Kisspeptin-10 inhibits cell migration in vitro via a receptor-GSK3 beta-FAK feedback loop in HTR8SVneo cells
Kisspeptin-10 inhibits cell migration in vitro via a receptor-GSK3 beta-FAK feedback loop in HTR8SVneo cells
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DOI：
10.1016/j.placenta.2012.02.001
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发表时间：
2012-05-01
期刊：
影响因子：
3.8
通讯作者：
Millar, R. P.
中科院分区：
文献类型：
--
作者：
Roseweir, A. K.;Katz, A. A.;Millar, R. P.
Kisspeptin抑制癌细胞转移和胎盘滋养细胞迁移。Kisspeptin基因在胎盘中的表达和循环Kisspeptin水平在正常妊娠期间发生变化，它们在子痫前期发生改变。因此，我们评估了kisspeptin-10对来自妊娠早期外渗滋养细胞（HTR8SVneo）的人胎盘细胞系体外迁移的影响。HTR8SVneo细胞特异性结合I-125-Kisspeptin-10，但kisspeptin-10不诱导肌醇磷酸的产生。kisspeptin-10抑制细胞迁移，在100 nM处抑制最大。研究了抑制细胞迁移的信号通路。用kisspeptin-10处理可引起GSK3 β丝氨酸位点(9)的磷酸化（抑制活性），在5分钟时增加3倍。ERK1/2和p38MAPK的瞬时磷酸化在10分钟达到峰值。局灶黏附激酶（FAK）在Tyr（925）上的磷酸化在10分钟内增加了3倍。抑制GSK3 β与β -连环蛋白释放到细胞质中相关。这些信号事件被G（q/11）、Src、EGFR、PI(3)K、PKC和MEK的抑制剂不同程度地阻断。数据表明kisspeptin/GPR54 egf受体的反式激活导致ERK1/2磷酸化，引起p90rsk的激活，进而通过Ser(9)磷酸化抑制GSK3 β。GSK3 β的失活导致β -连环蛋白释放到细胞质中，影响细胞-细胞粘附和FAK的Tyr（925）磷酸化，从而通过RAS/Raf-1增加ERK1/2的磷酸化，从而形成一个反馈回路，增强对迁移的影响。这些发现表明，kisspeptin-10通过刺激复杂的erk1 /2- p90风险- gsk3 β - fak反馈相互作用，抑制人胎盘滋养层来源的HTR8SVneo细胞的迁移。(C) 2012 Elsevier Ltd.版权所有。
Kisspeptin inhibits cancer cell metastasis and placental trophoblast cell migration. Kisspeptin gene expression in the placenta and circulating kisspeptin levels change during normal pregnancy and they are altered in preeclampsia. We therefore assessed the effect of kisspeptin-10 on the in vitro migration of a human placental cell line derived from first trimester extravillious trophoblasts (HTR8SVneo). HTR8SVneo cells specifically bound I-125-Kisspeptin-10 but kisspeptin-10 did not induce inositol phosphate production. Cell migration was inhibited by kisspeptin-10 with a maximal inhibition at 100 nM. The signaling pathways involved in inhibition of cell migration were examined. Treatment with kisspeptin-10 elicited phosphorylation of GSK3 beta at Ser(9) (which inhibits activity), with a 3-fold increase at 5 min. Transient phosphorylation of ERK1/2 and p38MAPK peaked at 10 min. Phosphorylation of focal adhesion kinase (FAK) at Tyr(925) increased 3-fold at 10 min. Inhibition of GSK3 beta correlated with release of beta-catenin into the cytoplasm. These signaling events were differentially blocked by inhibitors of G(q/11), Src, EGFR, PI(3)K, PKC and MEK. The data suggest that kisspeptin/GPR54 EGF-receptor transactivation leads to phosphorylation of ERK1/2, causing activation of p90rsk which in turn inhibits GSK3 beta via Ser(9) phosphorylation. Inactivation of GSK3 beta results in release of beta-catenin into the cytoplasm, affecting cell-cell adhesion and Tyr(925) phosphorylation of FAK, which increases phosphorylation of ERK1/2 via RAS/Raf-1 creating a feedback loop to enhance the effects on migration. These findings indicate that kisspeptin-10 inhibits the migration of human placental trophoblast-derived HTR8SVneo cells by stimulating complex ERK1/2-p90rsk-GSK3 beta-FAK feedback interactions. (C) 2012 Elsevier Ltd. All rights reserved.