A role for NRAGE in NF-κB activation through the non-canonical BMP pathway

Nicholas Matluk,Aldona Karaczyn,Tamara Adams,Joseph M Verdi,Jennifer A Rochira

doi:10.1186/1741-7007-8-7

Abstract

BackgroundPrevious studies have linked neurotrophin receptor-interacting MAGE protein to the bone morphogenic protein signaling pathway and its effect on p38 mediated apoptosis of neural progenitor cells via the XIAP-Tak1-Tab1 complex. Its effect on NF-κB has yet to be explored.ResultsHerein we report that NRAGE, via the same XIAP-Tak1-Tab1 complex, is required for the phosphorylation of IKK -α/β and subsequent transcriptional activation of the p65 subunit of NF-κB. Ablation of endogenous NRAGE by siRNA inhibited NF-κB pathway activation, while ablation of Tak1 and Tab1 by morpholino inhibited overexpression of NRAGE from activating NF-κB. Finally, cytokine profiling of an NRAGE over-expressing stable line revealed the expression of macrophage migration inhibitory factor.ConclusionModulation of NRAGE expression revealed novel roles in regulating NF-κB activity in the non-canonical bone morphogenic protein signaling pathway. The expression of macrophage migration inhibitory factor by bone morphogenic protein -4 reveals novel crosstalk between an immune cytokine and a developmental pathway.

Highlights

Previous studies have linked neurotrophin receptor-interacting MAGE protein to the bone morphogenic protein signaling pathway and its effect on p38 mediated apoptosis of neural progenitor cells via the XIAP-Tak1-Tab1 complex
Using a similar approach to Kendall et al in which the expression of neurotrophin receptor-interacting MAGE protein (NRAGE) was modulated through a series of loss of function and gain of function experiments, we have found that NRAGE is a required component in driving NF-B activation through the BMPR1a-XIAP-Tak1-Tab1 complex in 293HEK cells
NRAGE is required for NF-B activation in the noncanonical bone morphogenic protein (BMP)-4 Previous reports linked NRAGE to the XIAP-Tab1-Tak1 complex and phosphorylation of p38 [10,11]

Summary

Introduction

Previous studies have linked neurotrophin receptor-interacting MAGE protein to the bone morphogenic protein signaling pathway and its effect on p38 mediated apoptosis of neural progenitor cells via the XIAP-Tak1-Tab complex. The canonical BMP pathway regulates gene expression via SMAD1, 4, 5, and 8 [1] while the non-canonical BMP pathway regulates NF-B via the XIAP-Tak1-Tab complex [2,3]. Both pathways help direct proper proliferation and differentiation, embryogenesis and adulthood. The NF-B pathway consists of several transcription factors which are bound as homodimers or heterodimers; p65 (RelA), p50 (NF-kB1), p52 (NF-kB2), RelB, and c-Rel [4,5]. Previous research has linked the canonical NF-B pathway to the non-canonical BMP pathway via the formation of the XIAP-Tab1Tak complex [2,3,6,7,8]

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Discussion

Conclusion