title: Production of phosphatidylinositol 5-phosphate via PIKfyve and MTMR3 regulates cell migration.
abstract: Although phosphatidylinositol 5-phosphate (PtdIns5P) is present in many cell types and its biogenesis is increased by diverse stimuli, its precise cellular function remains elusive. Here we show that PtdIns5P levels increase when cells are stimulated to move and we find PtdIns5P to promote cell migration in tissue culture and in a Drosophila in vivo model. First, class III phosphatidylinositol 3-kinase, which produces PtdIns3P, was shown to be involved in migration of fibroblasts. In a cell migration screen for proteins containing PtdIns3P-binding motifs, we identified the phosphoinositide 5-kinase PIKfyve and the phosphoinositide 3-phosphatase MTMR3, which together constitute a phosphoinositide loop that produces PtdIns5P via PtdIns(3,5)P(2). The ability of PtdIns5P to stimulate cell migration was demonstrated directly with exogenous PtdIns5P and a PtdIns5P-producing bacterial enzyme. Thus, the identified phosphoinositide loop defines a new role for PtdIns5P in cell migration.
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Angela
authors.initials: A
authors.lastname: Oppelt
authors.forename: Viola H
authors.initials: VH
authors.lastname: Lobert
authors.forename: Kaisa
authors.initials: K
authors.lastname: Haglund
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Mackey
authors.forename: Lucia E
authors.initials: LE
authors.lastname: Rameh
authors.forename: Knut
authors.initials: K
authors.lastname: Liestøl
authors.forename: Kay Oliver
authors.initials: KO
authors.lastname: Schink
authors.forename: Nina Marie
authors.initials: NM
authors.lastname: Pedersen
authors.forename: Eva M
authors.initials: EM
authors.lastname: Wenzel
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Haugsten
authors.forename: Andreas
authors.initials: A
authors.lastname: Brech
authors.forename: Tor Erik
authors.initials: TE
authors.lastname: Rusten
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
authors.forename: Jørgen
authors.initials: J
authors.lastname: Wesche
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D058546:Class III Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis* / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
chemical_list: D018129:Phosphatidylinositol Phosphates; D034741:RNA, Small Interfering; C106336:phosphatidylinositol 3,5-diphosphate; C055525:phosphatidylinositol 3-phosphate; C113567:phosphatidylinositol 5-phosphate; D019869:Phosphatidylinositol 3-Kinases; D058546:Class III Phosphatidylinositol 3-Kinases; C492139:PIKFYVE protein, human; C444436:MTMR3 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor