Nkd1 in human Disease

In normal Wnt signaling, when the ligand activates the receptors to transduce the signal to the nucleus, the central signaling molecule called b-catenin becomes stabilized to activate transcription of Wnt target genes, including Nkd1 and Axin2.  In the absence of a Wnt signal, β-catenin is degraded by a destruction complex composed of APC, GSK3, Axin and CK1 proteins.  See the figure for details.  Somatic or germline mutations in APC are the major cause of sporadic and inherited colorectal cancers, respectively.  This results in constitutive activation of the pathway and transcription of its target genes.  Nkd1 and Axin2 are upregulated in the majority of colorectal cancer genes and are often used as markers of active Wnt signaling, especially Axin2. Our current understanding of Axin2 is that acts similarly to Axin in the destruction complex, but since this complex is inactive due to the APC mutations, Axin2, like Axin, is predicted to be functionless.  Our studies in zebrafish have demonstrated that Nkd1 is activated by the Wnt ligand, which then moves into the cytoplasm to interact with β-catenin and inhibit its nuclear accumulation.  We are currently following up on this in mammalian cells and in colorectal cancers.