TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo
TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo
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DOI：
10.1101/gad.1360605
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发表时间：
2005-11-15
影响因子：
10.5
通讯作者：
Ghosh, S
中科院分区：
文献类型：
--
作者：
Shim, JH;Xiao, CC;Ghosh, S
TGF-β激活激酶1（TAK 1）是MAPKKK家族的成员，被认为是诱导型转录因子NF-κ B和AP-1的关键调节因子，因此在调节介导炎症的基因中起关键作用。尽管体外生物化学研究已经揭示了TAK 1复合物的存在，该复合物包括TAK 1和衔接蛋白TAB 1和TAB 2，但仍不清楚该复合物的哪些成员对信号传导至关重要。为了分析TAK 1在体内的功能，我们已经删除了小鼠的Tak 1基因，由此产生的表型是早期胚胎致死。使用缺乏TAK 1、TAB 1或TAB 2的胚胎成纤维细胞，我们发现TNF-1、IL-1 R、TLR-3和TLR-4介导的NF-κ B和AP-1活化在Tak 1（m/m）细胞中严重受损，但在Tab 1（-/-）和Tab 2（-/-）细胞中正常。此外，Tak 1（m/m）细胞对TNF诱导的凋亡高度敏感。TAK 1在TNF-α和IL-1信号通路中介导IKK活化，其中其分别在RIP 1-TRAF 2和MyD 88-IRAK 1-TRAF 6下游起作用。然而，在LT-β信号传导后，通过旁路途径激活NF-κ B并不需要TAK 1。在TGF-β信号通路中，TAK 1缺失导致NF-κ B和c-Jun N-末端激酶（JNK）活化受损，而不影响Smad 2活化或TGF-β诱导的基因表达。因此，我们的研究表明，TAK 1作为IKK β和JNK的上游激活激酶，而不是IKK α，揭示了TAK 1在炎症信号通路中的意外特异性作用。
TGF-beta-activated kinase 1 (TAK1), a member of the MAPKKK family, is thought to be a key modulator of the inducible transcription factors NF-kappa B and AP-1 and, therefore, plays a crucial role in regulating the genes that mediate inflammation. Although in vitro biochemical studies have revealed the existence of a TAK1 complex, which includes TAK1 and the adapter proteins TAB1 and TAB2, it remains unclear which members of this complex are essential for signaling. To analyze the function of TAK1 in vivo, we have deleted the Tak1 gene in mice, with the resulting phenotype being early embryonic lethality. Using embryonic fibroblasts lacking TAK1, TAB1, or TAB2, we have found that TNFR1, IL-1R, TLR3, and TLR4-mediated NF-kappa B and AP-1 activation are severely impaired in Tak1(m/m) cells, but they are normal in Tab1(-/-) and Tab2(-/-) cells. In addition, Tak1(m/m) cells are highly sensitive to TNF-induced apoptosis. TAK1 mediates IKK activation in TNF-alpha and IL-1 signaling pathways, where it functions downstream of RIP1-TRAF2 and MyD88-IRAK1-TRAF6, respectively. However, TAK1 is not required for NF-kappa B activation through the alternative pathway following LT-beta signaling. In the TGF-beta signaling pathway, TAK1 deletion leads to impaired NF-kappa B and c-Jun N-terminal kinase (JNK) activation without impacting Smad2 activation or TGF-beta-induced gene expression. Therefore, our studies suggests that TAK1 acts as an upstream activating kinase for IKK beta and JNK, but not IKK alpha, revealing an unexpectedly specific role of TAK1 in inflammatory signaling pathways.