Physiological regulation of β-catenin stability by Tcf3 and CK1ϵ

Abstract

The wnt pathway regulates the steady state level of β-catenin, a transcriptional coactivator for the Tcf3/Lef1 family of DNA binding proteins. We demonstrate that Tcf3 can inhibit β-catenin turnover via its competition with axin and adenomatous polyposis for β-catenin binding. A mutant of β-catenin that cannot bind Tcf3 is degraded faster than the wild-type protein in Xenopus embryos and extracts. A fragment of β-catenin and a peptide encoding the NH2 terminus of Tcf4 that block the interaction between β-catenin and Tcf3 stimulate β-catenin degradation, indicating this interaction normally plays an important role in regulating β-catenin turnover. Tcf3 is a substrate for both glycogen synthase kinase (GSK) 3 and casein kinase (CK) 1ε, and phosphorylation of Tcf3 by CKIε stimulates its binding to β-catenin, an effect reversed by GSK3. Tcf3 synergizes with CK1ε to inhibit β-catenin degradation, whereas CKI-7, an inhibitor of CK1ε, reduces the inhibitory effect of Tcf3. Finally, we provide evidence that CK1ε stimulates the binding of dishevelled (dsh) to GSk3 binding protein (GBP) in extracts. Along with evidence that a significant amount of Tcf protein is nonnuclear, these findings suggest that CK1ε can modulate wnt signaling in vivo by regulating both the β-catenin-Tcf3 and the GBP-dsh interfaces.

Sox4 functions as a positive regulator of β-catenin signaling through upregulation of TCF4 during morular differentiation of endometrial carcinomas

“…Third, the TCF4 promoter was activated by transfection of Sox4, through a Sox-binding element located at À432 bp, as evidenced by inhibition of promoter activity by introducing a four-nucleotide alteration in the site, indicating regulation at the transcription level. Taken together with evidence that TCF3 can stabilize b-catenin protein through its competition with axin and APC, 36 our results suggest that transactivation of the TCF4 gene mediated by Sox4 may be the primary mechanism underlying activation of b-catenin/TCF4-driven transcription.…”

Wnt signaling through T-cell factor phosphorylation

“…Casein kinase 1ε (CK1ε) can phosphorylate TCF3 and enhance TCF-β-catenin complex formation, whereas GSK3β phosphorylates TCF3 to inhibit β-catenin-TCF3 interactions [81]. By contrast, casein kinase 1δ (CK1δ)-dependent phosphorylation has been reported to negatively influence LEF-1/β-catenin complex formation [82].…”

Wnt signalling and the mechanistic basis of tumour development

“…Firstly, Dishevelled is recruited (through an unknown mechanism) to the cell surface and phosphorylated by casein kinase Iε (CK Iε) [75]. The phosphorylated Dishevelled protein can form a complex with Frat1 and GSK3β which serves to inhibit the activity of GSK3β [75,76]. Secondly, the Wnt-Frizzled-LRP5/6 interaction facilitates the LRP5/6-mediated degradation of Axin [42].…”