DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate beta-catenin stability

Department of Biochemistry, Hiroshima University School of Medicine, Minami-ku, Hiroshima 734-8551, Japan.
Molecular and Cellular Biology (Impact Factor: 4.78). 07/1999; 19(6):4414-22. DOI: 10.1128/MCB.19.6.4414
Source: PubMed


The N-terminal region of Dvl-1 (a mammalian Dishevelled homolog) shares 37% identity with the C-terminal region of Axin, and this related region is named the DIX domain. The functions of the DIX domains of Dvl-1 and Axin were investigated. By yeast two-hybrid screening, the DIX domain of Dvl-1 was found to interact with Dvl-3, a second mammalian Dishevelled relative. The DIX domains of Dvl-1 and Dvl-3 directly bound one another. Furthermore, Dvl-1 formed a homo-oligomer. Axin also formed a homo-oligomer, and its DIX domain was necessary. The N-terminal region of Dvl-1, including its DIX domain, bound to Axin directly. Dvl-1 inhibited Axin-promoted glycogen synthase kinase 3beta-dependent phosphorylation of beta-catenin, and the DIX domain of Dvl-1 was required for this inhibitory activity. Expression of Dvl-1 in L cells induced the nuclear accumulation of beta-catenin, and deletion of the DIX domain abolished this activity. Although expression of Axin in SW480 cells caused the degradation of beta-catenin and reduced the cell growth rate, expression of an Axin mutant that lacks the DIX domain did not affect the level of beta-catenin or the growth rate. These results indicate that the DIX domains of Dvl-1 and Axin are important for protein-protein interactions and that they are necessary for the ability of Dvl-1 and Axin to regulate the stability of beta-catenin.

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    • "There is abundant evidence that the functional destruction complex is a multimer of the individual destruction complex proteins. One important underpinning of this idea is that Axin oligimerizes via self-polymerization of the DIX domain, and this multimerization is critical for its Wnt regulatory function (Kishida et al., 1999; Schwarz-Romond et al., 2007). Endogenous Axin forms small puncta in cultured cells and when overexpressed these puncta become more prominent, in a DIX-domain dependent fashion (Fagotto et al., 1999; Faux et al., 2008; Figure 1—figure supplement 1A). "
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    ABSTRACT: APC, a key negative regulator of Wnt signaling in development and oncogenesis, acts in the destruction complex with the scaffold Axin and the kinases GSK3 and CK1 to target βcatenin for destruction. Despite 20 years of research, APC's mechanistic function remains mysterious. We used FRAP, super-resolution microscopy, functional tests in mammalian cells and flies, and other approaches to define APC's mechanistic role in the active destruction complex when Wnt signaling is off. Our data suggest APC plays two roles: (1) APC promotes efficient Axin multimerization through one known and one novel APC:Axin interaction site, and (2) GSK3 acts through APC motifs R2 and B to regulate APC:Axin interactions, promoting high-throughput of βcatenin to destruction. We propose a new dynamic model of how the destruction complex regulates Wnt signaling and how this goes wrong in cancer, providing insights into how this multiprotein signaling complex is assembled and functions via multivalent interactions. DOI:
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.08022 · 9.32 Impact Factor
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    • "Further investigation identified that the DIX and PDZ domain of Dvl was required for Lrp6 phosphorylation. PDZ interacts with Frz, whereas DIX interacts with Axin (Kishida et al., 1999; Wong et al., 2003; Zeng et al., 2008). This suggests a sequence of events: Wnt ligand interacts with Frz and Lrp6, then Frz recruits Dvl to the membrane, which in turn, recruits Axin and its associated proteins such as GSK3β to the Wnt signaling complex or Wnt signalosome. "
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    01/2014, Degree: Masters of Science, Supervisor: Dr. Terry Van Raay
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    • "The interaction of Dsh with Fz is known to be important for planar-cell polarity (reviewed in Seifert and Mlodzik, 2007), a non-canonical Wnt signaling process. Since Dsh also binds to Axin (Kishida et al., 1999; Smalley et al., 1999), Dsh-Fz interaction may facilitate recruitment of Axin to the Arrow/LRP cytosolic domain. This Axin movement could be a crucial event in pathway activation (Cliffe et al., 2003; Lee et al., 2003). "
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