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首页> 外文期刊>Molecular and Cellular Biology >Distinct Mechanisms of Receptor and Nonreceptor Tyrosine Kinase Activation by Reactive Oxygen Species in Vascular Smooth Muscle Cells: Role of Metalloprotease and Protein Kinase C-δ
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Distinct Mechanisms of Receptor and Nonreceptor Tyrosine Kinase Activation by Reactive Oxygen Species in Vascular Smooth Muscle Cells: Role of Metalloprotease and Protein Kinase C-δ

机译：血管平滑肌细胞中活性氧对受体和非受体酪氨酸激酶活化的不同机制：金属蛋白酶和蛋白激酶C-δ的作用

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Reactive oxygen species (ROS) are implicated in cardiovascular diseases. ROS, such as H2O2, act as second messengers to activate diverse signaling pathways. Although H2O2 activates several tyrosine kinases, including the epidermal growth factor (EGF) receptor, JAK2, and PYK2, in vascular smooth muscle cells (VSMCs), the intracellular mechanism by which ROS activate these tyrosine kinases remains unclear. Here, we identified two distinct signaling pathways required for receptor and nonreceptor tyrosine kinase activation by H2O2 involving a metalloprotease-dependent generation of heparin-binding EGF-like growth factor (HB-EGF) and protein kinase C (PKC)-δ activation, respectively. H2O2-induced EGF receptor tyrosine phosphorylation was inhibited by a metalloprotease inhibitor, whereas the inhibitor had no effect on H2O2-induced JAK2 tyrosine phosphorylation. HB-EGF neutralizing antibody inhibited H2O2-induced EGF receptor phosphorylation. In COS-7 cells expressing an HB-EGF construct tagged with alkaline phosphatase, H2O2 stimulates HB-EGF production through metalloprotease activation. By contrast, dominant negative PKC-δ transfection inhibited H2O2-induced JAK2 phosphorylation but not EGF receptor phosphorylation. Dominant negative PYK2 inhibited H2O2-induced JAK2 activation but not EGF receptor activation, whereas dominant negative PKC-δ inhibited PYK2 activation by H2O2. These data demonstrate the presence of distinct tyrosine kinase activation pathways (PKC-δ/PYK2/JAK2 and metalloprotease/HB-EGF/EGF receptor) utilized by H2O2 in VSMCs, thus providing unique therapeutic targets for cardiovascular diseases.
机译：活性氧（ROS）与心血管疾病有关。 ROS（例如H 2 O 2 ）充当第二信使，以激活各种信号通路。尽管H 2 O 2 在血管平滑肌细胞（VSMC）中激活多种酪氨酸激酶，包括表皮生长因子（EGF）受体，JAK2和PYK2， ROS激活这些酪氨酸激酶的机制尚不清楚。在这里，我们确定了H 2 O 2 激活受体和非受体酪氨酸激酶所需的两个不同信号通路，这些通路涉及金属蛋白酶依赖性肝素结合型EGF样生长因子的产生。 （HB-EGF）和蛋白激酶C（PKC）-δ激活。金属蛋白酶抑制剂抑制H 2 O 2 诱导的EGF受体酪氨酸磷酸化，而该抑制剂对H 2 O 2 诱导的JAK2酪氨酸磷酸化。 HB-EGF中和抗体抑制H 2 O 2 诱导的EGF受体磷酸化。在表达用碱性磷酸酶标记的HB-EGF构建体的COS-7细胞中，H 2 O 2 通过金属蛋白酶激活刺激HB-EGF的产生。相比之下，显性负PKC-δ转染抑制H 2 O 2 诱导的JAK2磷酸化，但不抑制EGF受体的磷酸化。显性负PYK2抑制H 2 O 2 诱导的JAK2激活，但不抑制EGF受体激活，而显性负PKC-δ抑制H 2 的PYK2激活。 > O 2 。这些数据表明，H 2 O 2 利用了独特的酪氨酸激酶激活途径（PKC-δ/ PYK2 / JAK2和金属蛋白酶/ HB-EGF / EGF受体） VSMC，因此为心血管疾病提供了独特的治疗靶标。

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