IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and-2 MAP kinases
IκB kinase-induced interaction of TPL-2 kinase with 14-3-3 is essential for Toll-like receptor activation of ERK-1 and-2 MAP kinases
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DOI：
10.1073/pnas.1320440111
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发表时间：
2014-06-10
影响因子：
11.1
通讯作者：
Ley, Steven C.
中科院分区：
文献类型：
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作者：
Ben-Addi, Abduelhakem;Mambole-Dema, Agnes;Ley, Steven C.
在炎症反应中，MEK-1/2激酶TPL-2对于ERK-1/2 MAP激酶通路的toll样受体激活至关重要，但它可以在c端截断后转化细胞。ikappa B激酶（IKK）复合物磷酸化TPL-2 C末端调控ERK-1/2的全长TPL-2激活，其机制尚不清楚。在这里，我们发现IKK磷酸化TPL-2 Ser-400和TPL-2 Ser-443自磷酸化共同触发了TPL-2与14-3-3的关联。14-3-3募集到磷酸化的C端刺激TPL-2 MEK-1激酶活性，这是TPL-2激活ERK-1/2的必要条件。14-3-3与TPL-2的结合也是脂多糖诱导巨噬细胞产生肿瘤坏死因子所必需的，而巨噬细胞产生肿瘤坏死因子是由TPL-2独立于ERK-1/2激活调节的。我们的数据确定了激活TPL-2信号的关键步骤，并提供了c端缺失如何通过使其激酶活性独立于14-3-3结合而触发TPL-2的致癌潜力的机制见解。
The MEK-1/2 kinase TPL-2 is critical for Toll-like receptor activation of the ERK-1/2 MAP kinase pathway during inflammatory responses, but it can transform cells following C-terminal truncation. I kappa B kinase (IKK) complex phosphorylation of the TPL-2 C terminus regulates full-length TPL-2 activation of ERK-1/2 by a mechanism that has remained obscure. Here, we show that TPL-2 Ser-400 phosphorylation by IKK and TPL-2 Ser-443 autophosphorylation cooperated to trigger TPL-2 association with 14-3-3. Recruitment of 14-3-3 to the phosphorylated C terminus stimulated TPL-2 MEK-1 kinase activity, which was essential for TPL-2 activation of ERK-1/2. The binding of 14-3-3 to TPL-2 was also indispensible for lipopolysaccharide-induced production of tumor necrosis factor by macrophages, which is regulated by TPL-2 independently of ERK-1/2 activation. Our data identify a key step in the activation of TPL-2 signaling and provide a mechanistic insight into how C-terminal deletion triggers the oncogenic potential of TPL-2 by rendering its kinase activity independent of 14-3-3 binding.