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

• Type of Material: Article
• Authors: Jessica Gagne-Sansfacon, University of Sherbrooke; Ariane Langlois, University of Sherbrooke; Marie-Josee Langlois, University of Sherbrooke; Genevieve Coulombe, University of Sherbrooke; Sarah Tremblay, University of Sherbrooke; Vanessa Vaillancourt-Lavigueur, University of Sherbrooke; Cheng-Kui Qu, Emory University; Alfredo Menendez, University of Sherbrooke; Nathalie Rivard, University of Sherbrooke
• Language: English
• Date: 2019-01-01
• Publisher: Wiley
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/path.5177
• Title of Journal or Parent Work: Journal of Pathology
• ISSN: 0022-3417
• Volume: 247
• Issue: 1
• Start Page: 135
• End Page: 146
• Grant/Funding Information: Jessica Gagné‐Sansfaçon is a FRQS student scholar.; Nathalie Rivard is a recipient of a Canadian Research Chair in colorectal cancer and inflammatory cell signaling.; Nathalie Rivard and Alfredo Menendez are members of the FRQS‐Funded Centre de Recherche du CHUS.; This research was supported by a grant from Canadian Institutes of Health Research (CIHR) to Nathalie Rivard.
• Keywords: HOST-MICROBE INTERACTIONS; colitis; Oncology; MODULATION; ASSOCIATION; INTESTINAL INFLAMMATION; SUSCEPTIBILITY; Pathology; Science & Technology; ORGANOIDS; epithelial regeneration; Life Sciences & Biomedicine; wound healing; ERK/MAPK; intestinal barrier; NOTCH; ACTIVATION; goblet cells; Shp-2; DIFFERENTIATION; EXPRESSION
• Research Categories: Biology, Cell; Health Sciences, Oncology; Health Sciences, Pathology

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.