Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 290, Issue 4, Pages C1263-C1270Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00241.2005
Keywords
hydrogen peroxide; protein tyrosine phosphatase-proline, glutamate, serine, and threonine sequence protein; p130(cas)
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Funding
- NHLBI NIH HHS [R01 HL064981, HL-72902, HL-64981, HL-63886] Funding Source: Medline
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Recent data support the hypothesis that reactive oxygen species (ROS) play a central role in the initiation and progression of vascular diseases. An important vasoprotective function related to the regulation of ROS levels appears to be the antioxidant capacity of nitric oxide (NO). We previously reported that treatment with NO decreases phosphotyrosine levels of adapter protein p130(cas) by increasing protein tyrosine phosphatase-proline, glutamate, serine, and threonine sequence protein (PTP-PEST) activity, which leads to the suppression of agonist-induced H2O2 elevation and motility in cultured rat aortic smooth muscle cells (SMCs). The present study was performed to investigate the hypotheses that 1) IGF-I increases the activity of the small GTPase Rac1 as well as H2O2 levels and 2) NO suppresses IGF-I-induced H2O2 elevation by decreasing Rac1 activity via increased PTP-PEST activity and dephosphorylation of p130(cas). We report that IGF-I induces phosphorylation of p130(cas) and activation of Rac1 and that NO attenuates these effects. The effects of NO are mimicked by the overexpression of PTP-PEST or dominant-negative (dn)-p130(cas) and antagonized by the expression of dn-PTP-PEST or p130(cas). We conclude that IGF-I induces rat aortic SMC motility by increasing phosphotyrosine levels of p130(cas) and activating Rac1 and that NO decreases motility by activating PTP-PEST, inducing dephosphorylating p130(cas), and decreasing Rac1 activity. Decreased Rac1 activity lowers intracellular H2O2 levels, thus attenuating cell motility.
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