Abstract
Vascular smooth muscle (VSM) cell migration is a critical component in the development of atherosclerotic vascular disease. The recent characterization of raf kinase inhibitory protein (RKIP) as a mediator of epithelial cell migration prompted the investigation of a similar role in VSM cells. Locostatin (LOCO) a novel inhibitor of RKIP prevented VSM cell migration in a wound scrape culture model with an IC50 of 0.7 μM, while an inactive analog (UIC-1017) was without similar effects. At concentrations of up to 30 μM LOCO had no effect on VSM cell attachment or cell replication, and did not prevent serum-induced activation of ERK1/2. However LOCO, but not UIC, produced a rapid but transient activation of ERK1/2 in VSM cells. Western blotting experiments with RKIP antibodies revealed that VSM cells express a single immunoreactive protein of ~23kDa that is consistent with RKIP. Confocal imaging of migrating VSM cells demonstrated that RKIP was localized at the leading edge of lamellopodia. These studies provide evidence for a novel ERK-independent migration process in cultured VSM cells.
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