phosphatidylinositol-5-phosphate and Lymphoma--Large-Cell--Anaplastic

PtdIns5P is a lipid messenger acting as a stress-response mediator in the nucleus, and known to maintain cell activation through traffic alterations upon bacterial infection. Here, we show that PtdIns5P regulates actin dynamics and invasion via recruitment and activation of the exchange factor Tiam1 and Rac1. Restricted Rac1 activation results from the binding of Tiam1 DH-PH domains to PtdIns5P. Using an assay that mimics Rac1 membrane anchoring by using Rac1-His and liposomes containing Ni(2+)-NTA modified lipids, we demonstrate that intrinsic Tiam1 DH-PH activity increases when Rac1 is anchored in a PtdIns5P-enriched environment. This pathway appears to be general since it is valid in different pathophysiological models: receptor tyrosine kinase activation, bacterial phosphatase IpgD expression and the invasive NPM-ALK(+) lymphomas. The discovery that PtdIns5P could be a keystone of GTPases and cytoskeleton spatiotemporal regulation opens important research avenues towards unravelling new strategies counteracting cell invasion.

Topics: Actins; Bacterial Proteins; cdc42 GTP-Binding Protein; Fibroblast Growth Factor 1; Guanine Nucleotide Exchange Factors; Humans; Lymphoma, Large-Cell, Anaplastic; Neoplasm Invasiveness; Phosphatidylinositol Phosphates; Phosphoric Monoester Hydrolases; rac1 GTP-Binding Protein; Shigella flexneri; T-Lymphoma Invasion and Metastasis-inducing Protein 1