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

被引:88
作者
Frank, GD
Mifune, M
Inagami, T
Ohba, M
Sasaki, T
Higashiyama, S
Dempsey, PJ
Eguchi, S
机构
[1] Vanderbilt Univ, Sch Med, Dept Biochem, Nashville, TN 37232 USA
[2] Showa Univ, Inst Mol Oncol, Tokyo 1428555, Japan
[3] Sapporo Med Univ, Dept Biochem, Sapporo, Hokkaido 0608556, Japan
[4] Osaka Univ, Sch Allied Hlth Sci, Dept Biochem, Osaka 5650871, Japan
[5] Pacific NW Res Inst, Seattle, WA 98122 USA
关键词
D O I
10.1128/MCB.23.5.1581-1589.2003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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)-delta 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-delta 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-delta inhibited PYK2 activation by H2O2. These data demonstrate the presence of distinct tyrosine kinase activation pathways (PKC-delta/PYK2/JAK2 and metalloprotease/HB-EGF/EGF receptor) utilized by H2O2 in VSMCs, thus providing unique therapeutic targets for cardiovascular diseases.
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页码:1581 / 1589
页数:9
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