Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation
Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation
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DOI：
10.1073/pnas.0904998106
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发表时间：
2009-07-07
影响因子：
11.1
通讯作者：
Calissano, P.
中科院分区：
文献类型：
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作者：
Matrone, C.;Marolda, R.;Calissano, P.
本研究表明，由于NGF信号的失败，海马神经元中Abeta产生的增加诱导了酪氨酸激酶受体A（TrkA）的意外磷酸化，随后激活磷脂酶C γ（PLC γ）途径和神经元死亡。这种磷酸化似乎与已知参与淀粉样蛋白生成的2种激酶Src和CDK 5有因果关系，并与α和γ分泌酶介导的p75加工有关。TrkA磷酸化的药理学抑制和TrkA和/或p75受体的部分沉默防止PLC γ激活并保护神经元免于死亡。伴随着这些事件，TrkA，p75，Abeta肽，和PS1蛋白共免疫沉淀，这表明它们在随后的凋亡性死亡发病的直接相互作用。总之，这些发现描绘了一种细胞机制，其中相同的细胞转导系统可以将其细胞内信息从营养和抗凋亡信号转化为死亡信号，这也可能与阿尔茨海默病的发病有关。
The present study shows that increased Abeta production in hippocampal neurons, due to a failure of NGF signal, induces an unexpected phosphorylation of tyrosine kinase receptor A (TrkA), followed by activation of the phospholipase C gamma (PLC gamma) pathway and neuronal death. Such phosphorylation seems causally connected with 2 kinases known be involved in amyloidogenesis, Src and CDK5, and associated with alpha and gamma secretase-mediated p75 processing. Pharmacologic inhibition of TrkA phosphorylation and partial silencing of TrkA and/or p75 receptors prevent PLC gamma activation and protect neurons from death. Concomitantly with these events, TrkA, p75, Abeta peptides, and PS1 protein coimmunoprecipitate, suggesting their direct interplay in the subsequent onset of apoptotic death. Together, these findings depict a cellular mechanism whereby the same cellular transducing system may invert its intracellular message from trophic and antiapoptotic to a death signaling, which could also have relevance in the onset of Alzheimer's disease.