The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner
The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner
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DOI：
10.1038/ncb1780
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发表时间：
2008-10-01
影响因子：
21.3
通讯作者：
Landstroem, Marene
中科院分区：
文献类型：
--
作者：
Sorrentino, Alessandro;Thakur, Noopur;Landstroem, Marene
转化生长因子-β（TGF-β）是一种多功能细胞因子，可调节胚胎发育和组织稳态;然而，其活性异常发生在癌症中（1，2）。TGF-β通过其II型和I型受体（T β RII和T β RI）发出信号，导致Smad蛋白磷酸化（3，4）。TGF-β相关激酶1（TAK1）是丝裂原活化蛋白激酶（MAPKKK）家族的成员，最初被鉴定为TGF-β诱导的p38活化的效应子（5）。然而，其激活的分子机制是未知的。在这里，我们报告，泛素连接酶（E3）TRAF6与T β RI中存在的共识基序相互作用。TGF-β诱导的TRAF6的自泛素化和随后的TAK1-p38/JNK通路的激活需要T β RI-TRAF6相互作用，这导致细胞凋亡。T β RI激酶活性是激活经典Smad通路所必需的，而TRAF6的E3活性以受体激酶非依赖性方式调节TAK1的激活。有趣的是，TGF-β诱导的TRAF6介导的TAK1 Lys 34的Lys 63连接的多泛素化与TAK1活化相关。我们的数据表明，TGF-β通过T β RI与TRAF6的相互作用特异性激活TAK1，而Smad2的激活不依赖于TRAF6。
Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer(1,2). TGF-beta signals through its Type II and Type I receptors (T beta RII and T beta RI) causing phosphorylation of Smad proteins(3,4). TGF-beta-associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF-beta-induced p38 activation(5). However, the molecular mechanisms for its activation are unknown. Here we report that the ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in T beta RI. The T beta RI-TRAF6 interaction is required for TGF-beta-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1-p38/JNK pathway, which leads to apoptosis. T beta RI kinase activity is required for activation of the canonical Smad pathway, whereas E3 activity of TRAF6 regulates the activation of TAK1 in a receptor kinase-independent manner. Intriguingly, TGF-beta-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-beta specifically activates TAK1 through interaction of T beta RI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.