Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent 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)P 3 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 p110α, 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.