The APC-associated guanine nucleotide exchange factor (GEF) Asef regulates cell morphology and migration. Asef contains a pleckstrin homology (PH) domain in addition to DbI homology (13H), APC-binding (ABR), and Src homology 3 (SH3) domains. Here we show that the PH domain of Asef binds to phosphatidylinositol 3,4,5-trisphophate [Ptdlns(3,4,5)P3] and targets Asef to the cell-cell adhesion sites in MDCK II cells. Furthermore, we demonstrate that overexpression of Asef in MDCK II cells results in increases in the amounts of E-cadherin and the actin filaments at the sites of cell-cell contact. These results suggest that Asef is targeted via its PH domain to the cell-cell adhesion sites and is involved in the regulation of cell adhesion. (c) 2007 Elsevier Inc. All rights reserved.