Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI3-K, in neurotrophic factor-induced survival of sympathetic neurons
Analysis of Ret knockin mice reveals a critical role for IKKs, but not PI3-K, in neurotrophic factor-induced survival of sympathetic neurons
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DOI：
10.1038/cdd.2008.76
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发表时间：
2008-09-01
影响因子：
12.4
通讯作者：
Johnson, E. M., Jr.
中科院分区：
文献类型：
--
作者：
Encinas, M.;Rozen, E. J.;Johnson, E. M., Jr.
我们分析了GDNF对不同Ret敲打小鼠交感神经元的存活反应和下游信号的影响。缺乏酪氨酸1062(Ret中的一个多连接位点)完全阻止了GDNF介导的存活。重要的是，酪氨酸981的缺失虽然取消Akt的磷酸化，但对神经元的存活没有影响，这表明PI3-K/Akt通路不是交感神经元存活所必需的。相反，沉默B-Raf不仅可以完全阻止GDNF介导的细胞存活，也可以完全阻止NGF介导的细胞存活，而不依赖于MEK-1/2。我们认为IKKS是B-Raf保护作用的主要效应因子。首先，B-Raf与IKK相互作用并被激活。第二，IKKS的击倒逆转了构成活性形式的B-Raf所提供的保护。第三，敲除IKKS可以阻止NGF和GDNF介导的存活。总之，我们的数据描述了连接B-Raf和IKK的交感神经元的一条新的生存途径，而不依赖于PI3-K和MEK-1/2途径。
We analyzed the survival responses and downstream signaling elicited by GDNF on sympathetic neurons from different Ret knockin mice. Lack of tyrosine 1062, a multidocking site in Ret, completely prevented GDNF-mediated survival. Importantly, lack of tyrosine 981, although abrogating Akt phosphorylation, had no effect on neuronal survival, indicating that the PI 3-K/Akt pathway is not necessary for survival of sympathetic neurons. In contrast, silencing of B-Raf completely prevented not only GDNF-mediated but also NGF-mediated cell survival, independently of MEK-1/2. We identified IKKs as the main effectors of the protective effects of B-Raf. First, B-Raf interacted with and activated IKKs. Second, knockdown of IKKs reversed the protection afforded by a constitutively active form of B-Raf. Third, knockdown of IKKs prevented both NGF- and GDNF-mediated survival. In conclusion, our data delineate a novel survival pathway for sympathetic neurons linking B-Raf to IKKs, independently of both PI 3-K and MEK-1/2 pathways.