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The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration
The Src homology‐2 domain‐containing tyrosine phosphatase 2 (SHP‐2) regulates many cellular processes, including proliferation, differentiation and survival. Polymorphisms in the gene encoding SHP‐2 are associated with an increased susceptibility to develop ulcerative colitis. We recently reported t...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Ltd
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519201/ https://www.ncbi.nlm.nih.gov/pubmed/30376595 http://dx.doi.org/10.1002/path.5177 |
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author | Gagné‐Sansfacon, Jessica Langlois, Ariane Langlois, Marie‐Josée Coulombe, Geneviève Tremblay, Sarah Vaillancourt‐Lavigueur, Vanessa Qu, Cheng‐Kui Menendez, Alfredo Rivard, Nathalie |
author_facet | Gagné‐Sansfacon, Jessica Langlois, Ariane Langlois, Marie‐Josée Coulombe, Geneviève Tremblay, Sarah Vaillancourt‐Lavigueur, Vanessa Qu, Cheng‐Kui Menendez, Alfredo Rivard, Nathalie |
author_sort | Gagné‐Sansfacon, Jessica |
collection | PubMed |
description | The Src homology‐2 domain‐containing tyrosine phosphatase 2 (SHP‐2) regulates many cellular processes, including proliferation, differentiation and survival. Polymorphisms in the gene encoding SHP‐2 are associated with an increased susceptibility to develop ulcerative colitis. We recently reported that intestinal epithelial cell (IEC)‐specific deletion of Shp‐2 in mice (Shp‐2 (IEC‐KO)) leads to chronic colitis and colitis‐associated cancer. This suggests that SHP‐2‐dependent signaling protects the colonic epithelium against inflammation and colitis‐associated cancer development. To verify this hypothesis, we generated mice expressing the Shp‐2 E76K activated form specifically in IEC. Our results showed that sustained Shp‐2 activation in IEC increased intestine and crypt length, correlating with increased cell proliferation and migration. Crypt regeneration capacity was also markedly enhanced, as revealed by ex vivo organoid culture. Shp‐2 activation alters the secretory cell lineage, as evidenced by increased goblet cell numbers and mucus secretion. Notably, these mice also demonstrated elevated ERK signaling in IEC and exhibited resistance against both chemical‐ and Citrobacter rodentium‐induced colitis. In contrast, mice with IEC‐specific Shp‐2 deletion displayed reduced ERK signaling and rapidly developed chronic colitis. Remarkably, expression of an activated form of Braf in Shp‐2‐deficient mice restored ERK activation, goblet cell production and prevented colitis. Altogether, our results indicate that chronic activation of Shp‐2/ERK signaling in the colonic epithelium confers resistance to mucosal erosion and colitis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
format | Online Article Text |
id | pubmed-6519201 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley & Sons, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-65192012019-05-21 The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration Gagné‐Sansfacon, Jessica Langlois, Ariane Langlois, Marie‐Josée Coulombe, Geneviève Tremblay, Sarah Vaillancourt‐Lavigueur, Vanessa Qu, Cheng‐Kui Menendez, Alfredo Rivard, Nathalie J Pathol Original Papers The Src homology‐2 domain‐containing tyrosine phosphatase 2 (SHP‐2) regulates many cellular processes, including proliferation, differentiation and survival. Polymorphisms in the gene encoding SHP‐2 are associated with an increased susceptibility to develop ulcerative colitis. We recently reported that intestinal epithelial cell (IEC)‐specific deletion of Shp‐2 in mice (Shp‐2 (IEC‐KO)) leads to chronic colitis and colitis‐associated cancer. This suggests that SHP‐2‐dependent signaling protects the colonic epithelium against inflammation and colitis‐associated cancer development. To verify this hypothesis, we generated mice expressing the Shp‐2 E76K activated form specifically in IEC. Our results showed that sustained Shp‐2 activation in IEC increased intestine and crypt length, correlating with increased cell proliferation and migration. Crypt regeneration capacity was also markedly enhanced, as revealed by ex vivo organoid culture. Shp‐2 activation alters the secretory cell lineage, as evidenced by increased goblet cell numbers and mucus secretion. Notably, these mice also demonstrated elevated ERK signaling in IEC and exhibited resistance against both chemical‐ and Citrobacter rodentium‐induced colitis. In contrast, mice with IEC‐specific Shp‐2 deletion displayed reduced ERK signaling and rapidly developed chronic colitis. Remarkably, expression of an activated form of Braf in Shp‐2‐deficient mice restored ERK activation, goblet cell production and prevented colitis. Altogether, our results indicate that chronic activation of Shp‐2/ERK signaling in the colonic epithelium confers resistance to mucosal erosion and colitis. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. John Wiley & Sons, Ltd 2018-12-05 2019-01 /pmc/articles/PMC6519201/ /pubmed/30376595 http://dx.doi.org/10.1002/path.5177 Text en © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Papers Gagné‐Sansfacon, Jessica Langlois, Ariane Langlois, Marie‐Josée Coulombe, Geneviève Tremblay, Sarah Vaillancourt‐Lavigueur, Vanessa Qu, Cheng‐Kui Menendez, Alfredo Rivard, Nathalie The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration |
title | The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration |
title_full | The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration |
title_fullStr | The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration |
title_full_unstemmed | The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration |
title_short | The tyrosine phosphatase Shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration |
title_sort | tyrosine phosphatase shp‐2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration |
topic | Original Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519201/ https://www.ncbi.nlm.nih.gov/pubmed/30376595 http://dx.doi.org/10.1002/path.5177 |
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