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Molecular and Cellular Biology, March 2003, p. 1581-1589, Vol. 23, No. 5
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.5.1581-1589.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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-{delta}

Gerald D. Frank,1 Mizuo Mifune,1 Tadashi Inagami,1 Motoi Ohba,2 Terukatsu Sasaki,3 Shigeki Higashiyama,4 Peter J. Dempsey,5 and Satoru Eguchi1*

Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232,1 Institute of Molecular Oncology, Showa University, Tokyo 142-8555,2 Department of Biochemistry, Sapporo Medical University, Sapporo 060-8556,3 Department of Biochemistry, School of Allied Health Science, Osaka University Faculty of Medicine, Osaka 565-0871, Japan,4 Pacific Northwest Research Institute, Seattle, Washington 981225

Received 24 July 2002/ Returned for modification 4 September 2002/ Accepted 2 December 2002

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.

* Corresponding author. Mailing address: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146. Phone: (615) 322-4334. Fax: (615) 322-3201. E-mail: satoru.eguchi{at}vanderbilt.edu.

Molecular and Cellular Biology, March 2003, p. 1581-1589, Vol. 23, No. 5
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.5.1581-1589.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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