This continual elimination of β-catenin prevents β-catenin from reaching the nucleus, and Wnt target genes are thereby repressed by the DNA-bound T cell factor/lymphoid enhancer factor (TCF/LEF) family of proteins ( Figure 1a). CK1 and GSK3 sequentially phosphorylate the amino terminal region of β-catenin, resulting in β-catenin recognition by β-Trcp, an E3 ubiquitin ligase subunit, and subsequent β-catenin ubiquitination and proteasomal degradation ( He et al., 2004). In the absence of Wnt, cytoplasmic β-catenin protein is constantly degraded by the action of the Axin complex, which is composed of the scaffolding protein Axin, the tumor suppressor adenomatous polyposis coli gene product (APC), casein kinase 1 (CK1), and glycogen synthase kinase 3 (GSK3). The central logic of Wnt/β-catenin signaling has emerged from two decades of studies ( Figure 1). Wnt also activates a number of non-canonical signaling pathways that are independent of β-catenin and have been recently reviewed ( Seifert and Mlodzik, 2007 Wang and Nathans, 2007). For more comprehensive and historic perspective we refer readers to earlier reviews ( Clevers, 2006 Logan and Nusse, 2004) and the Wnt homepage ( The nematode Caenorhabditis elegans exhibits similar but also divergent Wnt/β-catenin pathways, which are covered elsewhere ( Mizumoto and Sawa, 2007) and in the accompanying review (Kimble 2009).
This review focuses on our current understanding of Wnt/β-catenin signaling, drawing mainly from genetic, developmental and biochemical analyses in Drosophila, Xenopus, mice and humans. A critical and most studied Wnt pathway is canonical Wnt signaling, which functions by regulating the amount of the transcriptional co-activator β-catenin that controls key developmental gene expression programs. As a result, mutations in the Wnt pathway are often linked to human birth defects, cancer and other diseases ( Clevers, 2006). Signaling by the Wnt family of secreted glycolipoproteins is one of the fundamental mechanisms that direct cell proliferation, cell polarity and cell fate determination during embryonic development and tissue homeostasis ( Logan and Nusse, 2004).