Rac1b recruits Dishevelled and β-catenin to Wnt target gene promoters independent of Wnt3A stimulation

Pethe, Vaijayanti; Charames, George S.; Bapat, Bharati

doi:10.3892/ijo.2011.1066

Cited by 7 publications

(11 citation statements)

References 26 publications

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“… 67 , 68 , 69 In addition, a protein complex composed of RAC1B, β-catenin and disheveled functions to enhance nuclear translocation of transcription factors required for increased interaction with the target promoters. 46 These studies corroborate our proposed mechanism that KRT19 directly interacts with the β-catenin-RAC1 complex to promote nuclear translocation of β-catenin and activate NUMB transcription.…”

Section: Discussionsupporting

confidence: 85%

“… 42 , 43 , 44 , 45 Our results revealed that KRT19 knockdown markedly suppressed nuclear translocation of RAC1, a binding partner of β-catenin that aids nuclear translocation of the latter. 43 , 46 Meanwhile, the cytoplasm presented higher amounts of β-catenin and RAC1 in the shKRT19 cells compared with that in control cells.…”

Section: Resultsmentioning

confidence: 96%

“…As RAC1 was reported to be a binding partner of β-catenin and may help nuclear translocation of β-catenin, 43 , 46 we performed coimmunoprecipitation experiments and revealed the interaction of KRT19 with β-catenin and RAC1 in the breast cancer cell lines ( Figure 5a ). However, KRT19 knockdown significantly inhibited these interactions ( Figure 5b ).…”

Section: Resultsmentioning

confidence: 99%

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KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties

et al. 2016

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Studies have reported that interactions between keratins (KRTs) and other proteins initiate signaling cascades that regulate cell migration, invasion, and metastasis. In the current study, we found that expression of KRT19 was specifically high in breast cancers and significantly correlated with their invasiveness. Moreover, knockdown of KRT19 led to increased proliferation, migration, invasion, drug resistance, and sphere formation in breast cancer cells via an upregulated NOTCH signaling pathway. This was owing to reduced expression of NUMB, an inhibitory protein of the NOTCH signaling pathway. In addition, we found that KRT19 interacts with β-catenin/RAC1 complex and enhances the nuclear translocation of β-catenin. Concordantly, knockdown of KRT19 suppressed the nuclear translocation of β-catenin as well as β-catenin-mediated NUMB expression. Furthermore, modulation of KRT19-mediated regulation of NUMB and NOTCH1 expression led to the repression of the cancer stem cell properties of breast cancer patient-derived CD133high/CXCR4high/ALDH1high cancer stem-like cells (CSLCs), which showed very low KRT19 and high NOTCH1 expression. Taken together, our study suggests a novel function for KRT19 in the regulation of nuclear import of the β-catenin/RAC1 complex, thus modulating the NUMB-dependent NOTCH signaling pathway in breast cancers and CSLCs, which might bear potential clinical implications for cancer or CSLC treatment.

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

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KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties

et al. 2016

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“…In agreement, DVL3 but not β-catenin caused increased activation of RAC1B [20]. Follow-up studies have shown that RAC1B resides at the promoters of Wnt target genes, c-Myc and CCND1 , in HCT116 cells with aberrant Wnt pathway [64]. In HEK293T cells with intact Wnt signaling, RAC1B is tied to these same gene promoters independent of WNT3A stimulation and recruits DVL3 and β-catenin in the absence of WNT3A stimulation, suggesting a novel transcriptional coactivator role of RAC1B in β-catenin/TCF-mediated transcription [64].…”

Section: Regulation Of Signaling Pathways By Rac1bmentioning

confidence: 78%

RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression

Melzer

Hass

Lehnert

et al. 2019

Cells

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RAC1B is an alternatively spliced isoform of the monomeric GTPase RAC1. It differs from RAC1 by a 19 amino acid in frame insertion, termed exon 3b, resulting in an accelerated GDP/GTP-exchange and an impaired GTP-hydrolysis. Although RAC1B has been ascribed several protumorigenic functions such as cell cycle progression and apoptosis resistance, its role in malignant transformation, and other functions driving tumor progression like epithelial-mesenchymal transition, migration/invasion and metastasis are less clear. Insertion of exon 3b endows RAC1B with specific biochemical properties that, when compared to RAC1, encompass both loss-of-functions and gain-of-functions with respect to the type of upstream activators, downstream targets, and binding partners. In its extreme, this may result in RAC1B and RAC1 acting in an antagonistic fashion in regulating a specific cellular response with RAC1B behaving as an endogenous inhibitor of RAC1. In this review, we strive to provide the reader with a comprehensive overview, rather than critical discussions, on various aspects of RAC1B biology in eukaryotic cells.

