Table S1 from Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy
Laura HinzeRoxane LabrosseJames DegarTeng HanEmma M. SchatoffSabine SchreekSalmaan KarimConnor McGuckinJoshua R. SacherFlorence F. WagnerMartin StanullaChen YuanEwa SicińskaMarios GiannakisKimmie NgLukas E. DowAlejandro Gutiérrez
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Cancer Therapy
In the canonical Wnt signaling pathway, Wnts cause stabilization of β-catenin and consequent changes in gene expression. But not all Wnts appear to signal in this way. Developmental actions of Wnt-5, for example, appear not to be mediated by β-catenin, and now two papers show that Wnt-5 actually antagonizes canonical Wnt signaling. Westfall et al. explored developmental roles of WNt-5 in zebrafish. The dorsalization defects they observed when expression of maternal and zygotic Wnt-5 was removed were similar to effects of activation of canonical Wnt-β-catenin signaling and were associated with accumulation of β-catenin. Loss of Wnt-5 caused decreased Ca 2+ release, and overexpression of Ca 2+ -calmodulin-dependent protein kinase II partially rescued the effects of Wnt-5 mutation. Thus, the authors conclude that Wnt-5 actually antagonizes the effects of canonical Wnts, possibly by a Ca 2+ -mediated signal. Topol et al. offer an alternative mechanism. In cultured mammalian 293 cells and in a human colon cancer cell line, ectopic expression of Wnt-5a antagonized canonical Wnt signaling and caused degradation of β-catenin. Their analysis, however, indicated that Wnt-5's effects were largely independent of Ca 2+ -mediated signals. Rather, they propose that Wnt-5a may increase expression of Siah2, a component of the proteasome, which mediates degradation of β-catenin. In 293 cells, dominant-negative Siah2 reduced the effects of Wnt-5a on β-catenin signaling, and ectopic expression of Wnt-5a increased expression of Siah2. In Wnt-5a knockout mice, β-catenin also accumulated in the distal limb bud during development. Thus, in limb buds lacking Wnt-5a, unchecked canonical Wnt signaling may cause developmental abnormalities. Consistent with this idea, chondorgenesis is inhibited in Wnt5a –/– limbs, but was partially rescued by grafted chick embryonic fibroblast cells engineered to express a secreted antagonist of Wnt signaling. Both groups agree that proper development appears to require a balance of opposing Wnt signals and that disruption of that balance could contribute to abnormal canonical Wnt signaling, which is implicated in formation of some human cancers. T. A. Westfall, R. Brimeyer, J. Twedt, J. Gladon, A. Olberding, M. Furutani-Seiki, D. C. Slusarski, Wnt-5/pipetail functions in vertebrate axis formation as a negative regulator of Wnt/β-catenin activity. J. Cell Biol. 162 , 889-898 (2003). [Abstract] [Full Text] L. Topol, X. Jiang, H. Choi, L. Garrett-Beal, P. J. Carolan, Y. Yang, Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent β-catenin degradation. J. Cell Biol. 162 , 899-908 (2003). [Abstract] [Full Text]
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Beta-catenin
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WNT3A
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Wnt signaling is involved in many aspects of development and in the homeostasis of stem cells. Its importance is underscored by the fact that misregulation of Wnt signaling has been implicated in numerous diseases, especially colorectal cancer. However, how Wnt signaling regulates itself is not well understood. There are several Wnt negative feedback regulators, which are active antagonists of Wnt signaling, but one feedback regulator, Nkd1, has reduced activity compared to other antagonists, yet is still a negative feedback regulator. Here we describe our efforts to understand the role of Nkd1 using Wnt signaling compromised zebrafish mutant lines. In several of these lines, Nkd1 function was not any more active than it was in wild type embryos. However, we found that Nkd1's ability to antagonize canonical Wnt/β-catenin signaling was enhanced in the Wnt/Planar Cell Polarity mutants silberblick (slb/wnt11) and trilobite (tri/vangl2). While slb and tri mutants do not display alterations in canonical Wnt signaling, we found that they are hypersensitive to it. Overexpression of the canonical Wnt/β-catenin ligand Wnt8a in slb or tri mutants resulted in dorsalized embryos, with tri mutants being much more sensitive to Wnt8a than slb mutants. Furthermore, the hyperdorsalization caused by Wnt8a in tri could be rescued by Nkd1. These results suggest that Nkd1 functions as a passive antagonist of Wnt signaling, functioning only when homeostatic levels of Wnt signaling have been breached or when Wnt signaling becomes destabilized.
