Naked/NKD is a Context-Dependent Regulator of Wnt Signaling

Naked/NKD is a Context-Dependent Regulator of Wnt Signaling

NKD is a genetically defined immunodeficiency of CD56+CD3- natural killer (NK) cells that causes recurrent viral infections and cancer in children and adolescents. In addition, patients with NKD carry mutations in GATA2 and MCM4 that increase susceptibility to DNA instability during replication. Interestingly, these genetic changes are not always associated with cancer as they can also cause apoptosis and lead to a decrease in NK cell cytotoxicity in the absence of tumors, suggesting that NK cell defects may have other implications than cancer development.

Naked/NKD is a context-dependent regulator of Wnt signaling

To elucidate how Naked/NKD regulates Wnt signaling, we investigated the binding of recombinant Lip-NKD-HisC to Dishevelled and Axin, a key component of Wnt signalosomes, using a combination of proteome-wide and clonal analyses. We found that the formation of recombinant Lip-NKD-HisC aggregates was strongly dependent on the most conserved histidine residues within the HisC polyhistidine stretch, but it also requires two aromatic residues in HisC (Figure 1–figure supplement 1). Read more : https://www.ryderwear.com/collections/nkd

Co-aggregation between Naked/NKD and Dishevelled and Axin is required to mediate their cellular interaction. Loss of Naked/NKD reduces the signaling activity of Dishevelled and the levels of Axin, both of which are required for efficient Wnt signaling. These results suggest that Naked/NKD functions as a feedback regulator of Wnt signaling by destabilizing Dishevelled and Axin simultaneously in some circumstances. This is a novel mechanism of Wnt signaling regulation that may help explain why Naked/NKD is dispensable in some tissues and is not essential for Wnt signaling in most cases.