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Review
. 2006 Jun;7(1-2):41-9.
doi: 10.1007/s11154-006-9003-3.

Diseases of Wnt signaling

Mark L Johnson  1 , Nalini Rajamannan
Affiliations
Review

Diseases of Wnt signaling

Mark L Johnson et al. Rev Endocr Metab Disord. 2006 Jun.

Erratum in

  • Rev Endocr Metab Disord. 2007 Jun;8(2):183

Abstract

The Wnt signaling pathways play fundamental roles in the differentiation, proliferation, death and function of many cells and as a result are involved in critical developmental, growth and homeostatic processes in animals. There are four currently known pathways of Wnt signaling; the so-called canonical or Wnt/beta-catenin pathway, the Wnt/Ca(+2) pathway involving Protein Kinase A, the planar cell polarity pathway and a pathway involving Protein Kinase C that functions in muscle myogenesis. The best studied of these is the Wnt/beta-catenin pathway. The Wnts are an evolutionarily highly conserved family of genes/proteins. Control of the Wnt pathways is modulated by a number of the proteins that either interact with the Wnt ligands directly, or with the low density lipoprotein-receptor related proteins (LRP) 5 and 6 that along with one of several Frizzled proteins function as co-receptors for the Wnt ligands. Aberrant regulation resulting as a consequence of mutations in any of several components of the Wnt pathway and/or protein modulators of the pathway have been shown to cause a wide spectrum of diseases. This review will briefly touch on various diseases of Wnt signaling including cancer, aortic valve calcification and several bone related phenotypes. Our emerging understanding of Wnt signaling offers great hope that new molecular based screening tests and pharmaceutical agents that selectively target this pathway will be developed to diagnose and treat these diseases in the future.

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Figures

Fig. 1
Fig. 1
The Wnt/β-catenin signaling pathway. Wnt binds to the Lrp5 or 6 and Frizzled coreceptor complex which leads to the intracellular accumulation of β-catenin. β-catenin translocates to the nucleus where it binds to TCF/Lef transcription factors and regulates the expression of a number of target genes. Mutations in several components of the pathway have been shown to result in disease. Mutations in LRP5 can result in diseases of increased or decreased bone mass and vision problems. The Lrp5 receptor and Wnt pathway may also play a key role in aortic valve calcification. Mutations in APC, β-catenin and Axin have been shown to give rise to a number of different types of cancer. Downstream gene targets of β-catenin such as osteoprotegerin (OPG) and the secreted frizzled related proteins (sFRPs) are known to regulate osteoclastogenesis and may play a role in metastatic bone diseases that result in osteolytic lesions. Mutations in modulators of Wnt signaling such as the SOST gene, which produces sclerostin, give rise to the increased bone mass disease, sclerosteosis. These are just a few examples of the variety of diseases that have been attributed to the Wnt/β-catenin signaling pathway.
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