BACKGROUND: Recent studies identified that SH3 and multiple ankyrin repeat domains 2 (SHANK2) is located in a gene-amplified region 11q13 of various human cancers, and has oncogenic functions as a Hippo pathway suppressor in hepatocellular carcinoma. In this study, we tested whether SHANK2 acts as a cancer-promoting gene through its activation or overexpression in gastric cancer (GC). MATERIALS AND METHODS: We analyzed 5 GC cell lines and 172 primary tumor samples of GC, which were curatively resected in our hospital. RESULTS: Overexpression of SHANK2 protein was frequently detected in GC cell lines (4/5 cell lines, 80%). Knockdown of SHANK2 inhibited cell proliferation, migration and invasion of GC cells in a CONCLUSIONS: These findings suggest that SHANK2 plays a crucial role in tumor malignant potential through the Hippo pathway suppression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.