Physiological regulation of ss-catenin stability by Tcf3 and CK1 epsilon

The wnt pathway regulates the steady state level of beta -catenin, a transc riptional coactivator for the Tcf3/Lef1 family of DNA binding proteins. We demonstrate that Tcf3 can inhibit beta -catenin turnover via its competitio n with axin and adenomatous polyposis for beta -catenin binding. A mutant o f beta -catenin that cannot bind Tcf3 is degraded faster than the wild-type protein in Xenopus embryos and extracts. A fragment of beta -catenin and a peptide encoding the NH2 terminus of Tcf4 that block the interaction betwe en beta -catenin and Tcf3 stimulate beta -catenin degradation, indicating t his interaction normally plays an important role in regulating beta -cateni n turnover. Tcf3 is a substrate for both glycogen synthase kinase (GSK) 3 a nd casein kinase (CK) 1 epsilon, and phosphorylation of Tcf3 by CK1 epsilon stimulates its binding to beta -catenin, an effect reversed by GSK3. Tcf3 synergizes with CK1 epsilon to inhibit beta -catenin degradation, whereas C K1-7, an inhibitor of CK1 epsilon, reduces the inhibitory effect of Tcf3. F inally, we provide evidence that CK1 epsilon stimulates the binding of dish evelled (dsh) to GSk3 binding protein (GBP) in extracts. Along with evidenc e that a significant amount of Tcf protein is nonnuclear, these findings su ggest that CK1 epsilon can modulate wnt signaling in vivo by regulating bot h the beta -catenin-Tcf3 and the GBP-dsh interfaces.