Urokinase induces activation of STAT3 in lung epithelial cells.
Urokinase induces activation of STAT3 in lung epithelial cells.
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DOI：
10.1152/ajplung.00476.2005
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发表时间：
2006-10
期刊：
影响因子：
--
通讯作者：
S. Shetty;G. Rao;D. Cines;K. Bdeir
中科院分区：
文献类型：
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作者：
S. Shetty;G. Rao;D. Cines;K. Bdeir
尿激酶型纤溶酶原激活物（uPA）是一种丝氨酸蛋白酶，在多种生理和病理过程中发挥重要作用。我们实验室的研究表明，人肺上皮细胞暴露于uPA诱导增殖。为了了解uPA促有丝分裂信号传导事件，我们试图阐明其对人支气管上皮细胞系（Beas 2B）中酪氨酸磷酸化的影响。uPA以时间依赖性方式诱导几种蛋白质的酪氨酸磷酸化。这些蛋白质之一被确定为91-kDa的信号转导激活转录（Stat）3部分。uPA对Stat 3的酪氨酸磷酸化具有时间依赖性。uPA以时间依赖性方式诱导Stat 3-DNA结合活性。uPA诱导的Stat 3活化不需要uPA催化活性，因为单独的uPA氨基末端片段在引起这种效应方面与活性双链uPA（tcuPA）一样有效。单链uPA同样诱导Stat 3的酪氨酸磷酸化至与完整tcuPA相似的程度。纤溶酶不改变uPA诱导的Stat 3激活。此外，用显性负性Stat 3转染Beas 2B细胞阻断uPA诱导的DNA合成。这些结果首次揭示了uPA-uPAR相互作用导致Stat 3的活化，其催化活性独立，但依赖于其与其受体uPAR的相互作用，导致肺上皮细胞中的DNA合成。
Urokinase-type plasminogen activator (uPA) is a serine protease that plays a major role in diverse physiological and pathological processes. Studies from our laboratory have shown that exposure of human lung epithelial cells to uPA induces proliferation. To understand uPA mitogenic signaling events, we sought to elucidate its effects on tyrosine phosphorylation in a human bronchial epithelial cell line (Beas2B). uPA induced tyrosine phosphorylation of several proteins in a time-dependent manner. One of these proteins was identified as the 91-kDa signal transduction activator transcription (Stat)3 moiety. Tyrosine phosphorylation of Stat3 by uPA was time dependent. uPA induced Stat3-DNA binding activity in a time-dependent manner. uPA-induced Stat3 activation does not require uPA catalytic activity, as the uPA amino-terminal fragment alone was as potent as active two-chain uPA (tcuPA) in causing this effect. Single-chain uPA likewise induced tyrosine phosphorylation of Stat3 to a similar extent as intact tcuPA. Plasmin did not alter uPA-induced Stat3 activation. Furthermore, transfection of Beas2B cells with dominant-negative Stat3 blocked uPA-induced DNA synthesis. These results reveal for the first time that the uPA-uPAR interaction leads to activation of Stat3, independent of its catalytic activity but dependent on its interaction with its receptor, uPAR, leading to DNA synthesis in lung epithelial cells.