Casein Kinase I Transduces WNT Signals




Peters, John Michael

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Wnt signaling controls a diverse array of processes including cell growth, oncogenesis, and development. Components of the Wnt cascade are altered in several human cancers including colon cancers and melanomas. We set out to identify novel components of this signal transduction pathway via expression cloning in Xenopus embryos. This assay identified a protein kinase, casein kinase I (CKI), as a novel component of the Wnt signaling pathway. We first showed that expression of CKI produces Wnt phenotypes. First, CKI induced completely formed second axes, or Siamese twins, when injected into embryos. Second, embryos which had been ventralized by UV-irradiation were completely rescued by CKI, producing normal embryos. In order to extend these observations, we tested CKI in three biochemical assays of Wnt signaling. First, CKI expression stabilized b-catenin protein levels, a hallmark of Wnt signaling. Second, CKI induced the expression of Siamois and Xnr3, direct transcriptional targets of Wnt signaling. Finally, CKI expression dorsalized the ventral marginal zone in Xenopus, inducing markers of the Spemann organizer which is a product of Wnt signaling. We next investigated the ability of CKI inhibitors to block Wnt signaling in vivo. Two dominant negative forms of CKI and a specific pharmacological inhibitor of CKI all blocked the ability of Xwnt8 to induce dorsal axes and target genes in embryos. These data demonstrate that CKI function is required for transduction of Wnt signals. Additionally, we also demonstrated that CKI function is required for Wnt signaling in the nematode C. elegans, proving that CKI function in this pathway is conserved from invertebrates to vertebrates. We then investigated the biochemical mechanism of CKI function. Epistasis experiments indicated that CKI acts between Dishevelled and GSK-3. Yeast twohybrid assays showed that CKI strongly binds Dishevelled. Through in vivo phosphorylation experiments, we showed that CKI increases Disheveled phosphorylation and in vitro experiments showed that CKI can directly phosphorylate Dishevelled. To extend our studies we performed further experiments using additional CKI isoforms and found that many other isoforms can also reproduce markers of Wnt signaling. In summary, through a combination of gain-of-function and loss-of-function studies in invertebrates and vertebrates, we have shown that CKI is a novel and conserved component of the Wnt signaling pathway.

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