Suppression of cell migration by phospholipase C-related catalytically inactive proteindependent modulation of PI3K signalling

The metabolic processes of phosphatidylinositol 4,5-bisphosphate [PI(4,5) P-2] into PI(3,4,5) P-3 and the subsequent PI(3,4,5) P3 signalling are involved in cell migration. Dysfunctions in the control of this pathway can cause human cancer cell migration and metastatic growth. Here we investigated whether phospholipase C-related catalytically inactive protein (PRIP), a PI(4,5) P-2-binding protein, regulates cancer cell migration. PRIP overexpression in MCF-7 and BT-549 human breast cancer cells inhibited cell migration in vitro and metastasis development in vivo. Overexpression of the PRIP pleckstrin homology domain, a PI(4,5) P-2 binding motif, in MCF-7 cells caused significant suppression of cell migration. Consistent with these results, in comparison with wild-type cells, Prip-deficient mouse embryonic fibroblasts exhibited increased cell migration, and this was significantly attenuated upon transfection with a siRNA targeting p110 alpha, a catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI(3,4,5) P-3 production was decreased in Prip-overexpressing MCF-7 and BT-549 cells. PI3K binding to PI(4,5) P-2 was significantly inhibited by recombinant PRIP in vitro, and thus the activity of PI3K was downregulated. Collectively, PRIP regulates the production of PI(3,4,5) P-3 from PI(4,5) P-2 by PI3K, and the suppressor activity of PRIP in PI(4,5) P-2 metabolism regulates the tumour migration, suggesting PRIP as a promising target for protection against metastatic progression.