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Published online 27 August 2001. doi:10.1083/jcb.200102074
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© The Rockefeller University Press, 0021-9525/2001/9/983 $5.00
The Journal of Cell Biology, Volume 154, Number 5, September 3, 2001 983-994

Article

 Physiological regulation of ß-catenin stability by Tcf3 and CK1{epsilon}

Ethan Lee, Adrian Salic and Marc W. Kirschner

Department of Cell Biology, Harvard Medical School, Boston, MA 02115

Address correspondence to Marc W. Kirschner, Dept. of Cell Biology, Harvard Medical School, 240 Longwood Ave., C1-517, Boston, MA 02115. Tel.: (617) 432-2250. Fax: (617) 432-0420. E-mail: marc{at}hms.harvard.edu

The wnt pathway regulates the steady state level of ß-catenin, a transcriptional coactivator for the Tcf3/Lef1 family of DNA binding proteins. We demonstrate that Tcf3 can inhibit ß-catenin turnover via its competition with axin and adenomatous polyposis for ß-catenin binding. A mutant of ß-catenin that cannot bind Tcf3 is degraded faster than the wild-type protein in Xenopus embryos and extracts. A fragment of ß-catenin and a peptide encoding the NH2 terminus of Tcf4 that block the interaction between ß-catenin and Tcf3 stimulate ß-catenin degradation, indicating this interaction normally plays an important role in regulating ß-catenin turnover. Tcf3 is a substrate for both glycogen synthase kinase (GSK) 3 and casein kinase (CK) 1{epsilon}, and phosphorylation of Tcf3 by CKI{epsilon} stimulates its binding to ß-catenin, an effect reversed by GSK3. Tcf3 synergizes with CK1{epsilon} to inhibit ß-catenin degradation, whereas CKI-7, an inhibitor of CK1{epsilon}, reduces the inhibitory effect of Tcf3. Finally, we provide evidence that CK1{epsilon} 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 CK1{epsilon} can modulate wnt signaling in vivo by regulating both the ß-catenin-Tcf3 and the GBP-dsh interfaces.

Key Words: ß-catenin; Tcf; wnt; casein kinase; Xenopus


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