SAP-1 (PTPRH) is a receptor-type protein tyrosine phosphatase (RPTP) with a single catalytic domain in its cytoplasmic region and fibronectin type III-like domains in its extracellular region. The cellular localization and biological functions of this RPTP have remained unknown, however. We now show that mouse SAP-1 mRNA is largely restricted to the gastrointestinal tract and that SAP-1 protein localizes to the microvilli of the brush border in gastrointestinal epithelial cells. The expression of SAP-1 in mouse intestine is minimal during embryonic development but increases markedly after birth. SAP-1-deficient mice manifested no marked changes in morphology of the intestinal epithelium. In contrast, SAP-1 ablation inhibited tumorigenesis in mice with a heterozygous mutation of the adenomatous polyposis coli gene. These results thus suggest that SAP-1 is a microvillus-specific RPTP that regulates intestinal tumorigenesis.

The classification of thymic epithelial tumors is controversial because prediction of the biological behavior of these tumors from their morphologic appearance is difficult. The aim of this study was to evaluate the proliferative activity and rate of apoptosis of thymic epithelial tumors classified according to World Health Organization histological classification. We also attempted to determine the importance of a number of proapoptotic factors in these processes. We investigated 46 surgically resected thymic epithelial tumors (8 Type A, 8 Type AB, 7 Type B1, 7 Type B2, 6 Type B3, and 10 Type C). Immunohistochemical staining was performed to determine the tumor expression of p53 protein, Bax, Bcl-2, and survivin. In addition, the Ki-67 labeling index (LI) and apoptotic index (AI) of these tumors were evaluated. Type C thymoma had a higher LI (16.55 ؎ 12.12%) than did the other histological subtypes. Stage IV thymoma (12.36 ؎ 9.99%) had a higher LI than did Stage I tumor. The AI was significantly elevated in Type B1 thymoma (1.47 ؎ 0.55%). Overexpression of p53 protein was observed in Type B3 and C thymomas. p53 proteinpositive tumors had a higher LI than did p53 protein-negative tumors (P < .0001). Bcl-2 expression was observed in Type A, AB, and C thymomas. Bcl-2-positive thymoma had a lower AI than did Bcl-2-negative thymoma (P ‫؍‬ .0157). These results suggest that overexpression of p53 protein is associated with a higher tumor proliferative activity and that Bcl-2 acts as an inhibitor of apoptosis in thymoma.Bcl-2 and p53 protein expression may be useful markers in differentiating thymoma subtypes.

Post-translational modification of protein tyrosine phosphatases (PTPs) is implicated in functional modulation of these enzymes. Stomach cancer-associated protein tyrosine phosphatase-1 (SAP-1), as well as protein tyrosine phosphatase receptor type O (PTPRO) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are receptor-type PTPs (RPTPs), which belong to the R3 subtype RPTP family. Here, we have shown that the carboxyl (COOH)-terminal region of SAP-1 undergoes tyrosine phosphorylation by the treatment with a PTP inhibitor. Src family kinases are important for the tyrosine phosphorylation of SAP-1. Either Grb2 or Fyn, through their Src homology-2 domains, bound to the tyrosine-phosphorylated SAP-1. Moreover, both PTPRO and VE-PTP underwent tyrosine phosphorylation in their COOH-terminal regions. Tyrosine phosphorylation of VE-PTP or PTPRO also promoted their complex formations with Grb2 or Fyn. Forced expression of SAP-1, PTPRO or VE-PTP promoted cell spreading and lamellipodium formation of fibroblasts that expressed an activated form of Ras. In contrast, such effects of non-tyrosine-phosphorylated forms of these RPTPs were markedly smaller than those of wild-type RPTPs. Our results thus suggest that tyrosine phosphorylation of R3 subtype RPTPs promotes their complex formations with Grb2 or Fyn and thus participates in the regulation of cell morphology.

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.

Hepatoid carcinoma of the ovary is an ovarian carcinoma that has phenotypic properties in common with hepatocellular carcinomas. However, the extent of the tumor cells' similarity to and their difference from hepatocytes is largely unknown. In addition, the precursor cell of origin for hepatoid carcinoma of the ovary has not been identified. Three cases of alpha-fetoprotein-producing hepatoid carcinoma of the ovary that were admixed with an adenocarcinoma of common surface epithelial type are reported. The hepatoid carcinomas had a trabecular architecture with canaliculi detected by polyclonal (but not monoclonal) anticarcinoembryonic antigen antibodies. A hepatic phenotype in the hepatoid tumor cells was further supported by the production of albumin mRNA by in situ hybridization. The adenocarcinomas in the three cases were mucinous (Case 1), serous (Case 2), and endometrioid (Case 3), respectively. The cytokeratin (CK) profile in both the hepatoid and adenocarcinomatous components was CK18+/CK19+/CK20+/-, whereas normal and neoplastic hepatocytes were CK18+/CK19-/CK20-. Although this study supports a hepatic phenotype in ovarian hepatoid carcinoma, the CK profile of hepatoid carcinoma differs from that of normal and neoplastic hepatocytes but resembles that of the associated common epithelial adenocarcinoma. These findings suggest that hepatoid carcinoma of the ovary is probably derived from carcinomas of surface epithelial origin by a process of neometaplasia or transdifferentiation.