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The Wnt/β signaling pathway (Wnt-SP) is a phylogenetically ancient mechanism that regulates development and maintains tissue homeostasis through the control of cell proliferation, differentiation, migration, and apoptosis. The accurate regulation of the canonical Wnt/β-catenin signaling pathway (Wnt-SP) is critical for embryogenesis and postnatal development; and impaired signal transduction at one of its stages leads to various diseases, including organ malformations, cancers, metabolic and neurodegenerative disorders. The literature review discusses the biological role of the canonical Wnt-SP in the development of the skeleton and in the remodeling of bone tissue. The Wnt signal transmission changes observed during genetic mutations cause various human skeletal diseases. Understanding the functional mechanism involved in the development of bone abnormality could open new horizons in the treatment of osteoporosis, by affecting the Wnt-SP. The design of antibodies to sclerostin, a Wnt-SP inhibitor, is most promising now. The paper summarizes the studies that have investigated the canonical Wnt-SP and designed drugs to treat osteoporosis.
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Sclerostin
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Wnt signaling is a major and highly conserved developmental pathway that guides many important events during embryonic and larval development. In adulthood, misregulation of Wnt signaling has been implicated in tumorigenesis and various age-related diseases. These effects occur through highly complicated cell-to-cell interactions mediated by multiple Wnt-secreted proteins. While they share a high degree of sequence similarity, their function is highly diversified. Although the role of Wnt ligands during development is well studied, very little is known about the possible actions of Wnt signaling in natural aging. In this study, Caenorhabditis elegans serves, for the first time, as a model system to determine the role of Wnt ligands in aging. Caenorhabditis elegans has five Wnt proteins, mom-2, egl-20, lin-44, cwn-1, and cwn-2. We show that all five Wnt ligands are expressed and active past the development stages. The ligand mom-2/Wnt plays a major detrimental role in longevity, whereas the function of lin-44/Wnt is beneficial for long life. Interestingly, no evidence was found for Wnt signaling being involved in cellular or oxidative stress responses during aging. Our results suggest that Wnt signaling regulates aging-intrinsic genetic pathways, opening a new research direction on the role of Wnt signaling in aging and age-related diseases.
