Protein tyrosine phosphatase SAP-1 protects against colitis through regulation of CEACAM20 in the intestinal epithelium

Abstract

Intestinal epithelial cells contribute to regulation of intestinal immunity in mammals, but the detailed molecular mechanisms of such regulation have remained largely unknown. Stomach-cancer-associated protein tyrosine phosphatase 1 (SAP-1, also known as PTPRH) is a receptor-type protein tyrosine phosphatase that is localized specifically at microvilli of the brush border in gastrointestinal epithelial cells. Here we show that SAP-1 ablation in interleukin (IL)-10-deficient mice, a model of inflammatory bowel disease, resulted in a marked increase in the severity of colitis in association with up-regulation of mRNAs for various cytokines and chemokines in the colon. Tyrosine phosphorylation of carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 20, an intestinal microvillus-specific transmembrane protein of the Ig superfamily, was greatly increased in the intestinal epithelium of the SAP-1-deficient animals, suggesting that this protein is a substrate for SAP-1. Tyrosine phosphorylation of CEACAM20 by the protein tyrosine kinase c-Src and the consequent association of CEACAM20 with spleen tyrosine kinase (Syk) promoted the production of IL-8 in cultured cells through the activation of nuclear factor-κB (NF-κB). In addition, SAP-1 and CEACAM20 were found to form a complex through interaction of their ectodomains. SAP-1 and CEACAM20 thus constitute a regulatory system through which the intestinal epithelium contributes to intestinal immunity.

Role of Src Family Kinases in Regulation of Intestinal Epithelial Homeostasis

“…We next investigated whether IEC-specific ablation of Csk affects the numbers of Paneth cells, goblet cells, or enteroendocrine cells in the intestinal epithelium. The number of Paneth cells, which were stained with antibodies to lysozyme (21), was significantly reduced at the base of crypts in the ileum of Csk CKO mice at 8 weeks of age ( Fig. 3D and E).…”

“…Mouse IECs were isolated as previously described (21), with slight modifications. In brief, the freshly isolated ileum or colon of adult mice was washed with PBS, cut into small pieces, washed three times with Hanks' balanced salt solution (HBSS) containing 1% fetal bovine serum and 25 mM HEPES-NaOH (pH 7.5), and then incubated three or four times on a rolling platform for 15 min at room temperature in HBSS containing 5 mM EDTA and 25 mM HEPES-NaOH (pH 7.5).…”

“…Frozen sections with a thickness of 5 m were prepared with a cryostat, mounted on glass slides, and air dried. The sections were then stained with primary antibodies and fluorescent dye-labeled secondary antibodies as described previously (21). Images were obtained with a fluorescence microscope (BX51; Olympus, Tokyo, Japan) or a confocal laser scanning microscope (LSM710; Carl Zeiss, Oberkochen, Germany).…”

Coevolution of paired receptors in Xenopus carcinoembryonic antigen-related cell adhesion molecule families suggests appropriation as pathogen receptors

“…They are clustered distally from the CEACAM1-related genes. They differ in domain organization and sequence among each other and exhibit specialized functions [25][26][27]. However, they are conserved between mammalian species which allows unequivocal assignment of orthologs [3].…”

Estudo dinâmico da expressão gênica global durante a interação STEC-enterócito utilizando séries temporais

“…A proteína BAHD está hipoexpressa nas células do cólon de pacientes com colite ulcerativa (Zhu et al, 2015). O hub CEACAM20 codifica para uma proteína da família de Ig transmembrana específica de microvilos de enterócitos que se liga a tirosina kinase ativando NF-κβ, além de induzir a produção de citocinas, como a IL-8 (Murata et al, 2015).…”