Wnt5a regulates distinct signalling pathways by binding to Frizzled2

Sato, Akira; Yamamoto, Hideki; Sakane, Hiroshi; Koyama, Hirofumi; Kikuchi, Akira

doi:10.1038/emboj.2009.322

Cited by 283 publications

(338 citation statements)

References 51 publications

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“…Because Wnt5a has been classically shown to inhibit b-catenin signaling via Frizzled-2, we next examined any changes in its expression after PH. 16 A notable increase in Frizzled-2 RNA and protein expression was noted at days 1 to 3 after PH, suggesting an active Wnt5aeFrizzled-2 axis during these times of LR ( Figure 2, B and C).…”

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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“…Wnt5a bound to Fz2, Fz5 and Fz8 but not to Fz6 and Fz7 (Sato et al, 2010) (data not shown), and Ror2, a single transmembrane protein, is known to function as a Wnt5a receptor (Oishi et al, 2003). To examine which receptor(s) are involved in cell migration of DU145 cells, we depleted Wnt receptors by siRNA (Supplementary Figure S2b).…”

Section: Mechanism Of Wnt5a-induced Invasion By Pca Cellsmentioning

confidence: 99%

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

et al. 2010

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Wnt5a is a representative ligand that activates the b-catenin-independent pathway in Wnt signaling. Although it has been reported that abnormal activation of the Wnt/ b-catenin-dependent pathway is often observed in human prostate cancer, the involvement of the b-catenin-independent pathway in this cancer is unclear. Abnormal expression of Wnt5a and b-catenin was observed in 27 (28%) and 49 (50%) of 98 prostate cancer cases, respectively, by immunohistochemical analyses. Simultaneous expression of Wnt5a and b-catenin was observed in only five cases, suggesting their exclusive expression. The positive detection of Wnt5a was correlated with high Gleason scores and biochemical relapse of prostate cancer, but that of b-catenin was not. Knockdown and overexpression of Wnt5a in human prostate cancer cell lines reduced and stimulated, respectively, their invasion activities, and the invasion activity required Frizzled2 and Ror2 as Wnt receptors. Wnt5a activated Jun-N-terminal kinase through protein kinase D (PKD) and the inhibition of PKD suppressed Wnt5a-dependent cell migration and invasion. In addition, Wnt5a induced the expression of metalloproteinase-1 through the recruitment of JunD to its promoter region. These results suggest that Wnt5a promotes the aggressiveness of prostate cancer and that its expression is involved in relapse after prostatectomy.

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“…Wnt5a, for example, preferentially activates PCP signaling and competes with Wnt-3a for binding to FZD2, thereby suppressing the β-catenin-dependent pathway [32].…”

Section: Wnts and Their Receptorsmentioning

confidence: 99%