Nm23-H1 regulates contact inhibition of locomotion which is affected by ephrin-B1

Abstract

Contact inhibition of locomotion (CIL) is the process by which cells stop the continual migration in the same direction after collision with another cell. Highly invasive malignant cells exhibit diminished CIL when they contact stromal cells, which allows invasion of the tissue by tumors. We show that Nm23-H1 is essential for the suppression of Rac1 through inactivation of Tiam1 at the sites of cell-cell contact, which plays a pivotal role in CIL. U87MG cells show CIL when they contact normal glia. In spheroid confrontation assays U87MG cells showed only limited invasion of the glial population, but reduction of Nm23-H1 expression in U87MG cells abrogated CIL resulting in invasion. In U87MG cells, Nm23-H1 is translocated to the sites of contact with glia through association with α-catenin and N-cadherin. Mutants of Nm23-H1, which lacked the binding ability with Tiam1, or α-catenin did not restore CIL. Moreover, the expression of ephrin-B1 in tumor cells disrupted CIL and promoted invasion. As one mechanism, ephrin-B1 inhibits the association of Nm23-H1 with Tiam1, which contributes for activation of Rac1. These results indicate a novel function of Nm23-H1 to control CIL, and its negative regulation by ephrin-B1.