STRUCTURE/FUNCTION OF VASCULAR INTEGRINS

血小板-血小板、血小板-基质和内皮-基质相互作用 整合素介导的止血和抗凝血反应 血栓形成。血管系统中的整合素包括糖蛋白 血小板表面IIb/IIIa(AlphaIIb/Beta3)与纤维连接蛋白 细胞表面受体(FNR)和玻璃体连结蛋白受体(VNR) 内皮细胞和其他血管细胞。作为该计划的一部分的研究 项目和其他实验室之间的相互作用已经表明 整合素受体及其配体不仅提供了一种机制 细胞黏附和聚集，但启动各种细胞信号 对多种细胞功能是必不可少的，比如运动性， 细胞因子的产生和细胞分裂。这些信号包括 激活激酶，细胞细胞骨架重排，以及 基因的诱导。本续订计划项目的总体重点将是 确定和表征这些整合素- 中介信号被转导。参与其中的细胞信号 激活AlphaIIb/Beta3称为CIB。胞质结构域序列 参与与细胞骨架蛋白、酪氨酸激酶、 磷酸酶和低分子量GTP酶的图谱将使用 体外诱变和多肽方法。血小板的调节 将检测酪氨酸磷酸酶对酪氨酸的磷酸化作用。这个 血管扩张剂刺激的磷蛋白Vasp在肌动蛋白中的作用 将探索AlphaIIb/Beta3的聚合和活化。这个 整合素介导的细胞锚定和有丝分裂原协同作用 将探索细胞周期遍历的信号产生和调节 以确定导致这种协作性的途径。这个 整合素信号向细胞周期蛋白依赖性信号转导的可能性 将检查肌动蛋白。这些都应该继续澄清 整合素作为信号转导分子及其独特作用 血管生物学中的蛋白质。

Platelet-platelet, platelet-matrix, and endothelial-matrix interactions mediated by integrins are essential reactions in hemostasis and thrombosis. Hey integrins in the vasculature include glycoproteins IIb/IIIa (alphaIIb/beta3) on the platelet surface and the fibronectin receptor (FnR) and vitronectin receptor (VnR) on the surface of endothelial and other vascular cells. Studies as part of this Program Project and in other laboratories have shown that the interaction between integrin receptors and their ligands not only provides a mechanism for cell adhesion and aggregation, but initiates a variety of cellular signals that are essential for diverse cellular functions such as motility, production of cytokines, and cell division. These signals include activation of kinases, rearrangement of the cellular cytoskeleton, and induction of genes. The overall focus of this renewal Program Project will be identify and characterize the pathways through which these integrin- mediated signals are transduced. The cellular signals involved in activation of alphaIIb/beta3 termed CIB. Cytoplasmic domain sequences involved in the interaction with cytoskeletal proteins, tyrosines kinases, phosphatases, and low molecular weight GTPases will be mapped using in vitro mutagenesis and peptide approaches. The regulation of platelet tyrosine phosphorylation by tyrosine phosphatases will be examined. The role of VASP, a vasodilator-stimulated phosphoprotein, in actin polymerization and activation of alphaIIb/beta3 will be explored. The cooperative effects of integrin-mediated cell anchorage and mitogens on signal generation and regulation of cell cycle traverse will be explored in order to identify the pathways responsible for this cooperativity. The possible transduction of signals from integrins to cyclin-dependent kinases will be examined. These should continue to clarify the role of integrins as signal transduction molecules and the unique effects of these proteins in vascular biology.