Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation

Topol, L. Z.; Jiang, Xueyuan; Choi, Hosoon; Garrett-Beal, Lisa; Carolan, Peter J.; Yang, Yingzi

doi:10.1083/jcb.200303158

Cited by 674 publications

(617 citation statements)

References 63 publications

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“…Because Wnt5a and Wnt11 are two classic noncanonical Wnt ligands that have been shown to have an antagonistic role on Wnt/b-catenin signaling, we next determined their expression during LR after PH in wild-type mice compared with the corresponding sham controls. 14,15 Indeed, Wnt5a RNA and protein expression, but not Wnt11, increased at 1 to 3 days after PH (data not shown) ( Figure 2, A and C). Because Wnt5a has been classically shown to inhibit b-catenin signaling via Frizzled-2, we next examined any changes in its expression after PH.…”

Section: Wnt5a and Frizzled-2 Expression Increases Temporally During Lrmentioning

confidence: 86%

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Yang

Cusimano

Monga

et al. 2015

The American Journal of Pathology

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Activation of Wnt/b-catenin signaling during liver regeneration (LR) after partial hepatectomy (PH) is observed in several species. However, how this pathway is turned off when hepatocyte proliferation is no longer required is unknown. We assessed LR in liver-specific knockouts of Wntless (Wls-LKO), a protein required for Wnt secretion from a cell. When subjected to PH, Wls-LKO showed prolongation of hepatocyte proliferation for up to 4 days compared with littermate controls. This coincided with increased b-catenineT-cell factor 4 interaction and cyclin-D1 expression. Wls-LKO showed decreased expression and secretion of inhibitory Wnt5a during LR. Wnt5a expression increased between 24 and 48 hours, and Frizzled-2 between 24 and 72 hours, after PH in normal mice. Treatment of primary mouse hepatocytes and liver tumor cells with Wnt5a led to a notable decrease in b-catenineT-cell factor activity, cyclin-D1 expression, and cell proliferation. Intriguingly, Wnt5a-LKO did not display any prolongation of LR because of compensation by other cells. In addition, Wnt5a-LKO hepatocytes failed to respond to exogenous Wnt5a treatment in culture because of a compensatory decrease in Frizzled-2 expression.In conclusion, we demonstrate Wnt5a to be, by default, a negative regulator of b-catenin signaling and hepatocyte proliferation, both in vitro and in vivo. We also provide evidence that the Wnt5a/Frizzled-2 axis suppresses b-catenin signaling in hepatocytes in an autocrine manner, thereby contributing to timely conclusion of the LR process. (Am J Pathol 2015, 185: 2194e2205; http:// dx

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Section: Wnt5a and Frizzled-2 Expression Increases Temporally During Lrmentioning

confidence: 86%

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Yang

Cusimano

Monga

et al. 2015

The American Journal of Pathology

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“…S37A and D29-48 b-catenins were kindly provided by Y. Yang (Topol et al, 2003). Vectors pcDNA3-S33Y b-catenin (Addgene plasmid 19286; (Kolligs et al, 1999)) and pCMV-Neo-Bam APC (Addgene plasmid 16507; (Morin et al, 1997)) were provided by E Fearon and K Kinzler, respectively.…”

Section: Materials and Methods Cdnasmentioning

confidence: 99%

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

et al. 2010

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Constitutive activation of Wnt/b-catenin signaling in cancer results from mutations in pathway components, which frequently coexist with autocrine Wnt signaling or epigenetic silencing of extracellular Wnt antagonists. Among the extracellular Wnt inhibitors, the secreted frizzled-related proteins (SFRPs) are decoy receptors that contain soluble Wnt-binding frizzled domains. In addition to SFRPs, other endogenous molecules harboring frizzled motifs bind to and inhibit Wnt signaling. One of such molecules is V3Nter, a soluble SFRP-like frizzled polypeptide that binds to Wnt3a and inhibits Wnt signaling and expression of the b-catenin target genes cyclin D1 and c-myc. V3Nter is derived from the cell surface extracellular matrix component collagen XVIII. Here, we used HCT116 human colon cancer cells carrying the DS45 activating mutation in one of the alleles of b-catenin to show that V3Nter and SFRP-1 decrease baseline and Wnt3a-induced b-catenin stabilization. Consequently, V3Nter reduces the growth of human colorectal cancer xenografts by specifically controlling cell proliferation and cell cycle progression, without affecting angiogenesis or apoptosis, as shown by decreased

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“…Additionally, complicated crosstalk exists between the canonical and the noncanonical Wnt pathways. Several lines of evidence suggest that noncanonical Wnt signaling antagonizes Wnt/b-catenin signaling (47,48). It is believed that CaMKII activates a kinase cascade phosphorylating NEMO-like kinase, which interferes with DNA binding of TCF/LEF-1 (47).…”

Section: Noncanonical Wnt Signaling In Angiogenesismentioning

confidence: 99%

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

et al. 2012

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SummaryThe Wnt signaling pathway is involved in a wide range of developmental and physiological processes, such as cell fate specification, tissue morphogenesis, and homeostasis. Thus, its dysregulation has been found in multiple diseases, including some cardiovascular disorders. The loss or gain of function of Wnt pathway components results in abnormal vascular development and angiogenesis. Further study has revealed that Wnt signaling in endothelial cells appears to contribute to vascular morphogenesis and endothelial cell specification. Owing to the significance of Wnt signaling in angiogenesis, Wnt antagonists have been considered potential treatments for neovascular disorders. In line with this, members of the Dkk protein family (Dkks), well-known Wnt antagonists, have been recently found to regulate angiogenesis. This review summarizes our present knowledge of the roles of Wnt signaling and Wnt antagonists, particularly Dkks, in angiogenic regulation and explores the therapeutic potential of Wnt antagonists.

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Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation

Cited by 674 publications

References 63 publications

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

WNT5A Inhibits Hepatocyte Proliferation and Concludes β-Catenin Signaling in Liver Regeneration

Blocking Wnt signaling by SFRP-like molecules inhibits in vivo cell proliferation and tumor growth in cells carrying active β-catenin

The Wnt pathway and the roles for its antagonists, DKKS, in angiogenesis

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