Nathalie Rivard
Universite de Sherbrooke, Canada
Title: Epithelial SHP-2 protects the intestinal mucosa against colitis and colorectal cancer
Biography
Biography: Nathalie Rivard
Abstract
SHP-2 is a Src homology 2-containing protein tyrosine phosphatase (PTP) expressed in most embryonic and adult tissues. SHP-2 regulates many cellular functions including growth, differentiation, innate immune response, chemotaxis and survival. Genetic and biochemical evidence demonstrate that SHP-2 can regulate major signalling pathways including the RAS/MAPK, PI3K/Akt and JAK/STAT pathways. Interestingly, variations within the human gene locus encoding SHP-2 have been associated with increased susceptibility to develop ulcerative colitis. We thus analyzed the role of SHP-2 in the intestine by first generating mice with an intestinal epithelial cell (IEC)-specific deletion of SHP-2 expression (SHP-2IEC-KO mice). Interestingly, these mice rapidly develop inflammation one month after birth, with clinical and histopathological features similar to ulcerative colitis. Alterations in goblet/aaneth cell ratio were observed two weeks after birth, before the onset of inflammation and were associated with significant alterations in microbiota composition. With age, SHP-2IEC-KO mice developed colitis-associated adenocarcinomas. To further analyze the protective role of SHP-2 in the intestinal epithelium, we have also generated mice expressing a constitutive active form of SHP-2 specifically in IECs (SHP-2IEC-E76K mice). These mice were either challenged with Dextran Sulfate Sodium (DSS) to induce chemical colitis or with Citrobacter rodentium to induce infectious colitis. Results showed that SHP-2IEC-E76K mice were resistant to DSS treatment or C. rodentium infection. Thus, SHP-2 activation exerts protective actions against mucosal damage and during infection with an A/E bacterial pathogen. Finally, we found reduced SHP-2 expression in intestinal biopsies from patients with active colitis, emphasizing the inverse relationship between SHP-2 expression and colonic inflammatory phenotype. Overall, our results indicate that SHP-2 maintains barrier function in the colon and thereby, helps to prevent spontaneous microbiota-driven inflammation and colitis-associated cancer development.