NRAGE is a Negative Regulator of Nerve Growth Factor-Stimulated Neurite Outgrowth in PC12 Cells Mediated through TrkA-Erk Signaling

NRAGE, also denominated as MAGE-D1 or Dlxin-1, is firstly identified as a molecule interacting with NGF low affinity receptor p75NTR. It facilitates cell cycle arrest and NGF-dependent neuronal apoptosis. Here we report that NRAGE is downregulated while p75NTR is upregulated during the process of NGF-induced neuronal differentiation of PC12 cells. Knockdown of NRAGE by RNA interference accelerates NGF-mediated neurite outgrowth. In addition, in the NRAGE-suppressed cells, NGF-induced ERK activation is increased and this activation is MEK-dependent. Conversely, NRAGE overexpression significantly represses NGF-induced ERK activation. Further studies revealed that NRAGE downregulates TrkA expression through a post-transcriptional manner and thereby blocks NGF-induced TrkA phos-phrylation at tyrosine-490. Altogether, these data indicate for the first time that NRAGE is an endogenous inhibitor for NGF-induced neuronal differentiation of PC12 cells by regulating TrkA-ERK signaling. (C) 2010 Wiley-Liss, Inc.

NRAGE，也被称为MAGE - D1或Dlxin - 1，最初被鉴定为一种与神经生长因子（NGF）低亲和力受体p75NTR相互作用的分子。它促进细胞周期停滞以及神经生长因子依赖的神经元凋亡。在此我们报道，在神经生长因子诱导PC12细胞神经元分化过程中，NRAGE下调而p75NTR上调。通过RNA干扰敲低NRAGE可加速神经生长因子介导的轴突生长。此外，在NRAGE受抑制的细胞中，神经生长因子诱导的细胞外调节蛋白激酶（ERK）激活增加，且这种激活是丝裂原活化蛋白激酶激酶（MEK）依赖性的。相反，NRAGE过表达显著抑制神经生长因子诱导的ERK激活。进一步研究表明，NRAGE通过转录后方式下调TrkA表达，从而阻断神经生长因子诱导的TrkA在酪氨酸 - 490位点的磷酸化。总之，这些数据首次表明NRAGE是神经生长因子诱导PC12细胞神经元分化的内源性抑制剂，其通过调节TrkA - ERK信号通路发挥作用。（C）2010威利 - 利斯公司