We identified RECK, a membrane-anchored glycoprotein negatively regulating the activities of MMPs, as a molecule interacting with Tgat oncoprotein consisting of RhoGEF domain and the unique C-terminal 15 amino acids. The Tgat increased the invasive potential of NIH3T3 cells expressing endogenous mouse RECK and this effect was partially inhibited by the co-expression of human RECK. On the contrary, the expression of exogenous human RECK in HT1080 cell line lacking the endogenous RECK expression reduced its invasive activity, which was recovered by the Tgat co-expression. Moreover, a Tgat mutant lacking the C-terminal region lost the potential to compete the function of RECK in HT1080 cells. These findings indicate that Tgat is the functional inhibitor of RECK, and the activation of MMPs induced by Tgat is likely to enhance invasive activities of cancer cells expressing Tgat. (c) 2007 Elsevier Inc. All rights reserved.