You Wnt some, you lose some: oncogenes in the Wnt signaling pathway
Introduction
The development of a complex multicellular organism from a fertilized egg is tightly controlled in space and time by a complex and sophisticated interplay of signaling pathways. This is particularly true for signaling pathways in which secreted factors, such as members of the Hedgehog, TGF-β and Wnt families, are involved. It is of crucial importance that these signaling pathways are regulated at multiple levels. Indeed, breakdown of this regulation, leading to inappropriate activation of the signaling pathways, has been implicated in cancer. The highly conserved Wnt proteins, which drive the Wnt signaling pathway, determine many important cell-fate decisions throughout development by controlling gene expression, cell behavior, cell adhesion and cell polarity. In this review we look at recent developments regarding the role of the three (putative) oncogenes Wnt, β-catenin and Legless/Bcl9 in the Wnt signaling pathway (Figure 1).
Section snippets
The Wnt signaling pathway
The binding of a particular secreted Wnt ligand to its corresponding receptor, a member of the Frizzled (Frz) family, activates the highly conserved Wnt signaling pathway [1] (Figure 1). Depending on the specific Wnt/Frz signal received, the downstream Wnt pathway subsequently diversifies into at least three branches, which crossregulate one another as well as interacting with other signaling networks 1., 2., 3., 4..
Three pathways are activated by Wnt: the Wnt/Ca2+ pathway, the planar cell
The canonical Wnt pathway: a brief overview
The Wnt canonical pathway regulates, through a core set of evolutionarily highly conserved proteins, the ability of the multi-functional protein and proto-oncogene β-catenin to activate the transcription of specific target genes [1]. In the absence of Wnt signals, free cytoplasmic β-catenin is actively targeted for degradation. This destruction is triggered by the phosphorylation of β-catenin at its amino terminus following its association with a multiprotein complex containing, amongst other
The prototypical oncogene Wnt: receptor regulation
Members of the Wnt family have distinct biological roles. The first-identified Wnt gene, mouse Wnt1, was pinpointed by virtue of its ability to induce mammary tumors when expressed ectopically in mice [30]. Since then, numerous Wnt genes have been identified. In particular, Wnts have been implicated in the abnormal proliferation of human breast tissue. The mechanism of action of these various Wnt genes, and the way in which they are regulated, is complex. Several membrane-associated proteins
The oncogene β-catenin: regulation
The serine/threonine kinase GSK3β binds to and phosphorylates several proteins involved in the Wnt pathway and is instrumental in the down-regulation of β-catenin, which it achieves by earmarking this protein for degradation by β-Trcp. The importance of the phosphorylation of β-catenin in controlling degradation is further underscored by the observation that the target phosphorylation sites (Ser45, Thr41, Ser37 and Ser33) are frequently mutated in human colorectal cancer, melanomas and several
The putative oncogene Legless: activation of Wnt target genes
It is well established that the formation of a β-catenin/TCF complex in combination with other factors — which include the CBP/p300 acetyltransferase, the TATA binding protein, DNA helicase Pontin52 and/or Brg-1 — is a prerequisite for the efficient activation of target genes. However, its mechanism of action remains poorly understood [45].
Two novel nuclear components of the β-catenin/TCF complex have recently been identified. Epistasis analysis of the β-catenin binding protein Legless in
Conclusions
The Wnt signaling cascade plays a decisive role in development, and deregulation causes cancer. Ongoing studies in this exciting field are revealing additional players in the Wnt pathway and are highlighting the complex and multifaceted nature of known participants. Although it is apparent that our knowledge of this pathway is increasing rapidly, many questions regarding regulation, specificity, and interactions with other signaling cascades require answering. The results will undoubtedly
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
We apologize to all researchers whose work we could not cite due to strict space constraints. We would like to thank ME van Gijn for helpful comments on the manuscript.
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