Departments of Cell Biology and Pathology, Biochemistry and Molecular Biology, Instituto de Neurociencias de Castilla y León (INCyL), Universidad de Salamanca, Salamanca 37007, Spain, Neural Development Group, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, and Institute of Biomedical Research of Salamanca, Salamanca 37007, Spain.
J Neurosci. 2014 Apr 23;34(17):6098-106. doi: 10.1523/JNEUROSCI.4271-13.2014.
Trk neurotrophin receptor ubiquitination in response to ligand activation regulates signaling, trafficking, and degradation of the receptors. However, the in vivo consequences of Trk ubiquitination remain to be addressed. We have developed a mouse model with a mutation in the TrkA neurotrophin receptor (P782S) that results in reduced ubiquitination due to a lack of binding to the E3 ubiquitin ligase, Nedd4-2. In vivo analyses of TrkAP782S indicate that defective ubiquitination of the TrkA mutant results in an altered trafficking and degradation of the receptor that affects the survival of sensory neurons. The dorsal root ganglia from the TrkAP782S knock-in mice display an increased number of neurons expressing CGRP and substance P. Moreover, the mutant mice show enhanced sensitivity to thermal and inflammatory pain. Our results indicate that the ubiquitination of the TrkA neurotrophin receptor plays a critical role in NGF-mediated functions, such as neuronal survival and sensitivity to pain.
原肌球蛋白受体激酶神经营养因子受体的泛素化反应配体激活调节受体的信号转导、运输和降解。然而，原肌球蛋白受体激酶泛素化的体内后果仍有待解决。我们开发了一种带有 TrkA 神经营养因子受体（P782S）突变的小鼠模型，由于缺乏与 E3 泛素连接酶 Nedd4-2 的结合，导致泛素化减少。TrkAP782S 的体内分析表明，TrkA 突变体的缺陷泛素化导致受体的运输和降解发生改变，从而影响感觉神经元的存活。TrkAP782S 基因敲入小鼠的背根神经节显示表达 CGRP 和 P 物质的神经元数量增加。此外，突变小鼠对热和炎症性疼痛的敏感性增强。我们的结果表明，TrkA 神经营养因子受体的泛素化在 NGF 介导的功能中起着关键作用，如神经元存活和对疼痛的敏感性。