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表明小径的 Wnt 在胚胎的开发期间起关键作用，其错误在许多人的癌症被含有。Axin，正规 Wnt 小径的一个关键部件，在 modulating Wnt 发信号起双作用：一方面， Axin 脚手架支持 -catenin 降级的 -catenin 破坏建筑群并且因此禁止 Wnt 信号 transduction；在另一方面， Axin 与 LRP5/6 交往并且便于 GSK3 的招募到血浆膜支持 LRP5/6 phosphorylation 并且 Wnt 发信号。有这二不同建筑群的 Axin 的微分集会不得不紧为适当 transduction 被控制上或离开 Wnt 信号。到目前为止，有多重机制，在 Axin 活动的规定揭示，例如 post-transcriptional 调整， homo/hetero-polymerization 和汽车抑制。这些机制可以合作地工作调制 Axin 的功能，从而在控制发信号的正规 Wnt 起一个重要作用。在这评论，我们将在正规 Wnt 发信号关于 Axin 功能的规定集中于最近的进步。
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Beta-catenin
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Members of the Wnt gene family, encoding secreted cystein-rich glycoproteins, have been isolated from a variety of organisms. They serve as important developmental signaling molecules and have been implicated to play crucial roles in such diverse processes as cancer, organogenesis and pattern formation. Experiments by Zakany and Duboule, and Rudnicki and Brown have suggested a role for Wnt molecules in negatively regulating chondrogenesis. However, neither of the two Wnt genes used in these studies is endogenously expressed in chondrogenic regions. We and others have found that in the chick limb at least four members of the Wnt gene family, Wnt-4, Wnt-5a, Wnt-5b, and Wnt-14, are expressed in defined regions of the developing chondrogenic elements. With the exception of Wnt-5b, which is expressed in perichondrial cells and prehypertrophic chondrocytes, the expression of the three other Wnt genes is restricted to the perichondrium surrounding the cartilage element. Viral misexpression studies in the chick suggested that Wnt-4 acts as a positive signal originating from the joint region and when misexpressed accelerates chondrocyte maturation, while Wnt-5a and Wnt-5b both negatively regulate chondrocyte maturation. We have further shown that they utilize different signaling pathways; while Wnt-4 signals through the canonical Wnt-pathway, Wnt-5a and Wnt-5b do not. Interestingly, the delay in chondrocyte maturation due to Wnt-5a misexpression is associated with an up regulation of Wnt-5b expression in the prehypertropic chondrocytes. Concomitantly, Wnt-5b misexpression also delays chondrocyte maturation. However, preliminary studies suggest that the two Wnt genes affect different steps in the maturation process. Wnt signaling, however, is not only regulating chondrogenesis but is also involved in the segmentation process of the appendicular skeleton. Localized misexpression of the fourth Wnt gene, Wnt-14, which is expressed early in the presumptive joint region, induces morphological and molecular changes indicative of an early joint interzone, suggesting that Wnt-14 plays a pivotal role in the induction of the joint interzone.
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Chondrogenesis
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Dysregulation of WNT signaling has been reported in many malignancies.This study was conducted to investigate the expression pattern of 14 members of the WNT gene family in different immunophenotypic subtypes of ALL.Semi-quantitative RT-PCR was performed on samples from 71 ALL patients and 36 age-matched healthy individuals. The ALL patients were categorized into B-ALL (76%), T-ALL (22.6%) and mixed lineage (1.4%) and the B-ALL cases were further classified into pro-B, pre-BI, pre-BII and immature/mature-B based on immuno-phenotypic results.Among the WNT genes, WNT-7B (p=0.026), WNT-9A (p=0.020) and WNT-16B (p=0.023) were significantly over-expressed, whereas WNT-2B (p=0.033), WNT-5A (p=0.016), WNT-7A (p<0.0001) and WNT-10A (p<0.0001) were down-regulated in B-ALL. Among the T-ALL subtype, however, significant down-regulation of WNT-2B, WNT-5B, WNT-7A, WNT-10A and WNT-11 was evident. Comparison between B-ALL subtypes showed significant over-expression of WNT-7B, WNT-9A and WNT-5B in certain subtypes.Our results suggest contribution of the WNT genes in leukemogenesis of ALL.
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Abstract Wnt/β-catenin signaling has been proved to play an important role in the development and promotion of cancer metastasis. The activation of Wnt signals can lead to duplicating, updating, metastasizing and relapsing. The Wnt signaling pathway is mainly divided into the Wnt/β-catenin pathway and the Wnt/calcium pathway. A better understanding of all the diverse functions of Wnt and their molecular mechanisms has evoked prevailing interest in identifying additional targets related to the Wnt /β-catenin pathways in breast cancer. A number of new target, related to Wnt /β-catenin pathways have been identified in recent years, including NOP14, BKCa channels, Emilin2, WISP, MicroRNAs, NRBP1, TRAF4, and Wntless. In this review, we will introduce the new targets related to the Wnt /β-catenin pathways in breast cancer.
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