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首页> 外文期刊>Molecular and Cellular Biology >TAK1-Mediated Serine/Threonine Phosphorylation of Epidermal Growth Factor Receptor via p38/Extracellular Signal-Regulated Kinase: NF-κB-Independent Survival Pathways in Tumor Necrosis Factor Alpha Signaling
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TAK1-Mediated Serine/Threonine Phosphorylation of Epidermal Growth Factor Receptor via p38/Extracellular Signal-Regulated Kinase: NF-κB-Independent Survival Pathways in Tumor Necrosis Factor Alpha Signaling

机译：TAK1介导的表皮生长因子受体的丝氨酸/苏氨酸磷酸化通过p38 /细胞外信号调节激酶：肿瘤坏死因子α信号传导中的NF-κB独立生存途径。

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摘要

The kinase TAK1, a mitogen-activated protein kinase kinase kinase (MAP3K), has been widely accepted as a key kinase activating NF-κB and MAPKs in tumor necrosis factor alpha (TNF-α) signaling. We have recently reported that TAK1 regulates the transient phosphorylation and endocytosis of epidermal growth factor receptor (EGFR) in a tyrosine kinase activity-independent manner. In the present study, we found that Thr-669 in the juxtamembrane domain and Ser-1046/1047 in the carboxyl-terminal regulatory domain were transiently phosphorylated in response to TNF-α. Experiments using chemical inhibitors and small interfering RNA demonstrated that TNF-α-mediated phosphorylation of Thr-669 and Ser-1046/7 were differently regulated via TAK1-extracellular signal-regulated kinase (ERK) and TAK1-p38 pathways, respectively. In addition, p38, but not ERK, was involved in the endocytosis of EGFR. Surprisingly, modified EGFR was essential to prevent apoptotic cellular responses; however, the EGFR pathway was independent of the NF-κB antiapoptotic pathway. These results demonstrated that TAK1 controls two different signaling pathways, IκB kinase-NF-κB and MAPK-EGFR, leading to the survival of cells exposed to the death signal from the TNF-α receptor.
机译：TAK1激酶是一种促分裂原活化的蛋白激酶激酶（MAP3K），已被广泛认为是激活肿瘤坏死因子α（TNF-α）信号传导中的NF-κB和MAPKs的关键激酶。我们最近报道，TAK1以酪氨酸激酶活性独立的方式调节表皮生长因子受体（EGFR）的瞬时磷酸化和内吞作用。在本研究中，我们发现近膜结构域中的Thr-669和羧基末端调节域中的Ser-1046 / 1047被瞬时磷酸化以响应TNF-α。使用化学抑制剂和小的干扰RNA进行的实验表明，TNF-α介导的Thr-669和Ser-1046 / 7磷酸化分别通过TAK1细胞外信号调节激酶（ERK）和TAK1-p38途径受到不同调节。另外，p38而不是ERK参与EGFR的胞吞作用。出乎意料的是，修饰的EGFR对于防止凋亡细胞反应至关重要。但是，EGFR途径独立于NF-κB抗凋亡途径。这些结果表明，TAK1控制两种不同的信号通路，即IκB激酶-NF-κB和MAPK-EGFR，从而导致暴露于TNF-α受体死亡信号的细胞得以存活。

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