Phosphorylation of epidermal growth factor receptor at serine 1047 by MAP kinase-activated protein kinase-2 in cultured lung epithelial cells treated with flagellin.
Phosphorylation of epidermal growth factor receptor at serine 1047 by MAP kinase-activated protein kinase-2 in cultured lung epithelial cells treated with flagellin.
复制标题
在用鞭毛蛋白处理的培养肺上皮细胞中，MAP 激酶激活的蛋白激酶 2 使表皮生长因子受体丝氨酸 1047 磷酸化。
DOI：
10.1016/j.abb.2012.11.006
复制
发表时间：
2013
影响因子：
3.9
通讯作者：
H Yamamoto
中科院分区：
文献类型：
--
作者：
N Noguchi;Y Kondo;N Maeda;S Higa-Nakamine;S Toku;J Maruyama;Y Isohama;I Kukita;K Sugahara;H Yamamoto
据报道，肿瘤坏死因子α（TNFα）激活p38 MAP激酶途径，随后磷酸化表皮生长因子受体（EGFR）的丝氨酸1047（Ser1047）。尽管据报道 Ser1047 的磷酸化诱导了 EGFR 的内化，但负责磷酸化的蛋白激酶尚未阐明。在本研究中，我们发现用鞭毛蛋白处理 A549 细胞（一种肺泡上皮细胞系）可诱导 p38 MAP 激酶激活，随后 EGFR Ser1047 磷酸化。磷酸化受到 p38 MAP 激酶抑制剂 SB203580 的强烈抑制。鞭毛蛋白处理激活 MAP 激酶激活蛋白激酶 2 (MAPKAPK-2)（一种 p38 MAP 激酶下游的蛋白激酶），而 MK2a 抑制剂（MAPKAPK-2 的抑制剂）可抑制鞭毛蛋白诱导的 EGFR Ser1047 磷酸化。与鞭毛蛋白处理不同，TNFα 处理诱导 EGFR Ser1047 和 Tyr1173 磷酸化。 SB203580 和 MK2a 抑制剂强烈抑制 EGFR 中 Ser1047 的磷酸化，但不抑制 Tyr1173。最后，体外细菌表达并激活的 MAPKAPK-2 在 Ser1047 位点磷酸化 EGFR。这些结果表明鞭毛蛋白调节 EGFR 在质膜上的停留时间，从而通过 MAPKAPK-2 磷酸化 Ser1047 来调节 EGFR 信号传导。
It has been reported that tumor necrosis factor α (TNFα) activated the p38 MAP kinase pathway, followed by phosphorylation of epidermal growth factor receptor (EGFR) at serine 1047 (Ser1047). Although the phosphorylation of Ser1047 reportedly induced an internalization of EGFR, a protein kinase responsible for the phosphorylation has not been elucidated. In the present study, we found that treatment with flagellin of A549 cells, an alveolar epithelial cell line, induced the activation of p38 MAP kinase, followed by phosphorylation of EGFR at Ser1047. The phosphorylation was strongly inhibited by SB203580, an inhibitor of p38 MAP kinase. The flagellin treatment activated MAP kinase-activated protein kinase-2 (MAPKAPK-2), a protein kinase downstream of p38 MAP kinase, and MK2a inhibitor, an inhibitor of MAPKAPK-2, inhibited the flagellin-induced phosphorylation of EGFR at Ser1047. Unlike the flagellin treatment, the TNFα treatment induced the phosphorylation of EGFR at both Ser1047 and Tyr1173. SB203580 and MK2a inhibitor strongly inhibited the phosphorylation of Ser1047 but not Tyr1173 in EGFR. Finally, bacterially expressed and activated MAPKAPK-2 phosphorylated EGFR at Ser1047 in vitro. These results suggest that flagellin regulates the residence time of EGFR on the plasma membrane and thus the signaling of EGFR through phosphorylation of Ser1047 by MAPKAPK-2.