Numerous epidemiological data indicate that vitamin D receptor (VDR) signaling induced by its ligand or active metabolite 1 alpha,25-dihydroxyvitamin D-3 (1 alpha,25(OH)(2)D-3) has anti-cancer activity in several colon cancers. 1 alpha,25(OH)(2)D-3 induces the epithelial differentiation of SW480 colon cancer cells expressing VDR (SW480-ADH) by upregulating E-cadherin expression; however, its precise mechanism remains unknown. We found that phosphatidylinositol-5-phosphate 4-kinase type II beta (PIPKII beta) but not PIPKII alpha is required for VDR-mediated E-cadherin induction in SW480-ADH cells. The syntenin-2 postsynaptic density protein/disc large/zona occludens (PDZ) domain and pleckstrin homology domain of phospholipase C-delta1 (PLC delta 1 PHD) possess high affinity for phosphatidylinositol-4,5-bisphosphate (PI(4,5)P-2) mainly localized to the nucleus and plasma membrane, respectively. The expression of syntenin-2 PDZ but not PLC delta 1 PHD inhibited 1 alpha,25(OH)(2)D-3-induced E-cadherin upregulation, suggesting that nuclear PI(4,5)P-2 production mediates E-cadherin expression through PIPKII beta in a VDR-dependent manner. PIPKII beta is also involved in the suppression of the cell motility induced by 1 alpha,25(OH)(2)D-3. These results indicate that PIPKII beta-mediated PI(4,5)P-2 signaling is important for E-cadherin upregulation and inhibition of cellular motility induced by VDR activation. (C) 2011 Elsevier Inc. All rights reserved.