Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration

• Published in: EMBO reports 2013-01, Vol.14 (1), p.57-64
• Main Authors: Oppelt, Angela, Lobert, Viola H, Haglund, Kaisa, Mackey, Ashley M, Rameh, Lucia E, Liestøl, Knut, Oliver Schink, Kay, Marie Pedersen, Nina, Wenzel, Eva M, Haugsten, Ellen M, Brech, Andreas, Erik Rusten, Tor, Stenmark, Harald, Wesche, Jørgen
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Cell adhesion & migration; Cell Line; cell migration; Cell Movement - physiology; Cellular biology; Class III Phosphatidylinositol 3-Kinases - genetics; Class III Phosphatidylinositol 3-Kinases - metabolism; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; EMBO20; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression Regulation; Humans; Insects; Kinases; MTMR3; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol Phosphates - biosynthesis; Phosphatidylinositol Phosphates - metabolism; PI3KIII; PIKfyve; Protein Binding; Protein Interaction Domains and Motifs; Protein Tyrosine Phosphatases, Non-Receptor - antagonists & inhibitors; Protein Tyrosine Phosphatases, Non-Receptor - genetics; Protein Tyrosine Phosphatases, Non-Receptor - metabolism; Proteins; PtdIns5P; RNA, Small Interfering - genetics; Scientific Report; Scientific Reports; Signal Transduction
• ISSN: 1469-221X; 1469-3178
• DOI: 10.1038/embor.2012.183

Although phosphatidylinositol 5‐phosphate (PtdIns5 P ) is present in many cell types and its biogenesis is increased by diverse stimuli, its precise cellular function remains elusive. Here we show that PtdIns5 P levels increase when cells are stimulated to move and we find PtdIns5 P to promote cell migration in tissue culture and in a Drosophila in vivo model. First, class III phosphatidylinositol 3‐kinase, which produces PtdIns3 P , was shown to be involved in migration of fibroblasts. In a cell migration screen for proteins containing PtdIns3 P ‐binding motifs, we identified the phosphoinositide 5‐kinase PIKfyve and the phosphoinositide 3‐phosphatase MTMR3, which together constitute a phosphoinositide loop that produces PtdIns5 P via PtdIns(3,5) P 2 . The ability of PtdIns5 P to stimulate cell migration was demonstrated directly with exogenous PtdIns5 P and a PtdIns5 P ‐producing bacterial enzyme. Thus, the identified phosphoinositide loop defines a new role for PtdIns5 P in cell migration. This study reports that stimulation of cells with FGF1 promotes PtdIns5P production and demonstrates that a PtdIns5 P ‐producing loop constituted by PI3KIII, PIKfyve and MTMR3 is required for cell migration.