNF受体相关因子2 （TRAF2）。尽管TRAF2 trf结构域结合ASK1、GCK和高度相关的激酶GCKR， RING finger结构域是激活它们所必需的。在这里，我们报道TNF以依赖TRAF2和Ubc13的方式激活GCKR和SAPK途径，Ubc13是二聚体泛素偶联酶复合物的成员之一。干扰LTbc13功能或表达可抑制TNF-和traf2介导的GCKR和SAPK激活，但对ASK1的影响很小。激活。TNF信号传导导致TRAF2多泛素化和寡聚化，导致GCKR的寡聚化、泛素化和激活，这些都对Ubc13功能的破坏很敏感。这些结果表明，LTbc13/Uev1A组装TRAF2赖氨酸63连接的多泛素链是tnf介导的GCKR和SAPK激活所必需的，但可能不是ASK1激活所必需的。
Tumor necrosis factor (TNF)-induced activation of apoptosis signal-regulating kinase 1 (ASK1.) and germinal center kinases (GCKs) and the subsequent activation of stress-activated protein kinases (SAPKs and c-Jun NH2-terminal kinases) requires TNF receptor-associated factor 2 (TRAF2). Although the TRAF2 TRAF domain binds ASK1, GCK, and the highly related kinase GCKR, the RING finger domain is needed for their activation. Here, we report that TNF activates GCKR and the SAPK pathway in a manner that depends upon TRAF2 and Ubc13, a member along with Uev1A of a dimeric ubiquitin-conjugating enzyme complex. Interference with LTbc13 function or expression inhibits both TNF- and TRAF2-mediated GCKR and SAPK activation, but has a minimal effect on ASK1. activation. TNF signaling leads to TRAF2 polyubiquitination and oligomerization and to the oligomerization, ubiquitination, and activation of GCKR, all of which are sensitive to the disruption of Ubc13 function. These results indicate that the assembly of a TRAF2 lysine 63-linked polyubiquitin chain by LTbc13/Uev1A is required for TNF-mediated GCKR and SAPK activation, but may not be required for ASK1 activation.