Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13122 Berlin
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INTRODUCTION |
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Intracellularly, Wnt signalling leads to stabilisation of cytosolic ß-catenin. In the absence of Wnts, ß-catenin is phosphorylated by glycogen synthase kinase 3ß (GSK3ß), which triggers ubiquitination of ß-catenin by ßTrCP and degradation in proteasomes. Phosphorylation of ß-catenin occurs in a multiprotein complex assembled by the scaffolding protein axin or conductin. In the presence of Wnts, dishevelled (dsh) blocks ß-catenin degradation, possibly by recruiting the GSK3ß inhibitor GBP to the complex. In certain tumors, mutation of axin, ß-catenin or the tumor suppressor APC also lead to stabilisation of ß-catenin. ß-catenin degradation is modulated by the casein kinase CK1 and by the protein phosphatases PP2A and PP2C.
Stabilised ß-catenin enters the cell nucleus and associates with TCF transcription factors, which leads to the transcription of Wnt-target genes. Smad4, Tsh, XSox17 and the histone acetyl transferase CBP modulate target gene expression. When ß-catenin is absent, certain TCFs repress transcription by interacting with the co-repressors groucho and CtBP. Phosphorylation of TCFs by a MAP-kinase pathway involving TAK1 and NLK negatively regulates Wnt signalling. ß-catenin also binds to cadherin cell adhesion molecules and provides a link to the actin cytoskeleton.
Data for the Wnt pathway have been obtained from a variety of systems and organisms. Related genes and alternative names follow: Wnt/Wingless; GBP/frat1; axin/conductin; GSK3ß/Zeste-white3/Shaggy; ßTrCP/Slimb/FWD1; TCF/LEF; CBP/p300.
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