BackgroundThe Wnt signaling pathway is a prehistoric biological feature that has been conserved throughout evolution. It is known to play a crucial role in the embryonic development of all kinds of animal species; particularly in the regeneration of tissues in adult of these organisms amongst other many processes. It has also been recorded that mutations and/or deregulated expression of mechanisms of the Wnt pathway is liable to induce disease. And of most importance in the various diseases is cancer. About 25 years ago, the first gene that encodes a Wnt signaling component, Int1, was identified and characterized molecularly from mouse tumour cells. In contrast, the homologous gene Wingless in Drosophila melanogaster, which in known to produce developmental defects in embryos, was characterized. These two scientific breakthrough served as springboard leading to identification and illustration epistatic relationships of further components of the Wnt pathway. It is evident today that Wnt, Notch, Hedgehog, TGF? and a handful of other signaling systems are significant molecular machineries responsible for the control embryonic development. The functions of these signaling systems are beyond cell and tissue boundaries, acting as morphogens that are produced from one cell or tissue type to stimulate surface receptors, signal transduction mechanisms and transcription factors in adjacent cells or tissues, which regulate processes such as cell proliferation, differentiation or survival. As development progresses, the activity of such signaling systems is strongly regulated. In cancer and other diseases however, this regulatory activity could be escaped. In that regard, a signaling cascade supposed to regulate the proliferation, survival of cells might become an oncogene as it undergoes a gain-of-function mutation. Alternatively, an inhibitor might lose its ability to regulate signaling and lose its functions as a tumour suppressor. In either way, as seen in Wnt signaling pathway, are linked to cancer. Therefore, a great deal of effort has been invested globally in developing therapeutic agents that function to improve the Wnt pathway. In addition, a lot of discoveries with regards to Wnt research has covered the spectrum of model organisms, including worms, frogs, mice and even humans and therefore harnessing successful interdisciplinary research.This review is intended for the historical antecedents leading to crucial discoveries about the components and functions of this essential pathway. Special attaention shall be given to Beta?catenin, its identification as part of the wnt signaling pathway, how its overlapping interaction domains for various binding partners allow this signaling to occur, our current knowledge of the various mammalian developmental processes regulated by Beta?catenin and how these could be used for therapeutic purposesHistorical antecedents;In 1982, Roel Nusse and Harold Varmus, reported from the University of California, San Francisco, that a tumour virus induced mammary gland tumours in mice by stimulating the expression of a gene that was initially unknown. This gene, they named Int1. They also speculated that a mutation that causes a loss-of-function in the mouse had occurred, which influences an absence of anterior cerebellum (REF. 2)) this malformation was linked to a mutant allele of Int1 (REFs 3,4). A Drosophila melanogaster mutant without wings, Wingless (Wg), was pronounced in 1973 (REF. 5), with a fly gene which was a homologue of mammalian Int1 (REFs 6,7). The Wg mutation was also associated with segmentation defects in Drosophila embryos. Afterward, the developmental phenotypes were linked to alterations in components of the Wnt signaling pathway. In 1995, the findings on these Drosophila mutants was awarded the Nobel Prize in Physiology. Currently, the term Wnt is an amalgam of Wg and Int10. Pursuant to these findings however, there had been some earlier work on Wnt signaling, in ‘precloning’ times, during which the underlying mechanisms had not been discovered. In the 1930s, laboratory mice were used to establish that, viral insertion can promote mammary tumours (see REF. 11 for an example). Even before this discovery, Mangold and Spemann’s 1935’s Nobel Prize award experiment which was conducted in 1924 which illustrated that a protein which was later known as wnt which was transplanted in the tissue could induce a second body axis, a phenomenon referred to as twin-headed, in newts embryo 12, 13. Moreover in 1902, Morgan, illustrated that   lithium chloride can  also induced double axes in frog embryos through activation of a pathway that was later termed the Wnt signaling pathway14,15.The canonical wnt signaling pathwayAlmost a decade after the discovery of Int1, almost all successful research into the Wnt pathway was in the developmental field. In fact, a lot of the genes in the Wnt pathway, that were first discovered to function momentarily in development, turned out to be oncogenes and tumour suppressors when deregulated in human cancer. This fact was confirmed by studies conducted by Nüsslein-Volhard and Wieschaus’s genetic screen in the late 1970s and early 1980s8,9, using Drosophila mutants to display defects in embryonic segmentation similar to Wingless mutants. These were linked to mutations in armadillo (?-catenin in vertebrates), disheveled or porcupine genes.In addition, McMahon and Moon and several others have employed biochemical analyses demonstrate direct interactions between wnt pathway and ?-catenin. Particular to this is that ?-catenin, which is known to interact with the cell-adhesion molecule E-cadherin, are transported to the nucleus where it interact with the transcription factors lEF1 and TCF. This converts lEF1 into a transcriptional activator30–32. The foregoing finding was a breakthrough in elucidating the mechanism by which cytoplasmic Wnt signals confer alterations in gene expression in the nucleus. Conversely, regulators that oppose the Wnt pathway, produced a complete loss of the body axis36–38. Genetic analyses in mice has been used to illustrate that Axin1 or ?