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

被引:37
作者
Ryu, Jung Min [1 ,2 ,3 ]
Baek, Young Bin [1 ,2 ]
Shin, Myung Sun [1 ,2 ]
Park, Ji Hoon [1 ,2 ]
Park, Soo Hyun [3 ]
Lee, Jang Hern [1 ,2 ]
Han, Ho Jae [1 ,2 ]
机构
[1] Seoul Natl Univ, Dept Vet Physiol, Coll Vet Med, Seoul 151741, South Korea
[2] Seoul Natl Univ, Res Inst Vet Sci, Seoul 151741, South Korea
[3] Chonnam Natl Univ, Dept Vet Physiol, Coll Vet Med, Kwangju 500757, South Korea
基金
新加坡国家研究基金会;
关键词
PROTEIN-COUPLED RECEPTOR; SMOOTH-MUSCLE-CELLS; SPHINGOSINE 1-PHOSPHATE RECEPTORS; ENDOTHELIAL GROWTH-FACTOR; SELF-RENEWAL; DIFFERENTIATION; ACTIVATION; EXPRESSION; ANGIOGENESIS; MAINTENANCE;
D O I
10.1016/j.scr.2013.08.013
中图分类号
Q813 [细胞工程];
学科分类号
摘要
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, S1P(1-5) receptors were expressed in mouse ES cells and S1P increased S1P(1-3) receptor expression level. S1P treatment stimulated the cellular proliferation in S1P(1/3)-dependent manner, located in lipid rafts. In response to S1P, beta-arrestin was recruited to S1P1/3 receptor and c-Src was activated. S1P also increased the binding of S1P(1/3) receptor with Flk-1. Similar to responses for VEGF, S1P increased Flk-1 phosphorylation, which was blocked by beta-arrestin siRNA, and PP2, but not by VEGF-A(164) antibody or VEGF siRNA. In addition, S1P induced VEGF expression and VEGFR2 kinase inhibitor (SU1498) blocked the S1P-induced cellular proliferation. However, VEGF-A(164) 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 beta-arrestin/c-Src pathways stimulated mouse ES cell proliferation. (C) 2013 The Authors. Published by Elsevier B. V. All rights reserved.
引用
收藏
页码:69 / 85
页数:17
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