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“…Previously, it was demonstrated that Wnt3a does not affect TcdA-induced β-catenin nuclear translocation inhibition ( Lima et al, 2014 ). Because TcdA glucosylates Rho GTPases, such as Rac1 (without affecting Rac1 gene expression in vivo , as shown in Supplementary Figure 1 ), which induces the recruitment of β-catenin to the nucleus ( Wu et al, 2008 ; Pethe et al, 2011 ; Jamieson et al, 2015 ), we investigated whether upregulation of Rac1 through transfection of pcDNA3-EGFP-Rac1-Q61L (as shown in Supplementary Figures 2 , 3 ) could recover Wnt3a-induced β-catenin nuclear translocation in the intestinal epithelial (IEC-6) cells challenged with TcdA. We found that Wnt3a alone induced β-catenin nuclear activity in a manner independent of pcDNA3-EGFP-Rac1-Q61L transfection in the IEC-6 cells, while its transcriptional regulatory response (as demonstrated by the TOPflash/FOPflash, ratio) was inhibited by TcdA with either Wnt3a or Rac1 upregulation alone.…”

Section: Resultsmentioning

confidence: 99%

Clostridioides difficile Toxin A-Induced Wnt/β-Catenin Pathway Inhibition Is Mediated by Rac1 Glucosylation

et al. 2020

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Clostridioides difficile toxin A (TcdA) has been shown to inhibit cellular Wnt signaling, the major driving force behind the proliferation of epithelial cells in colonic crypts, likely through the inhibition of β-catenin nuclear translocation. Herein, we aimed to advance the understanding of this mechanism by replicating the findings in vivo and by investigating the specific role of Rac1, a member of the Rho GTPase family, on the inhibition of the Wnt-induced β-catenin nuclear translocation triggered by TcdA. To investigate the effects of TcdA on the Wnt/β-catenin pathway in vivo , we injected the ileal loops of C57BL/6 mice with TcdA [phosphate-buffered saline (PBS) as the control] to induce C. difficile disease-like ileitis. After 4 h post-injection, we obtained ileum tissue samples to assess Wnt signaling activation and cell proliferation through Western blotting, immunohistochemistry, and qPCR. To assess the role of Rac1 on Wnt signaling inhibition by TcdA, we transfected rat intestinal epithelial cells (IEC-6) with either a constitutively active Rac1 plasmid (pcDNA3-EGFP-Rac1-Q61L) or an empty vector, which served as the control. We incubated these cells with Wnt3a-conditioned medium (Wnt3a-CM) to induce Wnt/β-catenin pathway activation, and then challenged the cells with TcdA. We assessed Wnt signaling activation in vitro with TOP/FOPflash luciferase assays, determined nuclear β-catenin translocation by immunofluorescence, measured cyclin D1 protein expression by Western blotting, and quantified cell proliferation by Ki67 immunostaining. In vivo , TcdA decreased β-catenin, cyclin D1, and cMYC expression and inhibited the translocation of β-catenin into the nucleus in the ileum epithelial cells. In addition, TcdA suppressed cell proliferation and increased Wnt3a expression, but did not alter Rac1 gene expression in the ileum tissue. In vitro , constitutively active Rac1 prevented Wnt signaling inhibition by enabling the β-catenin nuclear translocation that had been blocked by TcdA. Our results show that TcdA inhibits Wnt/β-catenin pathway in vivo and demonstrate that this inhibition is likely caused by a Rac1-mediated mechanism.

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Rac1b recruits Dishevelled and β-catenin to Wnt target gene promoters independent of Wnt3A stimulation

Cited by 7 publications

References 26 publications

KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties

KRT19 directly interacts with β-catenin/RAC1 complex to regulate NUMB-dependent NOTCH signaling pathway and breast cancer properties

RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression

Clostridioides difficile Toxin A-Induced Wnt/β-Catenin Pathway Inhibition Is Mediated by Rac1 Glucosylation

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