Niacin activates the PI3K/Akt cascade via PKC- and EGFR-transactivation-dependent pathways through hydroxyl-carboxylic acid receptor 2.
Niacin activates the PI3K/Akt cascade via PKC- and EGFR-transactivation-dependent pathways through hydroxyl-carboxylic acid receptor 2.
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烟酸通过羟基羧酸受体 2 通过 PKC 和 EGFR 反式激活依赖性途径激活 PI3K/Akt 级联。
DOI：
10.1371/journal.pone.0112310
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zhou N
中科院分区：
文献类型：
--
作者：
Sun H;Li G;Zhang W;Zhou Q;Yu Y;Shi Y;Offermanns S;Lu J;Zhou N
烟酸已被证明可以激活PI 3 K/Akt信号级联反应，以防止中风后的脑损伤和紫外线诱导的皮肤损伤;然而，HCA 2诱导Akt激活的潜在分子机制仍有待阐明。使用稳定表达HCA 2的CHO-K1细胞和A431细胞（一种具有高水平内源性功能性HCA 2受体表达的人表皮样细胞系），我们首先证明烟酸以时间依赖性方式在Thr 308和Ser 473处诱导稳健的Akt磷酸化，在5分钟时活化最大，随后通过HCA 2在30分钟时降低至基线，并且百日咳毒素显著阻断了该活化。在两种细胞系中，PKC抑制剂GF 109203 x和Go 6983、CHO-HCA 2细胞中PDGFR选择性抑制剂tyrphostin A9以及A431细胞中MMP抑制剂GM 6001和EGFR特异性抑制剂AG 1478也显著抑制HCA 2介导的Akt激活。这些结果表明PKC通路和PDGFR/EGFR反式激活通路在HCA 2介导的Akt激活中起重要作用。进一步的研究表明，PI 3 K和Gβγ亚基可能在HCA 2诱导的Akt活化中起重要作用。此外，使用识别在Thr 389处磷酸化的p70 S6 K1的抗体的免疫印迹分析显示，烟酸通过PI 3 K/Akt途径诱发p70 S6 K1活化。我们的研究结果为HCA 2激活所涉及的信号通路提供了新的见解。
Niacin has been demonstrated to activate a PI3K/Akt signaling cascade to prevent brain damage after stroke and UV-induced skin damage; however, the underlying molecular mechanisms for HCA2-induced Akt activation remain to be elucidated. Using CHO-K1 cells stably expressing HCA2 and A431 cells, a human epidermoid cell line with high levels of endogenous expression of functional HCA2 receptors, we first demonstrated that niacin induced a robust Akt phosphorylation at both Thr308 and Ser473 in a time-dependent fashion, with a maximal activation at 5 min and a subsequent reduction to baseline by 30 min through HCA2, and that the activation was significantly blocked by pertussis toxin. The HCA2-mediated activation of Akt was also significantly inhibited by the PKC inhibitors GF109203x and Go6983 in both cell lines, by the PDGFR-selective inhibitor tyrphostin A9 in CHO-HCA2 cells and by the MMP inhibitor GM6001 and EGFR-specific inhibitor AG1478 in A431 cells. These results suggest that the PKC pathway and PDGFR/EGFR transactivation pathway play important roles in HCA2-mediated Akt activation. Further investigation indicated that PI3K and the Gβγ subunit were likely to play an essential role in HCA2-induced Akt activation. Moreover, Immunobloting analyses using an antibody that recognizes p70S6K1 phosphorylated at Thr389 showed that niacin evoked p70S6K1 activation via the PI3K/Akt pathway. The results of our study provide new insight into the signaling pathways involved in HCA2 activation.
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