FIG. 10.

Nrx in Wnt/Dvl and Toll-like receptor 4 (TLR4) signaling. Nrx was shown to suppress the Wnt/β-catenin pathway, which is involved in embryonic development and cancer. Secreted Wnt proteins bind to receptors of the Frizzled family and activate a signaling cascade. This process involves the cytosolic dishevelled (Dvl) protein, which inhibits the glycogen synthase kinase-3 (GSK3)-containing destruction apparatus and thereby phosphorylation and degradation of beta-catenin (β-cat). β-cat translocates into the nucleus and activates the transcription of Wnt-regulated target genes. Reduced Nrx binds to Dvl and suppresses Wnt/β-catenin signaling, whereas via “redox signals” oxidized Nrx does not. Similarly, reduced Nrx can inhibit TLR4 signaling, which is essential for embryonic development and the innate immune response. Lipopolysaccharide (LPS) stimulates the oligomerization of TLR4, inducing the recruitment of signal transduction adaptor proteins, such as myeloid differentiation primary response protein (MyD88). MyD88 activates a cascade of IKK and MAP kinases, leading to the phosphorylation and degradation of the inhibitor protein IκB, translocation of NF-κB (comprising subunits p65 and p50) into the nucleus, and activation of target genes. Reduced Nrx binds to Flightless-1 (Fli-1), forming an inhibitory complex with Myd88, suppressing TLR4-signaling.