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Wnt/β-Catenin Pathway

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Science's STKE  15 Feb 2005:
Vol. 2005, Issue 271, pp. cm1
DOI: 10.1126/stke.2712005cm1

Abstract

Wnts are secreted glycoproteins that act as ligands to stimulate receptor-mediated signal transduction pathways in both vertebrates and invertebrates. Activation of Wnt pathways can modulate cell proliferation, survival, cell behavior, and cell fate in both embryos and adults. The Wnt/β-catenin pathway is the best understood Wnt signaling pathway, and its core components are highly conserved during evolution, although tissue-specific or species-specific modifiers of the pathway are likely. In the absence of a Wnt signal, cytoplasmic β-catenin is phosphorylated and degraded in a complex of proteins. Wnt signaling through the Frizzled serpentine receptor and low-density lipoprotein receptor-related protein-5 or -6 (LRP5 or 6) coreceptors activates the cytoplasmic phosphoprotein Dishevelled, which blocks the degradation of β-catenin. As the amount of β-catenin rises, it accumulates in the nucleus, where it interacts with specific transcription factors, leading to regulation of target genes. Inappropriate activation of the pathway in response to mutations is linked to a wide range of cancers, including colorectal cancer and melanoma. The pathway is linked to bone density syndromes and to neurodegenerative diseases, and the pathway may also be involved in the retinal disease familial exudative vitreoretinopathy.

Description

This record contains general information about the Wnt/β-catenin Pathway collected across species.

Wnts are secreted glycoproteins that act as ligands to stimulate receptor-mediated signal transduction pathways in both vertebrates and invertebrates. Activation of Wnt pathways can modulate cell proliferation, survival, cell behavior, and cell fate. Wnt signaling pathways often work in a combinatorial manner with other pathways, including the fibroblast growth factor (FGF) and transforming growth factor β (TGF-β) pathways. The Wnt/β-catenin pathway is the best understood Wnt signaling pathway, and is highly conserved during evolution, although other Wnt signaling pathways exist. Despite this conservation, the pathway described here (Fig. 1) has some elements that have been observed only in some species, so the reader is referred to the specific pathways to understand how the pathway is known to operate in a specific organism and context (see Table 1 for specific pathways available in the Connections Maps database).

Fig. 1.

Pathway image captured from the dynamic graphical display of the information in the Connections Maps available 21 January 2005. For a key to the colors and symbols and to access the underlying data, please visit the pathway (About Connections Map). The image has been scaled to fit on a single printed page; however, readability may be best achieved by opening the file with Adobe Acrobat Reader and zooming in to enlarge to the image.

Table 1.

Specific examples of the Wnt/β-catenin pathway in the Connections Maps database. These specific pathways are based on the canonical Wnt/β-Catenin Pathway.

In the absence of Wnt signaling, a cytoplasmic degradation complex [consisting of at least axin, adenomatous polyposis coli (APC) protein, glycogen synthase kinase 3 (GSK-3), and β-catenin] leads to the phosphorylation of APC, β-catenin, and axin by GSK-3. This promotes interaction of β-catenin with β-transducin-repeat–containing protein (β-TrCP), leading to the ubiquitination of β-catenin and its degradation by the proteasome. Thus, at steady state in the absence of Wnt signaling, β-catenin is rapidly degraded in the cytoplasm. In addition, nuclear levels of β-catenin are kept low by its interaction with APC and axin, both of which exist in the nucleus and have a nuclear export activity that shuttles β-catenin back to the cytoplasm. An oversimplified animated rendition of the cytoplasmic degradation process and how it is modulated by Wnt signaling is linked to the Connections Map, and information for use of this animation in teaching in also available (see the Teaching Resource below).

To activate the pathway, secreted Wnts are thought to interact with serpentine receptors encoded by the Frizzled gene family and with coreceptors such as low-density lipoprotein receptor-related protein-5 and -6 (LRP5 and 6). The Wnt-Frizzled interaction is enhanced by some proteoglycans, such as the glypican-related protein Dally, and it is antagonized by several secreted proteins, including Dickkopf and secreted frizzled-related protein (sFRP) family members. Activation of Frizzled homologs by Wnt ligands leads to activation of the modular protein Dishevelled, through a process likely involving heterotrimeric guanine nucleotide-binding proteins (G proteins) and the phosphorylation of Dishevelled. LRP5 or LRP6 may also activate the pathway in response to Wnts, although this mechanism is less clear. In response to activation of Frizzled, Dishevelled has been reported to interact directly with Frizzled and then function through binding components of the degradation complex to reduce the function of GSK-3. This in turn reduces the phosphorylation and degradation of β-catenin, generally leading to its accumulation in the nucleus. In the nucleus, before Wnt signaling, lymphoid-enhancing factor (LEF) and T cell factor (TCF) homologs (collectively known as TCF/LEF) bind to DNA with sequence specificity in promoter and enhancer regions of target genes, and along with Groucho and C-terminal binding protein (CtBP), often repress gene expression. Elevation of β-catenin levels by Wnt signaling leads to binding of β-catenin to TCF /LEF, promoting changes in the transcriptional machinery that lead to activation of target genes. Constitutive activation of the Wnt/β-catenin pathway has been observed in transformed cells due to inactivating mutations in APC and axin that reduce β-catenin degradation, and to mutations in the GSK-3 phosphorylation sites of β-catenin that render it stable. In addition to the involvement of this pathway in cancers, it is also implicated in neurodegenerative diseases, regulation of bone density, osteoarthritis, and regulation of survival and proliferation of stem cells. Additional information regarding the pathway, including amino acid sequence alignments, can be accessed at the Wnt homepage (http://www.stanford.edu/~rnusse/wntwindow.html).

There are several methods for manipulating and exploring the function of the Wnt pathway. The preferred mechanism for activating the pathway is to use purified Wnt (available commercially) or, at least, Wnt-conditioned media. The pathway can be activated downstream of the ligand by treating cells with GSK-3 inhibitors (available commercially) or by expression of activated forms of β-catenin that have been mutated so that they cannot be phosphorylated by GSK-3, and therefore are not readily degraded. Both c-myc epitope-tagged and green fluorescent protein (GFP)-tagged forms of β-catenin are available for such experiments. In most systems, gain-of-function of β-catenin completely mimics stimulation of the pathway by ligand-bound receptor. Evidence that the pathway has indeed been activated can be obtained using luciferase reporter assays in cultured cells, and monitoring GFP or β-galactosidase expression in fish or mice transgenic for Wnt-responsive reporters. Loss-of-function of the Wnt pathway can be achieved by expression of axin or of TCF/LEF homologs from which the N-terminal β-catenin binding site has been removed. These mutant TCF/LEF proteins bind to target genes of this pathway and constitutively repress the genes in a manner that cannot be overcome by elevation of β-catenin levels. Blocking the pathway can also be achieved by expression of secreted antagonists of the pathway, such as Dickkopf1 (Dkk1). Finally, effective RNA interference (RNAi) sequences have been published, some of which are available commercially. In general, it is prudent to pursue both gain-of-function and loss-of-function through at least two independent mechanisms to control for a variety of potential variables.

Pathway Details

URL: About Connections Map

Scope: Canonical

Related Resources

Teaching Resources

R. T. Moon, β-catenin signaling and axis specification. Sci. STKE 2004, tr6(2004). [Abstract] [Resource Details]

References

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