NRAGE is a negative regulator of nerve growth factor‐stimulated neurite outgrowth in PC12 cells mediated through TrkA‐ERK signaling

Abstract

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.

The Ubiquitin Ligase Praja1 Reduces NRAGE Expression and Inhibits Neuronal Differentiation of PC12 Cells

“…On the other hand, Feng et al . have reported opposite effects, seeing a reduction of neuronal differentiation and associated ERK signalling after NRAGE overexpression and an increased NGF-induced ERK activation after knocking down NRAGE [28]. Moreover, previous studies have demonstrated that p75 NTR -mediated apoptosis – rather than differentiation – is facilitated by NRAGE in various cell types including PC12 [24], [27] and that Praja1 targets various anti-apoptotic factors [13].…”

“…NRAGE is highly expressed in the developing and adult nervous system, often but not exclusively together with p75 NTR [23], [24]. NRAGE has been shown to be pro-apoptotic in various cell types [24]–[27] and to be involved in the neuronal differentiation of pheochromocytoma (PC12) cells [28], [29]. PC12 cells endogenously express the NRAGE activator p75 NTR [24], which is known to mediate NGF-signalling in cell survival, differentiation and cell death [18], [24].…”

Effects of neurotrophin receptor‐mediated MAGE homology on proliferation and odontoblastic differentiation of mouse dental pulp cells

“…NRAGE suppresses metastasis of melanoma and pancreatic cancers in vivo and in in vitro studies ; NRAGE also promotes proliferation of oesophageal carcinoma cells . Meanwhile, NRAGE provides endogenous regulation of neuronal proliferation and differentiation of PC12 cells . According to previous studies, NRAGE modulates function of Dlx/Msx to promote myogenic differentiation and strong NRAGE mRNA signals have been found in cell layers surrounding cartilaginous elements in bone rudiments, during digit formation in embryogenesis.…”

The effects of short-term JNK inhibition on the survival and growth of aged sympathetic neurons

“…The role of NRAGE in neuronal growth is less clear; in PC12 cells, both growth-suppressing (Feng et al, 2010) and growth-promoting effects have been reported (Reddy et al, 2010), while in NRAGE knockout mice neuronal growth was found to be normal (Bertrand et al, 2008).…”