-catenin control axis formation36,39. It also is as well noteworthy that Costanini and collaborators’ analysis of the Axin1 mutation 36 was the classical mouse mutant Fused, described in 1949 40). This was subsequently recognized as part of the Wnt pathway. The identification and characterization of another negative regulator of the Wnt pathway. In all, the concluding statement goes to support that, the basic mechanism and the components of Wnt signaling are passed from one generation to another between invertebrates and vertebrates. This therefore suggests that the conservation within and among members of the Wnt pathway and their similar interactions in various organisms suggests that this pathway is paramount to human development and may be implicated in human disease. Dating from the mid-1990s, many more components of the Wnt signaling pathway have been discovered. The known components of the Wnt signaling pathway can be amassed as follows; secreted Wnt proteins bind to Frizzled receptors and lRP5–lRP6 co-receptors in the plasma membrane. Several inhibitors of this interaction were discovered at the end of the 1990s. For instance, during head formation, DKK1 antagonizes Wnt signaling in mice77. Apart from that, secreted proteins as those of Norrin and R-Spondin has also been shown to be activators of the canonical Wnt pathway. This comes about as a result of their interaction with Frizzled–lRP receptors79,80. In the mid-1990s, it was shown by the groups of Polakis, Nusse, Wieschaus and collaborators81–83 that the control of ?-catenin stability is critical in Wnt signaling. Consequently, in the absence of Wnt ligands, cytoplasmic ?-catenin is recruited into an obliteration complex, where it interacts with APC and the axins, and this is N-terminally phosphorylated by casein kinase 1? (CK1?) and GSK3?84?88. Right after phosphorylation, ?-catenin is targeted for proteasome-dependent degradation which involves interaction with ?-TrCP (?-transducin repeat-containing protein). 89–92 Thus, in the non-stimulated state, there is a down regulation of cytoplasmic ?-catenin levels and lEF and TCF in the nucleus interact with Grouchos to suppress Wnt-specific target genes93–95. Mutations which occur in genes that regulate ?-catenin stability, such as those that encode members of the destruction complex, or ?-catenin, are known to be significant in cancer progression. Once canonical Wnt ligands are available, lRP5–lRP6 is phosphorylated by CK1? and GSK3?96,97, and Dishevelled is translocated to the plasma membrane, where it cooperates with frizzled receptors and polymerizes with other Dishevelled molecules98,99. Phosphorylation of lRP5 or lRP6 as well as the formation of the Dishevelled polymer, as well as internalization with caveolin100, are used as mediators for the recruitment of axin to the plasma membrane and inactivation of the destruction complex. As soon as they are recruited into the nucleus, ?-catenin forms a transcriptionally active complex with lEF and TCF transcription factors30–32 through the displacement of Grouchos and interacting with other co-activators such as Pygopus, CBP and (CREB-binding protein)101–105. CBP and Hyrax control gene expression through chromatin remodelling and by influencing RNA polymerase II. The discovery of protooncogene MYC is a direct transcriptional target of Wnt–?-catenin signaling as the transforming activity in cancer in 1998 was a breakthrough106. It must however be mentioned that, the first direct ?-catenin target gene, lEF, in Drosophila had been identified by Bienz107. Canonical Wnt signaling in cancerBefore 1993, there had not been an overlap between research on Wnt signaling and human cancer. Then in the end of 1993, Vogelstein, Kinzler and Polakis first published an important biochemical interaction of the tumour suppressor, APC, and the Wnt pathway component ?-catenin 113,114. In that report, they explained; two types of repeat in APC are essential for interaction with ?-catenin, and they consist of three 15-amino-acid and seven 20-amino-acid repeats and these compete with E-cadherin for ?-catenin binding 115. The first clue to the molecular pathogenesis of adenomatous polyposis, a colon cancer, was the 1987 finding that familial adenomatous polyposis (FAP), is associated with deletions of the specific chromosome region 5q21–22 117,118. FAP is known to be associated with the development of hundreds to thousands of adenomatous polyps in the colon, some of which are able to develop into malignant carcinomas if surgical recessions are not performed. Two years down the line, that is in 1989, truncating mutations in APC were characterized in patients with FAP and/or frequent sporadic colorectal cancers; sporadic colorectal cancer is made of approximately 85% of human colorectal cancers119,120 (116). A high rate of APC mutations were frameshift, which resulted in truncations of about 50% of the APC protein 121. However, just a single APC mutation is insufficient to induce adenomatous polyposis, meaning a second mutation is always required. In fact, several APC mutations accumulate before the region that encodes the SAMP repeats regions regulating the interaction of APC with scaffold proteins of the ??catenin destruction complex 37,122. Following this, an APC mouse mutant with a truncation mutation after the region that encodes the first SAMP repeat would not develop tumours123. It was first reported in a rather narrow sampling that about 10% of sporadic colorectal cancers contain activating mutations in CTNNB1 128–130. But a more recent and more extensive mutational studies found that the frequency in sporadic colorectal cancers is somewhat closer to 1% 131. The study examined over 3,500 different human cancers to determine the occurrence of CTNNB1 mutations. The study recorded over 700 cases mutations that were predominantly centered in the N terminus of CTNNB1 121,133. These recorded mutations in the N terminus either caused the deletion of an N-terminal fragment or altered the N-terminal phosphorylation sites Ser45, Thr41, Ser37, Ser33. Exon 3 of Ctnnb conditional mutation deletion in mice, adenomatous polyposis or other cancers develop134. Consequently, the tumour-causing mutations in APC, AXIN1, AXIN2 and CTNNB1 generally will lead to inappropriate stabilization of ?-catenin. 135–137. Loss-of-function mutations can also occur in WTX, which encodes component of the ?-catenin destruction complex that was recently discovered 138,139. Moreover, uncontrolled Wnt–?-catenin signaling caused by elevated ?-catenin levels also induces aggressive fibromatosis and pulmonary fibrosis140,141. Of significant interest is the recent discovery that, activating LRP5 mutations are also known in thyroid tumours150. It therefore makes sense to predict that inappropriate activation of developmental signaling pathways that are responsible for and promote tumour progression. 

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