KIKUCHI Akira ≪Molecular Biology and Biochemistry≫ “CKAP4 is a Dickkopf1 receptor and involved in tumor progression”

PublishJournal of Clinical Investigation (2016) doi:10.1172/JCI84658

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It is well established that Dickkopf1 (Dkk1) is a secreted protein that inhibits Wnt signaling pathway and functions as a tumor suppressor. In contrast, it was also reported that Dkk1 overexpression is associated with poor prognosis of pancreas, lung, esophageal, kidney, and breast cancers. Therefore, Dkk1 was suggested to exhibit its own signaling to promote cancer cell proliferation in a cancer cell context. However, the mechanism is not understood. We found that Dkk1 stimulates cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4) as a novel Dkk1 receptor. Dkk1-CKAP4 signaling activated AKT through the formation of a complex between CKAP4 and phosphatidylinositol 3-kinase (PI3K). Both Dkk1 and CKAP4 were frequently expressed in tumor lesions of pancreatic and lung cancers and their simultaneous expression was negatively correlated with prognosis. Knockdown of Dkk1 and CKAP4 in cancer cells decreased AKT activity and inhibited their xenograft tumor formation. In addition, an anti-CKAP4 polyclonal antibody blocked the binding of Dkk1 to CKAP4 and inhibited xenograft tumor formation induced by cancer cells. These results suggest that the Dkk1-CKAP4 axis constitutes a novel cancer signaling and represents a therapeutic target for cancers expressing both Dkk1 and CKAP4.