We have previously shown that the expression of periostin is significantly downregulated in human bladder cancer tissues and that periostin suppresses cell invasiveness and metastasis of cancer cells. To clarify the molecular mechanism of this suppression by periostin, we searched for periostin-binding proteins and identified TAB1, which interacts with and activates TAK1, by mass analysis of proteins co-precipitated with periostin in 293T cells expressing periostin. The association between periostin and TAB1 was confirmed by a pulldown assay in 293T cells co-tranfected with expression plasmids of periostin, TAB1 and TAK1. TAK1 was also co-precipitated with periostin in this assay. Co-transfection experiments in 293T also showed that periostin could activate TAK1. Introduction of siRNA for TAB1 suppressed TAK1 activation by periostin. Analyses with deletion mutants of periostin revealed that the C-terminal region of periostin was necessary and sufficient for the association with TAB1 and the TAK1 activation. The suppression of invasiveness by periostin was attenuated by siRNA targeting TAK1 or TAB1 in 293T (human embryonic kidney) and T24 (human bladder carcinoma) cell lines. These findings indicate that periostin is involved in the suppression of cell invasiveness via the TAB1/TAK1 signaling pathway.