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Stem Cell Res. 2014 Jan;12(1):69-85. doi: 10.1016/j.scr.2013.08.013. Epub 2013 Sep 7.

Sphingosine-1-phosphate-induced Flk-1 transactivation stimulates mouse embryonic stem cell proliferation through S1P1/S1P3-dependent β-arrestin/c-Src pathways.

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  • 1Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-741, Republic of Korea; Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
  • 2Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-741, Republic of Korea.
  • 3Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
  • 4Department of Veterinary Physiology, College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul 151-741, Republic of Korea. Electronic address: hjhan@snu.ac.kr.

Abstract

Although recent findings showed that the bioactive lipid metabolites can regulate the ES cell functions, the physiological relevance of interaction between sphingosine-1-phosphate (S1P) and Flk-1 and its related signaling molecules are not yet clear in ES cell proliferation. In the present study, S1P1-5 receptors were expressed in mouse ES cells and S1P increased S1P1-3 receptor expression level. S1P treatment stimulated the cellular proliferation in S1P1/3-dependent manner, located in lipid rafts. In response to S1P, β-arrestin was recruited to S1P1/3 receptor and c-Src was activated. S1P also increased the binding of S1P1/3 receptor with Flk-1. Similar to responses for VEGF, S1P increased Flk-1 phosphorylation, which was blocked by β-arrestin siRNA, and PP2, but not by VEGF-A164 antibody or VEGF siRNA. In addition, S1P induced VEGF expression and VEGFR2 kinase inhibitor (SU1498) blocked the S1P-induced cellular proliferation. However, VEGF-A164 antibody or VEGF siRNA partially blocked S1P-induced cellular proliferation, suggesting that both VEGF-dependent Flk-1 activation and VEGF-independent Flk-1 activation are involved in S1P-induced ES cell proliferation. S1P and VEGF-induced phosphorylation of ERK and JNK were blocked by pretreatment with SU1498. Moreover, inhibition of ERK and JNK blocked S1P-induced cellular proliferation. In conclusion, S1P-elicited transactivation of Flk-1 mediated by S1P1/3-dependent β-arrestin/c-Src pathways stimulated mouse ES cell proliferation.

© 2013.

KEYWORDS:

CDK; CLM; Cholesterol-loaded MβCD.; Cyclin dependent kinase; ERK; ESC; Embryonic stem cell; Extracellular signal-regulated kinases; Fetal Liver Kinase 1; Flk-1; JNK; Methyl-β-cyclodextrin; MβCD; RTK; Receptor tyrosine kinase; S1P; Sphingosine-1-phosphate; VEGF; Vascular endothelial growth factor; c-Jun N-terminal kinases

PMID:
24145189
[PubMed - indexed for MEDLINE]
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