title: Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts.
abstract: Both of the sphingosine kinase (SK) subtypes SK-1 and SK-2 catalyze the production of the bioactive lipid molecule sphingosine 1-phosphate (S1P). However, the subtype-specific cellular functions are largely unknown. In this study, we investigated the cellular function of SK-2 in primary mouse renal mesangial cells (mMC) and embryonic fibroblasts (MEF) from wild-type C57BL/6 or SK-2 knockout (SK2ko) mice. We found that SK2ko cells displayed a significantly higher proliferative and migratory activity when compared to wild-type cells, with concomitant increased cellular activities of the classical extracellular signal regulated kinase (ERK) and PI3K/Akt cascades, and of the small G protein RhoA. Furthermore, we detected an upregulation of SK-1 protein and S1P3 receptor mRNA expression in SK-2ko cells. The MEK inhibitor U0126 and the S1P1/3 receptor antagonist VPC23019 blocked the increased migration of SK-2ko cells. Additionally, S1P3ko mesangial cells showed a reduced proliferative behavior and reduced migration rate upon S1P stimulation, suggesting a crucial involvement of the S1P3 receptor. In summary, our data demonstrate that SK-2 exerts suppressive effects on cell growth and migration in renal mesangial cells and fibroblasts, and that therapeutic targeting of SKs for treating proliferative diseases requires subtype-selective inhibitors.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schwalm
authors.forename: Tankica Maneva
authors.initials: TM
authors.lastname: Timcheva
authors.forename: Iuliia
authors.initials: I
authors.lastname: Filipenko
authors.forename: Mahsa
authors.initials: M
authors.lastname: Ebadi
authors.forename: Lotte P
authors.initials: LP
authors.lastname: Hofmann
authors.forename: Uwe
authors.initials: U
authors.lastname: Zangemeister-Wittke
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Andrea
authors.initials: A
authors.lastname: Huwiler
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000235:genetics / Q000502:physiology*; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); C000594250:sphingosine kinase 2, human; D000099157:Sphingosine Kinase