Developmental switch in NF-κB signalling required for neurite growth
Developmental switch in NF-κB signalling required for neurite growth
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DOI：
10.1242/dev.035295
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发表时间：
2009-10-15
期刊：
影响因子：
4.6
通讯作者：
Davies, Alun M.
中科院分区：
文献类型：
--
作者：
Gavalda, Nuria;Gutierrez, Humberto;Davies, Alun M.
对于给定的细胞类型，特定的细胞外信号在细胞内信号网络中产生特征的活动模式，从而导致不同的细胞类型的特定反应。在这里，我们报告了已知的第一次在细胞内信号网络中发生发育转换，这是在相同细胞类型中对相同的细胞外信号做出相同的反应所必需的。我们发现，尽管BDNF促进胚胎和出生后小鼠感觉神经元的轴突生长需要NF-kappa B信号，但在这些阶段的NF-kappa B激活机制和轴突生长所需的p65 NF-kappa B亚单位的磷酸化状态之间存在发育切换。出生前不久，BDNF通过一种非典型的机制激活了NF-kappa B，该机制涉及到由Src家族蛋白激酶将I kappa Bα酪氨酸磷酸化，并在丝氨酸536处去磷酸化p65。出生后即刻，通过丝氨酸磷酸化I kappa Bα激活NF-kappa B信号，以及通过丝氨酸536处p65的结构性去磷酸化激活NF-kappa B信号是BDNF促进轴突生长所必需的。在高度分化的细胞类型中，核因子-kappa B信号的这种突然的发育切换说明了信号网络在对相同的细胞外信号产生相同的细胞反应时的意外可塑性。
For a given cell type, particular extracellular signals generate characteristic patterns of activity in intracellular signalling networks that lead to distinctive cell-type specific responses. Here, we report the first known occurrence of a developmental switch in the intracellular signalling network required for an identical cellular response to the same extracellular signal in the same cell type. We show that although NF-kappa B signalling is required for BDNF-promoted neurite growth from both foetal and postnatal mouse sensory neurons, there is a developmental switch between these stages in the NF-kappa B activation mechanism and the phosphorylation status of the p65 NF-kappa B subunit required for neurite growth. Shortly before birth, BDNF activates NF-kappa B by an atypical mechanism that involves tyrosine phosphorylation of I kappa B alpha by Src family kinases, and dephosphorylates p65 at serine 536. Immediately after birth, BDNF-independent constitutive activation of NF-kappa B signalling by serine phosphorylation of I kappa B alpha and constitutive dephosphorylation of p65 at serine 536 are required for BDNF-promoted neurite growth. This abrupt developmental switch in NF-kappa B signalling in a highly differentiated cell type illustrates an unsuspected plasticity in signalling networks in the generation of identical cellular responses to the same extracellular signal.