TAK1-dependent signaling requires functional interaction with TAB2/TAB3
TAK1-dependent signaling requires functional interaction with TAB2/TAB3
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DOI：
10.1074/jbc.m608867200
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发表时间：
2007-02-09
影响因子：
4.8
通讯作者：
Darnay, Bryant G.
中科院分区：
文献类型：
--
作者：
Besse, Arnaud;Lamothe, Betty;Darnay, Bryant G.
转化生长因子β激活激酶1（TAX 1）是MAPKKK家族的成员，最初被描述为在转化生长因子β信号通路中发挥重要作用，但最近的证据表明TAK 1参与白细胞介素（IL）-1和肿瘤坏死因子（TNF）通路。值得注意的是，两种同源蛋白质TAB 2和TAB 3已被鉴定为连接TAK 1与上游衔接子TRAF的衔接子。然而，TAB 2/TAB 3和TAK 1之间的相互作用是否是其激酶激活以及随后IKK和MAPK通路激活所必需的仍不清楚。在这里，我们表征了TAK 1中的TAB 2/TAB 3结合结构域，并进一步研究了这种相互作用对IL-1、TNF和RANKL信号传导的要求。通过缺失作图实验，我们证明了TAB 2/TAB 3的结合基序是位于TAK 1的最后C-末端100个残基内的非连续区域。然而，TAK 1的残基479-553.似乎是TAB 2/TAB 3相互作用的必要和充分条件。相反，TAB 2的残基574-693显示与TAK 1相互作用。含有TAK 1最后100个残基的绿色荧光蛋白融合蛋白（TAK 1-C100）可阻断内源性TAB 2/TAB 3与TAK 1的相互作用，阻断TAK 1的磷酸化，并抑制IL-1、TNF和RANKL诱导的IKK和MAPK的激活。此外，TAK 1-C100阻断了RANKL诱导的NFATc 1的核积聚，从而阻断了破骨细胞分化，这与催化失活的TAK 1阻断RANKL介导的信号传导的能力一致。值得注意的是，我们的研究提供了证据表明TAB 2/TAB 3与TAK 1的相互作用对于IL-1、TNF和RANKL介导的信号级联的激活至关重要。
Transforming growth factor beta-activated kinase 1 (TAX1), a member of the MAPKKK family, was initially described to play an essential role in the transforming growth factor beta-signaling pathway, but recent evidence has emerged implicating TAK1 in the interleukin (IL)-1 and tumor necrosis factor (TNF) pathways. Notably, two homologous proteins, TAB2 and TAB3, have been identified as adaptors linking TAK1 to the upstream adaptors TRAFs. However, it remains unclear whether the interaction between TAB2/TAB3 and TAK1 is necessary for its kinase activation and subsequent activation of the IKK and MAPK pathways. Here, we characterized the TAB2/TAB3-binding domain in TAK1 and further examined the requirement of this interaction for IL-1, TNF, and RANKL signaling. Through deletion mapping experiments, we demonstrated that the binding motif for TAB2/TAB3 is a non-contiguous region located within the last C-terminal 100 residues of TAK1. However, residues 479-553 of TAK1. appear to be necessary and sufficient for TAB2/TAB3 interaction. Conversely, residues 574-693 of TAB2 were shown to interact with TAK1. A green fluorescent protein fusion protein containing the last 100 residues of TAK1 (TAK1-C100) abolished the interaction of endogenous TAB2/TAB3 with TAK1, the phosphorylation of TAK1, and prevented the activation of IKK and MAPK induced by IL-1, TNF, and RANKL. Furthermore, TAK1-C100 blocked RANKL-induced nuclear accumulation of NFATc1 and consequently osteoclast differentiation consistent with the ability of a catalytically inactive TAK1 to block RANKL-mediated signaling. Significantly, our study provides evidence that the TAB2/TAB3 interaction with TAK1 is crucial for the activation of signaling cascades mediated by IL-1, TNF, and RANKL.