Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling.

ABSTRACT: The metabolic processes of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] into PI(3,4,5)P₃ 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)P₂-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)P₂ 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?, a catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI(3,4,5)P₃ production was decreased in Prip-overexpressing MCF-7 and BT-549 cells. PI3K binding to PI(4,5)P₂ 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)P₃ from PI(4,5)P₂ by PI3K, and the suppressor activity of PRIP in PI(4,5)P₂ metabolism regulates the tumour migration, suggesting PRIP as a promising target for protection against metastatic progression.

SUBMITTER: Asano S 

PROVIDER: S-EPMC5511194 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature