A role for NRAGE in NF-kappaB activation through the non-canonical BMP pathway.
BACKGROUND
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. Its effect on NF-kappaB has yet to be explored.


RESULTS
Herein we report that NRAGE, via the same XIAP-Tak1-Tab1 complex, is required for the phosphorylation of IKK -alpha/beta and subsequent transcriptional activation of the p65 subunit of NF-kappaB. Ablation of endogenous NRAGE by siRNA inhibited NF-kappaB pathway activation, while ablation of Tak1 and Tab1 by morpholino inhibited overexpression of NRAGE from activating NF-kappaB. Finally, cytokine profiling of an NRAGE over-expressing stable line revealed the expression of macrophage migration inhibitory factor.


CONCLUSIONS
Modulation of NRAGE expression revealed novel roles in regulating NF-kappaB 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.
Matluk
Nicholas
N
Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, ME 04074, USA.
Rochira
Jennifer A
JA
Karaczyn
Aldona
A
Adams
Tamara
T
Verdi
Joseph M
JM
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
D000951:Antigens, Neoplasm; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C120897:MAGED1 protein, human; D008263:Macrophage Migration-Inhibitory Factors; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase