Wnt Signaling Controls the Phosphorylation Status of β-Catenin*

By M. van Noort, J. Meeldijk, R. van der Zee, O. Destrée, Hans Clevers. Journal of Biological Chemistry, 2002

507 citations recorded by the source corpus.

At the heart of the canonical Wnt signaling cascade, adenomatous polyposis coli (APC), axin, and GSK3 constitute the so-called destruction complex, which controls the stability of β-catenin. It is generally believed that four conserved Ser/Thr residues in the N terminus of β-catenin are the pivotal targets for the constitutively active serine kinase GSK3. In cells that do not receive Wnt signals, glycogen synthase kinase (GSK) is presumed to phosphorylate β-catenin, thus marking the latter for proteasomal degradation. Wnt signaling inhibits GSK3 activity. As a consequence, β-catenin would no longer be phosphorylated and accumulate to form nuclear complexes with TCF/LEF factors. Although mutations in or near the N-terminal Ser/Thr residues stabilize β-catenin in several types of cancer, the hypothesis that Wnt signaling controls phosphorylation of these residues remains unproven. We have generated a monoclonal antibody that recognizes an epitope containing two of the four residues when both are not phosphorylated. The epitope is generated upon Wnt signaling as well as upon pharmacological inhibition of GSK3 by lithium, providing formal proof for the regulated phosphorylation of the Ser/Thr residues of β-catenin by Wnt signaling. Immunohistochemical analysis of mouse embryos utilizing the antibody visualizes sites that transduce Wnt signals through the canonical Wnt cascade.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/95c74beb535276712f4f4e83dce7cab42a39d81a

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In Molecular Biology

1. Hans Clevers
2. E. Batlle
3. C. Gottardi
4. R. Daugherty
5. B. Doble
6. J. Woodgett
7. R. Nusse
8. Elaine Fuchs

Citations in the corpus

• Phospho-regulation of β-Catenin Adhesion and Signaling Functions (2007, background): “Although there is currently no molecular explanation for the superior signaling activity of NH2 terminally unphosphorylated β-catenin, some studies observe that NH2 terminally unphosphorylated β-catenin accumulates more readily in nuclei (36,69,76), suggesting that phosphorylation of β-catenin at re”
• GSK-3: tricks of the trade for a multi-tasking kinase (2003, background): “As a result, β-catenin is dephosphorylated (van Noort et al., 2002) and escapes the ubiquitylation-dependent destruction machinery.”
• Loss of Apc in vivo immediately perturbs Wnt signaling, differentiation, and migration. (2004, methodology): “Immunohistochemistry was performed according to Batlle et al. (2002), Kongkanuntn et al. (1999), and Van Noort et al. (2002); Western analysis was performed according to Hinck et al. (1994) and Van Noort et al. (2002).”