Distinct Kinetic and Spatial Patterns of Protein Kinase C (PKC)- and Epidermal Growth Factor Receptor (EGFR)-dependent Activation of Extracellular Signal-regulated Kinases 1 and 2 by Human Nicotinic Acid Receptor GPR109A
Distinct Kinetic and Spatial Patterns of Protein Kinase C (PKC)- and Epidermal Growth Factor Receptor (EGFR)-dependent Activation of Extracellular Signal-regulated Kinases 1 and 2 by Human Nicotinic Acid Receptor GPR109A
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DOI：
10.1074/jbc.m111.241372
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发表时间：
2011-09-09
影响因子：
4.8
通讯作者：
Zhou, Naiming
中科院分区：
文献类型：
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作者：
Li, Guo;Deng, Xiaoyan;Zhou, Naiming
烟酸（niacin）作为降血脂药物已被广泛使用了几十年，最近，孤儿G蛋白偶联受体GPR 109 A已被鉴定为烟酸的受体。机理研究表明，烟酸活化后，GPR 109 A与G（i）蛋白偶联并抑制腺苷酸环化酶活性，导致游离脂肪酸释放的抑制。然而，GPR 109 A信号转导的潜在分子机制在很大程度上仍然未知。使用CHO-K1细胞稳定表达GPR 109 A和A431细胞，这是一个人表皮样细胞系与高水平的内源性表达的功能GPR 109 A受体，我们发现，激活细胞外信号调节激酶1和2（ERK 1/2）的烟酸是快速的，在5分钟达到峰值，并显着阻断百日咳毒素。此外，不同激酶抑制剂的时程实验表明，GPR 109 A通过基质金属蛋白酶/表皮生长因子受体反式激活途径在早期和晚期时间点（2-5分钟）诱导ERK 1/2激活;该途径不同于PKC途径介导的ERK 1/2磷酸化，其发生在早期时间点（
Nicotinic acid (niacin) has been widely used as a lipid-lowering drug for several decades, and recently, orphan G protein-coupled receptor GPR109A has been identified as a receptor for niacin. Mechanistic investigations have shown that, upon niacin activation, GPR109A couples to a G(i) protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for GPR109A signaling remain largely unknown. Using CHO-K1 cells stably expressing GPR109A and A431 cells, which are a human epidermoid cell line with high levels of endogenous expression of functional GPR109A receptors, we found that activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by niacin was rapid, peaking at 5 min, and was significantly blocked by pertussis toxin. Furthermore, time course experiments with different kinase inhibitors demonstrated that GPR109A induced ERK1/2 activation via the matrix metalloproteinase/epidermal growth factor receptor transactivation pathway at both early and later time points (2-5 min); this pathway was distinct from the PKC pathway-mediated ERK1/2 phosphorylation that occurs at early time points (