Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity

Da Gyum Lee; Hyun Sil Kim; Yeo Song Lee; Shin Kim; So Young Cha; Ichiro Ota; Nam Hee Kim; Yong Hoon Cha; Dong Hyun Yang; Yoonmi Lee; Gyeong Ju Park; Jong In Yook; Yong Chan Lee

doi:10.1038/ncomms5423

Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity

Da Gyum Lee, Hyun Sil Kim, Yeo Song Lee, Shin Kim, So Young Cha, Ichiro Ota, Nam Hee Kim, Yong Hoon Cha, Dong Hyun Yang, Yoonmi Lee, Gyeong Ju Park, Jong In Yook, Yong Chan Lee

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

55 Citations (Scopus)

Abstract

Cytotoxin-associated gene A (CagA) is an oncoprotein and a major virulence factor of H. pylori. CagA is delivered into gastric epithelial cells via a type IV secretion system and causes cellular transformation. The loss of epithelial adhesion that accompanies the epithelial-mesenchymal transition (EMT) is a hallmark of gastric cancer. Although CagA is a causal factor in gastric cancer, the link between CagA and the associated EMT has not been elucidated. Here, we show that CagA induces the EMT by stabilizing Snail, a transcriptional repressor of E-cadherin expression. Mechanistically we show that CagA binds GSK-3 in a manner similar to Axin and causes it to shift to an insoluble fraction, resulting in reduced GSK-3 activity. We also find that the level of Snail protein is increased in H. pylori infected epithelium in clinical samples. These results suggest that H. pylori CagA acts as a pathogenic scaffold protein that induces a Snail-mediated EMT via the depletion of GSK-3.

Original language	English
Article number	4423
Journal	Nature communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5423
Publication status	Published - 2014 Jul 23

Bibliographical note

Funding Information:
We thank Professor H.S. Cho for helpful discussion of CagA and GSK-3 structure, and for providing recombinant GSK-3b. We also thank E. Tunkle for preparation of the manuscript and K.Y. Kim for statistical analysis. This work was supported by grants from the National Research Foundation of Korea (NRF-2009-0094027, NRF-2010-0010739, NRF-2012M3A9B2052523, NRF-2013R1A1A1011652, NRF-2014R1A2A1A05004670).

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms5423

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title = "Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity",

abstract = "Cytotoxin-associated gene A (CagA) is an oncoprotein and a major virulence factor of H. pylori. CagA is delivered into gastric epithelial cells via a type IV secretion system and causes cellular transformation. The loss of epithelial adhesion that accompanies the epithelial-mesenchymal transition (EMT) is a hallmark of gastric cancer. Although CagA is a causal factor in gastric cancer, the link between CagA and the associated EMT has not been elucidated. Here, we show that CagA induces the EMT by stabilizing Snail, a transcriptional repressor of E-cadherin expression. Mechanistically we show that CagA binds GSK-3 in a manner similar to Axin and causes it to shift to an insoluble fraction, resulting in reduced GSK-3 activity. We also find that the level of Snail protein is increased in H. pylori infected epithelium in clinical samples. These results suggest that H. pylori CagA acts as a pathogenic scaffold protein that induces a Snail-mediated EMT via the depletion of GSK-3.",

author = "Lee, {Da Gyum} and Kim, {Hyun Sil} and Lee, {Yeo Song} and Shin Kim and Cha, {So Young} and Ichiro Ota and Kim, {Nam Hee} and Cha, {Yong Hoon} and Yang, {Dong Hyun} and Yoonmi Lee and Park, {Gyeong Ju} and Yook, {Jong In} and Lee, {Yong Chan}",

note = "Funding Information: We thank Professor H.S. Cho for helpful discussion of CagA and GSK-3 structure, and for providing recombinant GSK-3b. We also thank E. Tunkle for preparation of the manuscript and K.Y. Kim for statistical analysis. This work was supported by grants from the National Research Foundation of Korea (NRF-2009-0094027, NRF-2010-0010739, NRF-2012M3A9B2052523, NRF-2013R1A1A1011652, NRF-2014R1A2A1A05004670).",

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day = "23",

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Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity. / Lee, Da Gyum; Kim, Hyun Sil; Lee, Yeo Song; Kim, Shin; Cha, So Young; Ota, Ichiro; Kim, Nam Hee; Cha, Yong Hoon; Yang, Dong Hyun; Lee, Yoonmi; Park, Gyeong Ju; Yook, Jong In; Lee, Yong Chan.

In: Nature communications, Vol. 5, 4423, 23.07.2014.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity

AU - Lee, Da Gyum

AU - Kim, Hyun Sil

AU - Lee, Yeo Song

AU - Kim, Shin

AU - Cha, So Young

AU - Ota, Ichiro

AU - Kim, Nam Hee

AU - Cha, Yong Hoon

AU - Yang, Dong Hyun

AU - Lee, Yoonmi

AU - Park, Gyeong Ju

AU - Yook, Jong In

AU - Lee, Yong Chan

N1 - Funding Information: We thank Professor H.S. Cho for helpful discussion of CagA and GSK-3 structure, and for providing recombinant GSK-3b. We also thank E. Tunkle for preparation of the manuscript and K.Y. Kim for statistical analysis. This work was supported by grants from the National Research Foundation of Korea (NRF-2009-0094027, NRF-2010-0010739, NRF-2012M3A9B2052523, NRF-2013R1A1A1011652, NRF-2014R1A2A1A05004670).

PY - 2014/7/23

Y1 - 2014/7/23

N2 - Cytotoxin-associated gene A (CagA) is an oncoprotein and a major virulence factor of H. pylori. CagA is delivered into gastric epithelial cells via a type IV secretion system and causes cellular transformation. The loss of epithelial adhesion that accompanies the epithelial-mesenchymal transition (EMT) is a hallmark of gastric cancer. Although CagA is a causal factor in gastric cancer, the link between CagA and the associated EMT has not been elucidated. Here, we show that CagA induces the EMT by stabilizing Snail, a transcriptional repressor of E-cadherin expression. Mechanistically we show that CagA binds GSK-3 in a manner similar to Axin and causes it to shift to an insoluble fraction, resulting in reduced GSK-3 activity. We also find that the level of Snail protein is increased in H. pylori infected epithelium in clinical samples. These results suggest that H. pylori CagA acts as a pathogenic scaffold protein that induces a Snail-mediated EMT via the depletion of GSK-3.

AB - Cytotoxin-associated gene A (CagA) is an oncoprotein and a major virulence factor of H. pylori. CagA is delivered into gastric epithelial cells via a type IV secretion system and causes cellular transformation. The loss of epithelial adhesion that accompanies the epithelial-mesenchymal transition (EMT) is a hallmark of gastric cancer. Although CagA is a causal factor in gastric cancer, the link between CagA and the associated EMT has not been elucidated. Here, we show that CagA induces the EMT by stabilizing Snail, a transcriptional repressor of E-cadherin expression. Mechanistically we show that CagA binds GSK-3 in a manner similar to Axin and causes it to shift to an insoluble fraction, resulting in reduced GSK-3 activity. We also find that the level of Snail protein is increased in H. pylori infected epithelium in clinical samples. These results suggest that H. pylori CagA acts as a pathogenic scaffold protein that induces a Snail-mediated EMT via the depletion of GSK-3.

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VL - 5

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 4423

ER -

Helicobacter pylori CagA promotes Snail-mediated epithelial-mesenchymal transition by reducing GSK-3 activity

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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