title: ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion.
abstract: During the analysis of phosphotyrosine-containing proteins in scirrhous gastric carcinoma cell lines, we observed an unusual expression of Arf-GAP with Rho-GAP domain, ankyrin repeat and PH domain 3 (ARAP3), a multimodular signaling protein that is a substrate of Src family kinases. Unlike other phosphotyrosine proteins, such as CUB domain-containing protein 1 (CDCP1) and Homo sapiens chromosome 9 open reading frame 10/oxidative stress-associated Src activator (C9orf10/Ossa), which are overexpressed and hyperphosphorylated in scirrhous gastric carcinoma cell lines, ARAP3 was underexpressed in cancerous human gastric tissues. In this study, we found that overexpression of ARAP3 in the scirrhous gastric carcinoma cell lines significantly reduced peritoneal dissemination. In vitro studies also showed that ARAP3 regulated cell attachment to the extracellular matrix, as well as invasive activities. These effects were suppressed by mutations in the Rho-GTPase-activating protein (GAP) domain or in the C-terminal two tyrosine residues that are phosphorylated by Src. Thus, the expression and phosphorylation state of ARAP3 may affect the invasiveness of cancer by modulating cell adhesion and motility. Our results suggest that ARAP3 is a unique Src substrate that suppresses peritoneal dissemination of scirrhous gastric carcinoma cells.
authors.affiliation: Growth Factor Division and National Cancer Center Research Institute, Tsukiji, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Yagi
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Sasaki
authors.forename: R
authors.initials: R
authors.lastname: Kamata
authors.forename: Y
authors.initials: Y
authors.lastname: Nakanishi
authors.forename: Y
authors.initials: Y
authors.lastname: Kanai
authors.forename: R
authors.initials: R
authors.lastname: Sakai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002293:Adenocarcinoma, Scirrhous / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness; D010537:Peritoneum / Q000473:pathology*; D017434:Protein Structure, Tertiary; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C446512:ARAP3 protein, human; D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D019061:src-Family Kinases