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 p110α, 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.
Highlights
The cellular phosphoinositide metabolism pathway and its metabolite signalling are critically important for numerous cellular processes
PI(4,5)P2 is converted to PI(3,4,5)P3 by the class I subclass of phosphatidylinositol 3-kinases (PI3Ks) that are activated by extracellular stimuli, including platelet-derived growth factor (PDGF) and epidermal growth factor
PRIP1 inhibits the motility of MCF-7 and BT-549 breast cancer cells
Summary
The cellular phosphoinositide metabolism pathway and its metabolite signalling are critically important for numerous cellular processes. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] constitutes about only 1% of total plasma membrane lipids, but is an important lipid as a membrane-bound anchoring molecule and the precursor of three second messengers: inositol 1,4,5-trisphosphate [Ins(1,4,5)P3], diacylglycerol and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] These phospholipids and the metabolites are major signalling messengers of basic cellular processes, such as cell differentiation, proliferation, mitosis, migration, and cell survival. Orchestrated cell motility is oriented by polarised intracellular signalling, which forms protrusive structures, such as lamellipodia and filopodia, at the leading edge of cells[5]. This process is regulated by PI(3,4,5)P3 signalling in controlling the actin cytoskeleton in mammalian cells. The functions of PRIP in the regulation of phosphoinositide signalling have not been determined
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