TY - JOUR
T1 - ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion
AU - Yagi, R.
AU - Tanaka, M.
AU - Sasaki, K.
AU - Kamata, R.
AU - Nakanishi, Y.
AU - Kanai, Y.
AU - Sakai, R.
N1 - Funding Information:
The pEGFP-ARAP3 plasmid was a kind gift from Krugmann S (Cambridge, UK). This work was supported by a Grant-in-Aid for Cancer Research and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Science and Technology of Japan for the Third Term Comprehensive 10-Year Strategy for Cancer Control.
PY - 2011/3/24
Y1 - 2011/3/24
N2 - 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.
AB - 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.
KW - ARAP3
KW - Rho- GAP
KW - cell-ECM adhesion
KW - invasion
KW - scirrhous gastric carcinoma
UR - http://www.scopus.com/inward/record.url?scp=79953057231&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79953057231&partnerID=8YFLogxK
U2 - 10.1038/onc.2010.522
DO - 10.1038/onc.2010.522
M3 - Article
C2 - 21076469
AN - SCOPUS:79953057231
SN - 0950-9232
VL - 30
SP - 1413
EP - 1421
JO - Oncogene
JF - Oncogene
IS - 12
ER -
