Department of Neuroscience, Karolinska Institute, Stockholm 17177, Sweden.
Cell Rep. 2012 Dec 27;2(6):1563-70. doi: 10.1016/j.celrep.2012.11.009. Epub 2012 Dec 20.
Structural determinants underlying signaling specificity in the tumor necrosis factor receptor superfamily (TNFRSF) are poorly characterized, and it is unclear whether different signaling outputs can be genetically dissociated. The p75 neurotrophin receptor (p75(NTR)), also known as TNFRSF16, is a key regulator of trophic and injury responses in the nervous system. Here, we describe a genetic approach for dissecting p75(NTR) signaling and deciphering its underlying logic. Structural determinants important for regulation of cell death, NF-κB, and RhoA pathways were identified in the p75(NTR) death domain (DD). Proapoptotic and prosurvival pathways mapped onto nonoverlapping epitopes, demonstrating that different signaling outputs can be genetically separated in p75(NTR). Dissociation of c-Jun kinase (JNK) and caspase-3 activities indicated that JNK is necessary but not sufficient for p75(NTR)-mediated cell death. RIP2 recruitment and RhoGDI release were mechanistically linked, indicating that competition for DD binding underlies crosstalk between NF-κB and RhoA pathways in p75(NTR) signaling. These results provide insights into the logic of p75(NTR) signaling and pave the way for a genetic dissection of p75(NTR) function and physiology.
肿瘤坏死因子受体超家族（TNFRSF）中信号特异性的结构决定因素尚未得到很好的描述，也不清楚是否可以在遗传上区分不同的信号输出。p75 神经营养因子受体（p75（NTR）），也称为 TNFRSF16，是神经系统中营养和损伤反应的关键调节剂。在这里，我们描述了一种用于剖析 p75（NTR）信号传导并破译其潜在逻辑的遗传方法。在 p75（NTR）死亡结构域（DD）中鉴定出对细胞死亡、NF-κB 和 RhoA 途径调节很重要的结构决定因素。鉴定出的结构决定因素既可以调控细胞死亡，又可以调控 NF-κB 和 RhoA 途径，这表明在 p75（NTR）中可以在遗传上分离不同的信号输出。将促凋亡和抗凋亡途径映射到不重叠的表位上，表明不同的信号输出可以在遗传上分开。c-Jun 激酶（JNK）和半胱天冬酶-3 活性的分离表明 JNK 是 p75（NTR）介导的细胞死亡所必需的，但不是充分的。RIP2 募集和 RhoGDI 释放在机制上是相关的，表明 DD 结合的竞争是 p75（NTR）信号传导中 NF-κB 和 RhoA 途径相互作用的基础。这些结果提供了对 p75（NTR）信号传导逻辑的深入了解，并为 p75（NTR）功能和生理学的遗传剖析铺平了道路。
