Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition

Zhou, Binhua P.; Deng, Jiong; Xia, Weiya; Xu, Jihong; Li, Yan M.; Gündüz, Mehmet; Hung, Mien‐Chie

doi:10.1038/ncb1173

Cited by 1,470 publications

(1,638 citation statements)

References 37 publications

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“…Downregulation of E-cadherin is the key step toward the invasive phase in cancer and E-cadherin gene expression is mainly regulated by the Slug/Snail family of transcriptional repressors that bind to E-box sequences in the proximal E-cadherin promoter (Hemavathy et al, 2000). Snail is regulated by GSK3b by direct binding and phosphorylation, and inhibition of GSK3b results in upregulation of Snail and downregulation of E-cadherin (Zhou et al, 2004). This implies that Snail and GSK3b together function as a molecular switch for many signaling pathways leading to EMT, and may provide a new connection of Akt to E-cadherin.…”

Section: Discussionmentioning

confidence: 99%

“…Y Gan et al (Zhou et al, 2004). In DU145 cells, EGF induced robust GSK3b phosphorylation (inactivation) and LY294002 markedly inhibited this phosphorylation (Figure 7c To confirm the essential role of Snail in EGF-driven EMT and cell migration, we used small interfering RNAs (siRNAs) to knock down endogenous Snail expression in DU145 cells.…”

Section: Erk and Akt In Egfr Signaling And Cell Motilitymentioning

confidence: 93%

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Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

et al. 2010

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Upregulation of epidermal growth factor receptor (EGFR) and subsequent increases in extracellular-regulated kinase (ERK) and Akt signaling are implicated in prostate cancer progression. Impaired endocytic downregulation of EGFR also contributes to oncogenic phenotypes such as metastasis. Thus, understanding the roles of divergent signaling pathways in the regulation of EGFR trafficking and EGFRdriven invasive migration may enable the development of more effective therapies. In this study, we use the human prostate cancer cell lines, DU145 and PC3, to investigate the effects of both the ERK and Akt pathways on epidermal growth factor (EGF)-mediated EGFR signaling, trafficking and cell motility. We show that DU145 and PC3 cells overexpress EGFR and migrate in a ligand (EGF)-dependent manner. Next, we show that pharmacological inhibition of ERK (but not Akt) signaling enhances EGFinduced EGFR activation, ubiquitination and downregulation, and may lead to enhanced receptor turnover. These findings negatively correlate with ERK-mediated threonine phosphorylation of EGFR, implicating it as a possible mechanism. Further, we uncover that EGF promotes disassembly of cell-cell junctions, downregulation of E-cadherin and upregulation of the transcriptional repressor, Snail, typical characteristics of epithelial-mesenchymal transition (EMT). These effects are dependent on activation of Akt, as inhibition of Akt signaling abolishes EGF/EGFR-driven cell migration and EMT. Knockdown of endogenous Snail also prevents EGFR-mediated downregulation of E-cadherin, EMT and cell migration. Surprisingly, inhibition of the ERK pathway augments EGFR-dependent motility, occurring concomitantly with elevation of EGF-induced Akt activity. Collectively, our results suggest that EGF-triggered ERK activation has profound feedback on EGFR signaling and trafficking by EGFR threonine phosphorylation, and Akt has a pivotal role in EGFR-mediated cell migration by activating EMT. More important, our results also suggest that therapeutic targeting of ERK signaling may have undesirable outcomes (for example, augmenting EGFR-driven motility).

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Section: Discussionmentioning

confidence: 99%

Section: Erk and Akt In Egfr Signaling And Cell Motilitymentioning

confidence: 93%

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

et al. 2010

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“…Validation of discriminator genes in a mutant Snail-transfected MCF7 breast cancer cell line exhibiting features of EMT Snail, a zinc-finger transcription factor, plays a fundamental role in mediating EMT (Thiery, 2002;Zhou et al, 2004). Snail is highly unstable, but a variant of Snail (Snail-6SA) that abolishes two phosphorylation sites required, respectively, for nuclear to cytoplasmic translocation and subsequent ubiquitination, is much more stable and resides exclusively in the nucleus to induce EMT (Zhou et al, 2004).…”

