Wnt/β-Catenin Signaling Induces the Expression and Activity of βTrCP Ubiquitin Ligase Receptor

Abstract

Beta-transducing repeat-containing protein (betaTrCP) targets the ubiquitination and subsequent degradation of both beta-catenin and IkappaB, thereby playing an important role in beta-catenin/Tcf and NF-kappaB-dependent signaling. Here evidence is presented that beta-catenin/Tcf signaling elevates the expression of betaTrCP mRNA and protein in a Tcf-dependent manner, which does not require betaTrCP transcription. Induction of betaTrCP expression by the beta-catenin/Tcf pathway results in an accelerated degradation of the wild-type beta-catenin, suggesting that the negative feedback loop regulation may control the beta-catenin/Tcf pathway. This signaling also upregulated NF-kappaB transactivation without affecting the activity of IkappaB kinase, thereby establishing that the maintenance of the betaTrCP level is important for coordination between beta-catenin/Tcf and NF-kappaB signaling.

Inhibition of HOS expression and activities by Wnt pathway

“…This result is in agreement with our previous observations (Spiegelman et al, 2000). When the same Northern blot membrane was re-hybridized with HOS-speci®c probe, we observed a 4 ± 5-fold decrease in the levels of HOS message in the cells with activated Wnt/b-catenin signaling pathway (Figure 1a, middle panel).…”

“…We have recently found that the endogenous levels of bTrCP can be up regulated in some cells by the activation of the Wnt/b-catenin/Tcf signaling pathway, resulting in the activation of NF-kB-dependent transcription (Spiegelman et al, 2000). Since the pro®les of bTrCP and HOS expression may di er between various tissues and cell lines (Saitoh and Katoh, 2001;Spiegelman et al, 2001), in this study, we investigated the e ect of the Wnt/b-catenin signaling on the expression and activities of HOS.…”

FGF-20 and DKK1 are transcriptional targets of β-catenin and FGF-20 is implicated in cancer and development

“…For instance, Conductin/Axin2, which binds to b-catenin and induces its degradation, has been shown to be a direct transcriptional target of b-catenin/TCF (Jho et al, 2002;Leung et al, 2002). The ubiquitin receptor ligase, b-TrCP, which is involved in targeting b-catenin to proteosomes, is also activated by Wnt/b-catenin signaling (Spiegelman et al, 2000). In addition, Wingless, the Wnt-1 ortholog in Drosophila, induces the direct expression of naked cuticle, which inhibits Dishevelled and blocks further signaling (Rousset et al, 2001).…”

Wnt Signaling in Vertebrate Axis Specification

“…The b-transducin repeat-containing protein (bTrCP) is an E3 ubiquitin ligase that represents a nodal point for down-regulation of b-catenin, Gli, and NF-kB levels (Liu et al 1999a;Maniatis 1999). As Wnt signaling has been shown to up-regulate bTrCP activity in a negative-feedback loop (Spiegelman et al 2000), the effect on the Hh and NF-kB signaling may be expected. Also, the Wnt pathway negatively regulates the activity of GSK3 (Cook et al 1996;Itoh et al 1998b;Taelman et al 2010), an enzyme that has been implicated in the regulation (e.g., degradation) of a large number of proteins, in addition to b-catenin (Zhou et al 2004;Xu et al 2009).…”