TNIK was originally identified as a new member of the Germinal Center Kinase (GCK) family. It is known that TNIK regulates the c‐Jun N‐terminal kinase (JNK) pathway through its C‐terminus and the nuclear factor‐κB (NF‐κB) signaling pathways through its N‐terminal kinase domain. In addition, TNIK has been shown to regulate the filamentous‐actin (F‐actin) cytoskeleton. TCF‐4, β‐catenin and TNIK proteins form a complex in colorectal cancer cells. TNIK phosphorylates the TCF‐4 protein at the conserved serine. This phosphorylation is essential for full activation of Wnt signaling. Knockdown of TNIK decreased the transcriptional activity of the TCF‐4 and β‐catenin complex and inhibited the growth of colorectal cancer cells and xenografts. This growth inhibition was abrogated by expression of the catalytic domain of TNIK. 
The regulation of Wnt signaling by TNIK is conserved across species. Xenopus TNIK lacks the C‐terminal regulatory portion that is present in human TNIK, but the kinase domain is conserved. Xenopus TNIK is also essential for β‐catenin‐mediated determination of the dorsal axis. TNIK is an essential regulatory component of Wnt signaling, and colorectal cancer cells are highly dependent upon the expression and catalytic activity of TNIK for proliferation. Targeting of TNIK for pharmacological intervention was, thus, anticipated to inhibit Wnt signaling and suppress the growth of colorectal cancer cells.


1.Yamada T,et al. Cancer Sci. 2017;108(5):818–823.