Section: Confirmation Of Microarray Datamentioning

confidence: 99%

“…Snail is highly unstable, but a variant of Snail (Snail-6SA) that abolishes two phosphorylation sites required, respectively, for nuclear to cytoplasmic translocation and subsequent ubiquitination, is much more stable and resides exclusively in the nucleus to induce EMT (Zhou et al, 2004). The Snail-6SA transfectant (Snail-6SA-MCF7) exhibits features of EMT, including the fibroblastoid and migratory phenotypes together with the loss of E-cadherin and the expression of vimentin, as compared to wild-type Snailtransfectant (Snail-WT-MCF7) or parental MCF7 cell line (Figures 5a-c) (Zhou et al, 2004). Using these cell lines as an in vitro model of EMT, we used QRT-PCR to examine whether genes differentially upregulated in the four MCBs and in MCB subclass 2, which showed prominent sarcomatous growth akin to EMT, were also upregulated in Snail-6SA-MCF7, as compared to Snail-WT-MCF7 or parental MCF7 cell lines.…”

Section: Confirmation Of Microarray Datamentioning

confidence: 99%

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition

Lien

Hsiao

Lin³

et al. 2007

Oncogene

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Metaplastic carcinoma of the breast (MCB) is a poorly understood subtype of breast cancer. It is generally characterized by the coexistence of ductal carcinomatous and transdifferentiated sarcomatous components, but the underlying molecular alterations, possibly related to epithelial-mesenchymal transition (EMT), remain elusive. We performed transcriptional profiling using half-agenome oligonucleotide microarrays to elucidate genetic profiles of MCBs and their differences to those of ductal carcinoma of breasts (DCBs) using discarded specimens of four MCBs and 34 DCBs. Unsupervised clustering disclosed distinctive expression profiles between MCBs and DCBs. Supervised analysis identified gene signatures discriminating MCBs from DCBs and between MCB subclasses. Notably, many of the discriminator genes were associated with downregulation of epithelial phenotypes and with synthesis, remodeling and adhesion of extracellular matrix, with some of them have known or inferred roles related to EMT. Importantly, several of the discriminator genes were upregulated in a mutant Snail-transfected MCF7 cell known to exhibit features of EMT, thereby indicating a crucial role for EMT in the pathogenesis of MCBs. Finally, the identification of SPARC and vimentin as poor prognostic factors reinforced the role of EMT in cancer progression. These data advance our understanding of MCB and offer clues to the molecular alterations underlying EMT.

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“…Overexpression of Akt has been shown to induce EMT through nuclear factor-kB-dependent activation of Snail1 (Grille et al, 2003;Julien et al, 2007). Akt also participates in the Snail1 upregulation induced by epidermal growth factor (EGF) or insulinlike growth factor-1 (IGF-1) in different cell lines, increasing both gene transcription and protein stability (Zhou et al, 2004;Gan et al, 2010). Besides these effects on Snail1 expression, Akt has also been positioned downstream from Snail1 in transforming growth factorb-induced EMT (Cho et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Akt2 interacts with Snail1 in the E-cadherin promoter

et al. 2011

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Snail1 is a transcriptional factor essential for triggering epithelial-to-mesenchymal transition. Moreover, Snail1 promotes resistance to apoptosis, an effect associated to PTEN gene repression and Akt stimulation. In this article we demonstrate that Snail1 activates Akt at an additional level, as it directly binds to and activates this protein kinase. The interaction is observed in the nucleus and increases the intrinsic Akt activity. We determined that Akt2 is the isoform interacting with Snail1, an association that requires the pleckstrin homology domain in Akt2 and the C-terminal half in Snail1. Snail1 enhances the binding of Akt2 to the E-cadherin (CDH1) promoter and Akt2 interference prevents Snail1 repression of CDH1 gene. We also show that Snail1 binding increases Akt2 intrinsic activity on histone H3 and have identified Thr45 as a residue modified on this protein. Phosphorylation of Thr45 in histone H3 is sensitive to Snail1 and Akt2 cellular levels; moreover, Snail1 upregulates the binding of phosphoThr45 histone H3 to the CDH1 promoter. These results uncover an unexpected role of Akt2 in transcriptional control and point out to phosphorylation of Thr45 in histone H3 as a new epigenetic mark related to Snail1 and Akt2 action.

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Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition

Cited by 1,470 publications

References 37 publications

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial–mesenchymal transition

Akt2 interacts with Snail1 in the E-cadherin promoter

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