| Research Abstract |
Novel receptor tyrosine kinases including Sky, which we have cloned from a Hep G2 cDNA library, Axl/Ufo and Mer/Eyk form a subfamily based on a unique extracellular domain. Recently gamma-carboxyglutamic acid (Gla)-containing proteins, protein S and Gas6, have been reported to be physiological ligands for the Axl/Sky subfamily of receptor tyrosine kinases. In this study, we tried to elucidate the physiological importance of the novel signaling pathway mediated by this ligand-receptor system in the proliferation of vascular smooth muscle cells.
Both human protein S and rat Gas6 failed to induce proliferation of rat arterial vascular smooth muscle cells, however, rat Gas6 potentiated the mitogenic activity of thrombin as reported by Nakano et al. Species specificity has been reported to exist in the interaction between protein S or Gas6 and Axl/Sky receptor subfamily, we are now analyzing the effect of human protein S on the proliferation of bovine and human vascular smooth muscle cells.
Analysis of the binding ability of the soluble receptors of human Axl, human Sky and mouse Mer composed of the extracellular domain of receptors fused to the Fc domain of immunoglobulin G1 showed that rat Gas6, but not human protein S,bound to Axl, Sky and Mer. The C-terminal sex hormone-binding globulin-like domain of Gas6 was indispensable for the binding of Gas6 to Axl and the N-terminal Gla domain had a regulatory role on the interaction.
We developed a swine model of coronary spasms with intimal thickening by chronically treating the outside of the coronary arteries with a inflammatory cytokine, IL-1beta. In order to know whether the novel signaling pathway mediated by binding protein S and Gas6 to Axl/Sky receptor family is implicated in formation of the vasospastic lesions, we proceed to determine the expression of these molecules in the lesions with proliferation of vascular smooth muscle cells.
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