NKD1 and NKD2 are two mammalian orthologs of Drosophila Naked cuticle and have been shown to negatively regulate canonical Wnt signaling through an interaction with Dishevelled (Dvl) [
66‐
68]. In zebrafish, NKD1 and NKD2 antagonize both canonical and non-canonical Wnt signaling [
69]. Katoh investigated the expression of NKD1 and NKD2 in human cancer cell lines and primary gastric cancer. He found that NKD1 was up-regulated in the colorectal cancer cell line SW480, gastric cancer cell line TMK1, and pancreatic cancer cell line Hs700T, while NKD2 was up-regulated in the gastric cancer cell line MKN45, pancreatic cancer cell line BxPC-3, and esophageal cancer cell lines TE6, and TE13, indicating NKD1 and NKD2 might be candidate tumor suppressors [
70]. NKD2, but not NKD1, also interacts with the cytoplasmic C-terminal fragment of a Golgi-processed form of TGFα, coats TGFα-containing exocytic vesicles, and escorts those vesicles to the basolateral membrane of polarized epithelial cells in a myristoylation-dependent manner [
71]. NKD2 is an intrinsically unstructured protein and acts as a cargo recognition and targeting protein to ensure proper delivery and fusion of TGFα-containing exocytic vesicles [
72‐
74]. NKD2 can be stabilized by TGFα[
75] but down-regulated by Dishevelled in HEK293T cells [
76]. The above results indicate that NKD2 might be a regulator of both Wnt and EGFR signal pathways by regulation of TGFα delivery and Dishevelled stabilization. Although we have never observed a tertiary complex between NKD2, TGFα and Dishevelled, our results show that NKD2 forms a mutual degradation complex with Dvl-1 [
76], and that TGFα stabilizes NKD2 by suppressing the binding between NKD2 and its ubiquitin ligase AO7 [
75]. Based on our observations, we propose a model for the regulatory role of NKD2 in Wnt and EGFR signaling pathways: NKD2 binds to TGFα and escorts it to the plasma membrane, where TGFα gets released, and then NKD2 binds to Dvl-1 and targets each other for mutual degradation. NKD2 might be an important convergent point between Wnt and EGFR pathways to maintain the epithelial cell homeostasis.