Disheveled blocks the degradation of beta-catenin in response to Wnt signal by interacting with the scaffolding protein, Axin. To define this interaction in detail we undertook a mutational and binding analysis of the murine Axin and Disheveled proteins. The DIX domain of Axin was found to be important for association with Disheveled and two other regions of Axin (between residues 1-168 and 600-810) were identified that can promote the association of Axin and Disheveled. We found that the DIX domain of Disheveled is critical for association with Axin in vivo and for Disheveled activity. The Disheveled DIX domain controlled the ability of Disheveled to induce the accumulation of cytosolic beta-catenin whereas the PDZ domain was not essential to this function.
"The Axin-RGS domain is primarily thought to recruit APC into the β-catenin degradation complex, , , , where APC is essential for β-catenin ubiquitylation and degradation. Axin constructs lacking the RGS domain (AxinΔRGS) are unable to stimulate β-catenin degradation and are either inactive or act as dominant-negative proteins . "
[Show abstract][Hide abstract] ABSTRACT: Axin is a critical component of the β-catenin destruction complex and is also necessary for Wnt signaling initiation at the level of co-receptor activation. Axin contains an RGS domain, which is similar to that of proteins that accelerate the GTPase activity of heterotrimeric Gα/Gna proteins and thereby limit the duration of active G-protein signaling. Although G-proteins are increasingly recognized as essential components of Wnt signaling, it has been unclear whether this domain of Axin might function in G-protein regulation. This study was performed to test the hypothesis that Axin RGS-Gna interactions would be required to attenuate Wnt signaling. We tested these ideas using an axin1 genetic mutant (masterblind) and antisense oligo knockdowns in developing zebrafish and Xenopus embryos. We generated a point mutation that is predicted to reduce Axin-Gna interaction and tested for the ability of the mutant forms to rescue Axin loss-of-function function. This Axin point mutation was deficient in binding to Gna proteins in vitro, and was unable to relocalize to the plasma membrane upon Gna overexpression. We found that the Axin point mutant construct failed to rescue normal anteroposterior neural patterning in masterblind mutant zebrafish, suggesting a requirement for G-protein interactions in this context. We also found that the same mutant was able to rescue deficiencies in maternal axin1 loss-of-function in Xenopus. These data suggest that maternal and zygotic Wnt signaling may differ in the extent of Axin regulation of G-protein signaling. We further report that expression of a membrane-localized Axin construct is sufficient to inhibit Wnt/β-catenin signaling and to promote Axin protein turnover.
PLoS ONE 09/2012; 7(9):e44096. DOI:10.1371/journal.pone.0044096 · 3.23 Impact Factor
"Dishevelled (Dsh) is the upstream regulator of the β-catenin pathway. At the C-terminal end, Axin can bind with Dsh and this interaction reduces β-catenin binding , , , . Recently, more evidence demonstrates that Axin is involved in many other signaling pathways, including mTOR14, JNK MAPK15, parathyroid hormone16, and p53 signaling , , . "
[Show abstract][Hide abstract] ABSTRACT: Axin1 and its homolog Axin2 are scaffold proteins essential for regulating Wnt signaling. Axin-dependent regulation of Wnt is important for various developmental processes and human diseases. However, the involvement of Axin1 and Axin2 in host defense and inflammation remains to be determined.
Here, we report that Axin1, but not Axin2, plays an essential role in host-pathogen interaction mediated by the Wnt pathway. Pathogenic Salmonella colonization greatly reduces the level of Axin1 in intestinal epithelial cells. This reduction is regulated at the posttranslational level in early onset of the bacterial infection. Further analysis reveals that the DIX domain and Ser614 of Axin1 are necessary for the Salmonella-mediated modulation through ubiquitination and SUMOylation.
Axin1 apparently has a preventive effect on bacterial invasiveness and inflammatory response during the early stages of infection. The results suggest a distinct biological function of Axin1 and Axin2 in infectious disease and intestinal inflammation while they are functionally equivalent in developmental settings.
PLoS ONE 04/2012; 7(4):e34942. DOI:10.1371/journal.pone.0034942 · 3.23 Impact Factor
"Upon Wnt signalling, Dishevelled prevents β-catenin degradation by interfering with the interaction of the Axin-APC-GSK3β complex and β-catenin [1,5-8]. This activity involves a direct interaction between Dishevelled and Axin  and leads to an accumulation of cytoplasmic β-catenin, which enters the nucleus and interacts with transcription factors of the LEF/TCF family, inducing the transcription of Wnt-target genes. "
[Show abstract][Hide abstract] ABSTRACT: The dishevelled and axin genes encode multi-domain proteins that play key roles in WNT signalling. Dishevelled prevents beta-catenin degradation by interfering with the interaction of beta-catenin with the degradation-mediating Axin-APC-GSK3beta complex. This interference leads to an accumulation of cytoplasmic beta-catenin, which enters the nucleus and interacts with transcription factors that induce expression of Wnt-target genes. Axin, as a component of the degradation-mediating complex, is a potent negative regulator of Wnt signalling, whereas Dishevelled is a potent activator. Both Dishevelled and Axin possess a DIX (Dishevelled/Axin) domain, which mediates protein-protein interactions, specifically homodimerization.
An evolutionary trace analysis of DIX domains identified conserved residues which, when mapped onto the crystal structure of the Axin DIX domain and a comparative model of the Dishevelled DIX domain, allow their categorization as residues of either structural or functional importance. We identify residues that are structural and functional determinants of the DIX domain fold, as well as those that are specific to homodimerization of Axin and Dishevelled.
This report provides the first explanation of the mutant phenotypes caused by non-synonymous substitutions in the Dishevelled and Axin DIX domain by correlating their presumed functional significance with molecular structure.
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