title: FTY720-phosphate is dephosphorylated by lipid phosphate phosphatase 3.
abstract: FTY720 is a novel immunomodulatory drug efficacious in the treatment of multiple sclerosis. The drug is converted in vivo to the monophosphate, FTY720-P, by sphingosine kinase 2. This conversion is incomplete, suggesting opposing actions of kinase and phosphatase activities. To address which of the known lipid phosphatases might dephosphorylate FTY720-P, we overexpressed the broad specificity lipid phosphatases LPP1-3, and the specific S1P phosphatases (SPP1 and 2) in HEK293 cells, and performed in vitro assays using lysates of transfected cells. Among LPPs, only LPP3 was able to dephosphorylate FTY720-P; among SPPs, only SPP1 showed activity against FTY720-P. On intact cells, LPP3 acted as an ecto-phosphatase or FTY720-P, thus representing the major phosphatase involved in the equilibrium between FTY720 and FTY720-P observed in vivo.
authors.affiliation: Novartis Institutes for BioMedical Research, Vienna, Austria.
authors.forename: Diana
authors.initials: D
authors.lastname: Mechtcheriakova
authors.forename: Alexander
authors.initials: A
authors.lastname: Wlachos
authors.forename: Jury
authors.initials: J
authors.lastname: Sobanov
authors.forename: Frederic
authors.initials: F
authors.lastname: Bornancin
authors.forename: Gerhard
authors.initials: G
authors.lastname: Zlabinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Baumruker
authors.forename: Andreas
authors.initials: A
authors.lastname: Billich
mesh_terms: D002478:Cells, Cultured; D000068876:Fingolimod Hydrochloride; D006801:Humans; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D011409:Propylene Glycols / Q000737:chemistry / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D014162:Transfection
chemical_list: D010710:Phosphates; D011409:Propylene Glycols; C112948:lipid phosphate phosphatase; C521833:PLPP3 protein, human; D010711:Phosphatidate Phosphatase; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine