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 phosphrylation 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.