Schwalm, Stephanie; Maneva Timcheva, Tankica; Filipenko, Iuliia; Ebadi, Mahsa; Hofmann, Lotte P; Zangemeister-Wittke, Uwe; Pfeilschifter, Josef; Huwiler, Andrea (2015). Sphingosine kinase 2 deficiency increases proliferation and migration of renal mouse mesangial cells and fibroblasts. Biological chemistry, 396(6-7), pp. 813-825. De Gruyter 10.1515/hsz-2014-0289
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology |
Graduate School: |
Graduate School for Cellular and Biomedical Sciences (GCB) |
UniBE Contributor: |
Schwalm, Stephanie, Maneva Timcheva, Tankica, Filipenko, Iuliia, Zangemeister-Wittke, Uwe, Huwiler, Andrea |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1431-6730 |
Publisher: |
De Gruyter |
Language: |
English |
Submitter: |
Debora Scherrer |
Date Deposited: |
23 Feb 2016 09:01 |
Last Modified: |
05 Dec 2022 14:52 |
Publisher DOI: |
10.1515/hsz-2014-0289 |
PubMed ID: |
25781541 |
BORIS DOI: |
10.7892/boris.76763 |
URI: |
https://boris.unibe.ch/id/eprint/76763 |
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