Pyrroloquinoline quinone stimulates epithelial cell proliferation by activating epidermal growth factor receptor through redox cycling
Pyrroloquinoline quinone stimulates epithelial cell proliferation by activating epidermal growth factor receptor through redox cycling
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DOI：
10.1016/j.freeradbiomed.2012.07.015
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发表时间：
2012-09-15
影响因子：
7.4
通讯作者：
Akagawa, Mitsugu
中科院分区：
文献类型：
--
作者：
Kimura, Kazuki;Takada, Mayumi;Akagawa, Mitsugu
吡咯喹啉醌（PQQ）是细菌辅酶A酶的氧化还原辅因子，在哺乳动物中是一种重要的营养物质，具有强效生长因子的功能。然而，潜在的分子机制尚未阐明。本研究表明，PQQ诱导激活（酪氨酸自磷酸化）的表皮生长因子受体（EGFR）及其下游信号在配体非依赖性的方式，导致增加上皮细胞系A431的细胞增殖。PQQ抑制蛋白酪氨酸磷酸酶1B（PTP1B），其通过酪氨酸去磷酸化负调节埃格信号传导，通过其氧化还原循环活性氧化修饰催化半胱氨酸以产生H2O2。PQQ诱导的细胞内ROS的产生和EGFR的激活显着抑制预处理抗氧化剂。细胞内氧化还原状态通过PTP1B的氧化还原敏感催化半胱氨酸调节EGFR信号传导并调节细胞增殖。我们的数据表明，PQQ可以刺激上皮细胞增殖激活EGFR的氧化和随后失活的PTP1B通过其氧化还原循环。我们的研究结果提供了新的洞察机制，PQQ可能作为一种生长因子，以促进哺乳动物的生长。(c)2012 Elsevier Inc. All rights reserved.
Pyrroloquinoline quinone (PQQ), a redox cofactor for bacterial dehydrogenases, has been implicated to be an important nutrient in mammals functioning as a potent growth factor. However, the underlying molecular mechanisms have not been elucidated. The present study revealed that PQQ induces the activation (tyrosine autophosphorylation) of epidermal growth factor receptor (EGFR) and its downstream signaling in a ligand-independent manner, leading to increased cellular proliferation in an epithelial cell line A431. PQQ inhibited protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the EGER signaling by tyrosine dephosphorylation, to oxidatively modify the catalytic cysteine through its redox cycling activity to generate H2O2. PQQ-inducible intracellular ROS production and EGFR activation were significantly suppressed by the pre-treatment with antioxidants. The intracellular redox state regulates the EGFR signaling through the redox-sensitive catalytic cysteine of PTP1B and modulates cell proliferation. Our data suggest that PQQ may stimulate epithelial cell proliferation by activating EGFR by oxidation and subsequent inactivation of PTP1B via its redox cycling. Our results provide novel insight into the mechanisms by which PQQ may function as a growth factor to contribute to mammalian growth. (c) 2012 Elsevier Inc. All rights reserved.