Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells
Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells
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DOI：
10.1096/fj.04-1930fje
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发表时间：
2004-09-01
期刊：
影响因子：
4.8
通讯作者：
Audigier, Y
中科院分区：
文献类型：
--
作者：
Masri, B;Morin, N;Audigier, Y
我们报道了apelin(65-77)激活p70S6K，不仅在稳定转染apelin受体的CHO细胞中，而且在内源性表达apelin受体的脐静脉内皮细胞(HUVEC)中也是如此。Apelin(65-77)诱导T421/S424和T389残基上p70S6K的时间依赖性磷酸化。这种双重磷酸化与两个转导级联相关，分别涉及PI3K通路和ERK通路。PI3K途径可被Wortmannin阻断，导致T308或S473残基Akt的磷酸化，进而促进P70S6K在T421/S424和T389的磷酸化。蛋白酪氨酸激酶抑制剂PD 098059阻断ERK信号通路，导致p70S6K在T421/S424处的磷酸化。经百日咳毒素(PTX)和非典型PKCs抑制剂预处理后，Akt和p70S6K的磷酸化均被取消。此外，我们还证明了apelin(65-77)也能增加p70S6K的酶活性，并且上述抑制剂对T389磷酸化水平的影响与它们对酶活性的作用有关。有趣的是，主要结果在脐静脉内皮细胞中重现，并且apelin(65-77)促进这些细胞的胸腺嘧啶核苷掺入DNA，揭示apelin是一种新的内皮细胞有丝分裂多肽。
We report here that apelin (65-77) activates p70 S6 kinase (p70S6K), not only in CHO cells that have been stably transfected with the apelin receptor, but also in umbilical endothelial cells ( HUVEC), which express it endogenously. Apelin (65-77) induces a time-dependent phosphorylation of p70S6K at residues T421/S424 and T389. This dual phosphorylation is associated with two transduction cascades, involving a PI3K pathway and an ERK pathway, respectively. The PI3K pathway, which can be blocked by wortmannin, leads to phosphorylation of Akt at residues T308 or S473, which then promotes the phosphorylation of p70S6K at T421/S424 and T389. The ERK pathway is blocked by PD 098059, a MEK inhibitor, and results in the phosphorylation of p70S6K at T421/S424. Phosphorylation both of Akt and p70S6K is abrogated by pretreatment with pertussis toxin (PTX) and an inhibitor of atypical PKCs. In addition, we demonstrate that apelin (65-77) also increases the enzymatic activity of p70S6K and that the effects of the previously mentioned inhibitors on the level of T389 phosphorylation correlate with their action on enzyme activity. Interestingly, the main findings were reproduced in umbilical endothelial cells and apelin (65-77) promoted thymidine incorporation into DNA of these cells, revealing that apelin is a new mitogenic peptide for the endothelial cell.