NGF augments the autophosphorylation of Ret via inhibition of ubiquitin-dependent degradation.
NGF augments the autophosphorylation of Ret via inhibition of ubiquitin-dependent degradation.
复制标题
NGF 通过抑制泛素依赖性降解来增强 Ret 的自身磷酸化。
DOI：
10.1111/j.1471-4159.2006.04292.x
复制
发表时间：
2007
影响因子：
4.7
通讯作者：
Johnson,EugeneM
中科院分区：
文献类型：
--
作者：
Pierchala,BrianA;Tsui,CynthiaC;Milbrandt,Jeffrey;Johnson,EugeneM
神经生长因子（NGF）是出生后交感神经元营养维持所必需的。 NGF 的生长促进活性的一个重要部分来自异源受体酪氨酸激酶 Ret 的 NGF 依赖性磷酸化。我们发现 NGF 选择性地应用于维持在区室化培养物中的交感神经元的远端轴突，激活位于这些远端轴突中的 Ret。蛋白酶体或溶酶体降解途径的抑制模拟了 NGF 对 Ret 激活的影响。同样，NGF 抑制神经胶质细胞源性神经营养因子依赖性激活诱导的 Ret 降解，该过程需要泛素化和蛋白酶体降解。 NGF 诱导自磷酸化 Ret 主要在质膜中积累，而 GDNF 则促进活化 Ret 的内化。 NGF 处理的神经元中出现单泛素化而非多泛素化的 Ret 积聚，而胶质细胞系源性神经营养因子则促进 Ret 的强多泛素化。因此，NGF 通过抑制 Ret 内化和多泛素化之前正在进行的泛素介导的降解来刺激成熟交感神经元中的 Ret 活性。
Nerve growth factor (NGF) is required for the trophic maintenance of postnatal sympathetic neurons. A significant portion of the growth‐promoting activity of NGF is from NGF‐dependent phosphorylation of the heterologous receptor tyrosine kinase, Ret. We found that NGF applied selectively to distal axons of sympathetic neurons maintained in compartmentalized cultures activated Ret located in these distal axons. Inhibition of either proteasomal or lysosomal degradation pathways mimicked the effect of NGF on Ret activation. Likewise, NGF inhibited the degradation of Ret induced by glial cell line‐derived neurotrophic factor‐dependent activation, a process that requires ubiquitination and proteasomal degradation. NGF induced the accumulation of autophosphorylated Ret predominantly in the plasma membrane, in contrast to GDNF, which promoted the internalization of activated Ret. An accretion of monoubiquitinated, but not polyubiquitinated, Ret occurred in NGF‐treated neurons, in contrast to glial cell line‐derived neurotrophic factor that promoted the robust polyubiquitination of Ret. Thus, NGF stimulates Ret activity in mature sympathetic neurons by inhibiting the ongoing ubiquitin‐mediated degradation of Ret before its internalization and polyubiquitination.