Kaiso-induced intestinal inflammation is preceded by diminished E-cadherin expression and intestinal integrity

Robinson, Shaiya C.; Chaudhary, Roopali; Jiménez‐Saiz, Rodrigo; Rayner, Lyndsay G. A.; Bayer, Luke; Jordana, Manel; Daniel, Juliet M.

doi:10.1371/journal.pone.0217220

Cited by 8 publications

(10 citation statements)

References 47 publications

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“…In contrast, the decreased level or deprivation of pT606 phosphorylation of Kaiso could block the cytoplasmic transportation of Kaiso, repress CDH1 transcription, and promote the growth of cancer cells. Our results are consistent with the report that overexpression of Kaiso/Zbtb33 resulted in downregulation of Cdh1 in mice intestinal tissues (57).…”

Section: Discussionsupporting

confidence: 93%

T606-phosphorylation deprives the function of Kaiso as a transcription and oncogenic factor

Tian

Qin

et al. 2020

Preprint

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Section: Discussionsupporting

confidence: 93%

T606-phosphorylation deprives the function of Kaiso as a transcription and oncogenic factor

Tian

Qin

et al. 2020

Preprint

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“…In contrast, the decreased level or deprivation of pT606 phosphorylation of Kaiso could block the cytoplasmic transportation of Kaiso, repress CDH1 transcription and promote the growth of cancer cells. Our results are consistent with the report that overexpression of Kaiso/Zbtb33 resulted in downregulation of Cdh1 in mice intestinal tissues [60]. Together, these phenomena indicate that Kaiso phosphorylation may be a crucial determinant for the roles of Kaiso in cancer development through de‐repression of tumour‐related genes.…”

Section: Discussionsupporting

confidence: 93%

Kaiso phosphorylation at threonine 606 leads to its accumulation in the cytoplasm, reducing its transcriptional repression of the tumour suppressor CDH1

et al. 2022

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It is well known that the Kaiso protein (encoded by the ZBTB33 gene) is a transcription factor, and Kaiso–P120ctn [P120 catenin (CTNND1)] interaction increases the translocation of Kaiso from the nucleus into the cytoplasm. However, the regulatory mechanisms of Kaiso compartmentalisation are far from clear. Here, we reported that RAC‐alpha serine/threonine‐protein kinase (AKT1) could phosphorylate threonine residue 606 (T606) within the RSSTIP motif of Kaiso in the cytoplasm. The T606‐phosphorylated Kaiso (pT606‐Kaiso) could directly bind to 14‐3‐3 family proteins, and depletion of T606 phosphorylation by T606A mutation abolished most of the Kaiso–14‐3‐3 binding. In addition, the Kaiso–P120ctn interaction was essential for pT606‐Kaiso accumulation in the cytoplasm. Notably, enforced stratifin (14‐3‐3σ; SFN) overexpression could increase pT606‐Kaiso accumulation in the cytoplasm and de‐repress the transcription of Kaiso target gene cadherin 1 (CDH1), which is a tumour suppressor. Decreased amounts of both pT606‐Kaiso and CDH1 proteins were frequently observed in human gastric cancer tissues compared to paired normal controls. The mRNA levels of 14‐3‐3σ and Kaiso target gene CDH1 showed highly significant positive correlations in both human normal tissues and cancer cell lines by bioinformatics analyses. Furthermore, Kaiso T606A mutant (unable to be phosphorylated) significantly increased the migration and invasion of cancer cells in vitro and promoted the growth of these cells in vivo. In conclusion, Kaiso could be phosphorylated at T606 by AKT1 and pT606‐Kaiso accumulates in the cytoplasm through binding to 14‐3‐3/P120ctn, which de‐represses the Kaiso target gene CDH1 in normal tissues. Decreased Kaiso phosphorylation might contribute to the development of gastrointestinal cancer. The status of Kaiso phosphorylation is a determinant factor for the role of Kaiso in the development of cancer.

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“…In this regard, investigating the mechanisms by which inflammatory processes activate Wnt/β-catenin and consequent downstream signaling is important in understanding this disease. In addition, because E-cadherin directly binds to βcatenin, numerous studies implicated a positive correlation with E-cadherin dysregulation and Wnt/β-catenin signaling [35].…”

Section: Discussionmentioning

confidence: 99%

Bacteroides fragilis Toxin Induces Intestinal Epithelial Cell Secretion of Interleukin-8 by the E-Cadherin/β-Catenin/NF-κB Dependent Pathway

et al. 2022

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Enterotoxigenic Bacteroides fragilis (ETBF) has emerged as a gut microbiome pathogen that can promote colitis associated cancer in humans. ETBF secretes the metalloprotease, B. fragilis toxin (BFT), which can induce ectodomain cleavage of E-cadherin and IL-8 secretion through the β-catenin, NF-κB, and MAPK pathways in intestinal epithelial cells. However, it is still unclear whether E-cadherin cleavage is required for BFT induced IL-8 secretion and the relative contribution of these signaling pathways to IL-8 secretion. Using siRNA knockdown and CRISPR knockout studies, we found that E-cadherin cleavage is required for BFT mediated IL-8 secretion. In addition, genetic ablation of β-catenin indicates that β-catenin is required for the BFT induced increase in transcriptional activity of NF-κB, p65 nuclear localization and early IL-8 secretion. These results suggest that BFT induced β-catenin signaling is upstream of NF-κB activation. However, despite β-catenin gene disruption, BFT still activated the MAPK pathway, suggesting that the BFT induced activation of the MAPK signaling pathway is independent from the E-cadherin/β-catenin/NF-κB pathway. These findings show that E-cadherin and β-catenin play a critical role in acute inflammation following ETBF infection through the inflammatory response to BFT in intestinal epithelial cells.

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Kaiso-induced intestinal inflammation is preceded by diminished E-cadherin expression and intestinal integrity

Cited by 8 publications

References 47 publications

T606-phosphorylation deprives the function of Kaiso as a transcription and oncogenic factor

T606-phosphorylation deprives the function of Kaiso as a transcription and oncogenic factor

Kaiso phosphorylation at threonine 606 leads to its accumulation in the cytoplasm, reducing its transcriptional repression of the tumour suppressor CDH1

Bacteroides fragilis Toxin Induces Intestinal Epithelial Cell Secretion of Interleukin-8 by the E-Cadherin/β-Catenin/NF-κB Dependent Pathway

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