title: 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.
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;
authors.forename: Yoji
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;
authors.forename: Takenori
authors.initials: T
authors.lastname: Kotani
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan;
authors.forename: Yana
authors.initials: Y
authors.lastname: Supriatna
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;
authors.forename: Shinya
authors.initials: S
authors.lastname: Imada
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Kohichi
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Miki
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;
authors.forename: Edwin Widyanto
authors.initials: EW
authors.lastname: Daniwijaya
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan;
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Sadakata
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan;
authors.forename: Shinya
authors.initials: S
authors.lastname: Kusakari
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan;
authors.forename: Munemasa
authors.initials: M
authors.lastname: Mori
authors.affiliation: Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan;
authors.forename: Yoshitake
authors.initials: Y
authors.lastname: Kanazawa
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Drug Discovery Research Laboratories, Kyowa Hakko Kirin Co., Shizuoka 411-8731, Japan;
authors.forename: Katsuya
authors.initials: K
authors.lastname: Okawa
authors.affiliation: Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe 650-8586, Japan;
authors.forename: Mariko
authors.initials: M
authors.lastname: Takeda-Morishita
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;
authors.forename: Hideki
authors.initials: H
authors.lastname: Okazawa
authors.affiliation: Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, Gunma 371-8514, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan;
authors.forename: Takeshi
authors.initials: T
authors.lastname: Azuma
authors.affiliation: Division of Cancer Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan;
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.affiliation: Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan; matozaki@med.kobe-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002452:Cell Count; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000473:pathology; D005260:Female; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D016753:Interleukin-10 / Q000172:deficiency / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000172:deficiency / Q000378:metabolism*; D000072377:Syk Kinase; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C000602671:CEACAM20 protein, mouse; D015815:Cell Adhesion Molecules; D018925:Chemokines; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D016753:Interleukin-10; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; C000602672:SAP-1 protein, mouse
keywords: colitis; intestinal epithelial cells; intestinal immunity; protein tyrosine phosphatase