Nuclear Dvl, c-Jun, β-catenin, and TCF form a complex leading to stabiLization of β-catenin–TCF interaction

Gan, Xiaoqing; Wang, Jiyong; Xi, Ying; Wu, Zhili; Li, Yiping; Li, Lin

doi:10.1083/jcb.200710050

Cited by 219 publications

(255 citation statements)

References 48 publications

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“…Itoh et al showed notably that the nuclear localization of Xenopus Dvl is essential for its ability to stabilize b-catenin (Itoh et al, 2005;Gan et al, 2008). Here, we observe the colocalization of WWOX with Dvl-2 wild type or Dvl2NESm (a mutated form of Dvl-2 predominantly localized in the nucleus) in the cytoplasmic compartment (Figure 8).…”

Section: Discussionsupporting

confidence: 61%

“…Recently, it has been shown that Dvl proteins shuttle between the cytoplasm and the nucleus, and that their nuclear localizations are crucial for their functions in the Wnt/b-catenin pathway (Itoh et al, 2005;Yokoyama and Yin DMalbon 2007;Gan et al, 2008). Itoh et al showed notably that the nuclear localization of Xenopus Dvl is essential for its ability to stabilize b-catenin (Itoh et al, 2005;Gan et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

et al. 2009

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The WWOX gene encodes a candidate tumor suppressor protein (WWOX) implicated in a variety of human diseases such as cancer. To better understand the molecular mechanisms of WWOX action, we investigated novel partners of this protein. Using the two-hybrid system and a coimmunoprecipitation assay, we observed a physical association between WWOX and the Dishevelled protein (Dvl) family signaling elements involved in the Wnt/b-catenin pathway. We found that enforced WWOX expression inhibited, and inhibition of endogenous WWOX expression stimulated the transcriptional activity of the Wnt/b-catenin pathway. Inhibition of endogenous WWOX expression also enhanced the effect of Wnt-3a on b-catenin stability. Moreover, we observed the sequestration of Dvl-2 wild type and Dvl-2NESm, a mutated form of Dvl-2 predominantly localized in the nucleus, in the cytoplasm compartment by WWOX. Our results indicate that WWOX is a novel inhibitor of the Wnt/b-catenin pathway. WWOX would act, at least in part, by preventing the nuclear import of the Dvl proteins.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

et al. 2009

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“…Surprisingly, we found that the induction of Snail expression by decreasing AF6 expression was mediated primarily via Dvl2. Emerging work suggests that Dvl2 plays an important role in the nuclear regulation of gene expression [38][39][40] . Further analysis identified FOXE1, a transcription factor, as a binding partner of AF6.…”

Section: Discussionmentioning

confidence: 99%

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Chang

Peng

et al. 2015

Nat Commun

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Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

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“…Eventually, β-catenin is stabilized and accumulates in the nucleus to activate TCF/ LEF-1 target genes. Recent studies have unraveled that Dvl also functions in the nucleus [6], through stabilizing β-catenin/TCF interaction by forming a quaternary complex consisting of Dvl, c-Jun, β-catenin and TCF [7]. In addition to regulating the canonical Wnt signaling, Dvl has also been suggested to be an essential transducer in non-canonical Wnt signaling pathways [8,9].…”

Section: Introductionmentioning

confidence: 99%

Dishevelled interacts with p65 and acts as a repressor of NF-κB-mediated transcription

Deng

Wang

et al. 2010

Cell Res

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Dishevelled (Dvl) is a highly conserved protein family that plays an important role in mediating Wnt signaling from membrane to cytoplasm. Recently we reported that Dvl also functions in the nucleus by stabilizing the β-catenin/TCFs transcriptional complex. Here we describe that Dvl may function as a repressor of NF-κB. Our data show that Dvl directly binds to p65 and their interaction occurs in the nucleus. Dvl expression inhibits p65-mediated or TNF-α-stimulated activation of the NF-κB dependent reporter. This action of Dvl, however, is not dependent on Wnt or its downstream effector β-catenin. Chromatin immunoprecipitation assay shows that recruitment of p65 to the promoters of NF-κB target genes is significantly enhanced when expression of Dvl is knocked down. Consistently, the expression level of a subset of NF-κB target genes is also increased after knock-down of Dvl. Moreover, our data suggest that Dvl may relieve the anti-apoptotic effect of NF-κB, thus play a role in promoting apoptosis. Therefore, this work demonstrates a novel function of Dvl in modulating NF-κB-regulated gene transcription.

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Nuclear Dvl, c-Jun, β-catenin, and TCF form a complex leading to stabiLization of β-catenin–TCF interaction

Cited by 219 publications

References 48 publications

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

Inhibition of the Wnt/β-catenin pathway by the WWOX tumor suppressor protein

Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression

Dishevelled interacts with p65 and acts as a repressor of NF-κB-mediated transcription

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