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Author Notes:

Correspondence to: N Rivard, Department of Anatomy and Cell Biology, Cancer Research Pavilion, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3201 rue Jean Mignault, Sherbrooke, QC J1E4K8, Canada. E‐mail: nathalie.rivard@usherbrooke.ca

G‐S performed most of the research shown in Figures 1, ​,2,2, ​,3,3, ​,4,4, ​,5,5, ​,66 and in supplementary material, Figure S2.

GC performed the experiments shown in supplementary material, Figure S1, while AL performed experiments shown in some panels of Figures 4 and ​and55 and in supplementary material, Figure S2.

VV‐L and M‐JL helped with the handling of mice and cell lines.

M‐JL also contributed to the organoid experiments shown in Figure 6.

CKQ provided Ptpn11 E76KNeo/+ mice and revised the manuscript.

ST and AM designed the experiments shown in Figure 3D–G (C. rodentium infection) and revised the manuscript.

JG‐S, M‐JL and NR wrote the paper.

NR was in charge of overall direction and planning.

All authors read and approved the final manuscript.

We thank Pr Claude Asselin for critical reading of the manuscript.

We thank the RNomics and Electron Microscopy & Histology Platforms of the FMSS at the Université de Sherbrooke for services.

Special thanks to Drs David Dankort (McGill University) and Martin McMahon (University of Utah Health Sciences) for providing Braf V600E mice and to Dr Daniel Podolsky (UT Southwestern Medical Center) for sharing a Tff3 antibody.

No conflicts of interest were declared.

Subjects:

Research Funding:

This research was supported by a grant from Canadian Institutes of Health Research (CIHR) to Nathalie Rivard.

Jessica Gagné‐Sansfaçon is a FRQS student scholar.

Nathalie Rivard and Alfredo Menendez are members of the FRQS‐Funded Centre de Recherche du CHUS.

Nathalie Rivard is a recipient of a Canadian Research Chair in colorectal cancer and inflammatory cell signaling.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • Pathology
  • Shp-2
  • colitis
  • intestinal barrier
  • goblet cells
  • epithelial regeneration
  • wound healing
  • ERK/MAPK
  • HOST-MICROBE INTERACTIONS
  • INTESTINAL INFLAMMATION
  • SUSCEPTIBILITY
  • NOTCH
  • DIFFERENTIATION
  • EXPRESSION
  • ORGANOIDS
  • ASSOCIATION
  • MODULATION
  • ACTIVATION

The tyrosine phosphatase Shp-2 confers resistance to colonic inflammation by driving goblet cell function and crypt regeneration

Journal Title:

Journal of Pathology

Volume:

Volume 247, Number 1

Publisher:

, Pages 135-146

Type of Work:

Article | Final Publisher PDF

Abstract:

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.

Copyright information:

© 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 work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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