title: Sphingolipids inhibit vimentin-dependent cell migration.
abstract: The sphingolipids, sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), can induce or inhibit cellular migration. The intermediate filament protein vimentin is an inducer of migration and a marker for epithelial-mesenchymal transition. Given that keratin intermediate filaments are regulated by SPC, with consequences for cell motility, we wanted to determine whether vimentin is also regulated by sphingolipid signalling and whether it is a determinant for sphingolipid-mediated functions. In cancer cells where S1P and SPC inhibited migration, we observed that S1P and SPC induced phosphorylation of vimentin on S71, leading to a corresponding reorganization of vimentin filaments. These effects were sphingolipid-signalling-dependent, because inhibition of either the S1P2 receptor (also known as S1PR2) or its downstream effector Rho-associated kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) nullified the sphingolipid-induced effects on vimentin organization and S71 phosphorylation. Furthermore, the anti-migratory effect of S1P and SPC could be prevented by expressing S71-phosphorylation-deficient vimentin. In addition, we demonstrated, by using wild-type and vimentin-knockout mouse embryonic fibroblasts, that the sphingolipid-mediated inhibition of migration is dependent on vimentin. These results imply that this newly discovered sphingolipid-vimentin signalling axis exerts brake-and-throttle functions in the regulation of cell migration.
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, POB 123, FIN-20521, Turku, Finland Department of Biosciences, Åbo Akademi University, Tykistökatu 6A, FI-20520, Turku, Finland.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Hyder
authors.affiliation: Department of Biosciences, Åbo Akademi University, Tykistökatu 6A, FI-20520, Turku, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Kemppainen
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, POB 123, FIN-20521, Turku, Finland Department of Biosciences, Åbo Akademi University, Tykistökatu 6A, FI-20520, Turku, Finland.
authors.forename: Kimmo O
authors.initials: KO
authors.lastname: Isoniemi
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, POB 123, FIN-20521, Turku, Finland Environmental Science Lab, Faculty of Pharmacy, Meijo University, Yagotoyama 150, Tempaku. Nagoya 468-8503, Japan.
authors.forename: Susumu Y
authors.initials: SY
authors.lastname: Imanishi
authors.affiliation: Division of Biochemistry, Aichi Cancer Center Research Institute, Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan Department of Cellular Oncology, Graduate School of Medicine, Nagoya University, Showa-Ku, Nagoya 466-8550, Japan.
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Goto
authors.affiliation: Division of Biochemistry, Aichi Cancer Center Research Institute, Kanokoden, Chikusa-Ku, Nagoya 464-8681, Japan Department of Cellular Oncology, Graduate School of Medicine, Nagoya University, Showa-Ku, Nagoya 466-8550, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Inagaki
authors.affiliation: Department of Biosciences, Åbo Akademi University, Tykistökatu 6A, FI-20520, Turku, Finland.
authors.forename: Elnaz
authors.initials: E
authors.lastname: Fazeli
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, POB 123, FIN-20521, Turku, Finland Department of Biosciences, Åbo Akademi University, Tykistökatu 6A, FI-20520, Turku, Finland john.eriksson@abo.fi ktornqvi@abo.fi.
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
authors.affiliation: Department of Biosciences, Åbo Akademi University, Tykistökatu 6A, FI-20520, Turku, Finland Minerva Foundation Institute for Medical Research, Biomedicum Helsinki, Tukholmankatu 8, 00290 Helsinki, Finland john.eriksson@abo.fi ktornqvi@abo.fi.
authors.forename: Kid
authors.initials: K
authors.lastname: Törnquist
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D014746:Vimentin / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C477522:S1PR2 protein, human; D013107:Sphingolipids; D000081025:Sphingosine-1-Phosphate Receptors; D014746:Vimentin; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; C060506:sphingosine 1-phosphate; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; D013110:Sphingosine
keywords: Intermediate filament; Phosphorylation; ROCK; S1P; S1P2; S1PR2; SPC; Sphingosine 1-phosphate; Sphingosylphosphorylcholine; Vimentin; migration