SYNDECAN-4 SIGNALING IN CELL-MATRIX INTERACTIONS

细胞-基质相互作用已被证明调节细胞形态， 增殖、迁移、存活、分化和基质组装。 一种研究细胞-基质相互作用的模型涉及培养细胞 已定义的胞外成分。因此，当成纤维细胞被培养时 在纤维粘连蛋白上，它们附着、扩散、形成称为 局部粘连，他们组织了他们的肌动蛋白细胞骨架。确实有 至少有两条信号通路参与了这些细胞事件。一 途径涉及整合素和小的GTP结合蛋白Rho。 整合素信号是细胞与细胞相互作用的结果 纤维连接蛋白的结合域。第二条信号通路涉及一种 细胞表面硫酸肝素蛋白多糖(HSPG)和结果 细胞与纤维连接蛋白的肝素结合区的相互作用。 Syndecan 4是局灶性粘连中的HSPG。我们已经确定了一部小说 胞质，突触，它与胞质结构域相互作用 Syndecan-4。Syndecan-4和Syndesmos都与PKC-α和 Syndesmos、PKC和paxlin是第二个信号通路的一部分 导致局部粘连和肌动蛋白应激纤维的形成 与纤维连接蛋白相互作用。该提案分为五个具体目标 旨在检验这一假说。具体地说，建议分析 四个分子间相互作用的分子基础。这个 从这些分析中获得的结构信息将用于 确定结构特征的功能意义 负责互动。这将在细胞培养中完成 利用鸡胚胎成纤维细胞和禽类逆转录病毒表达 系统中，以及在小鼠中，我们建议扰乱基因 Syndecan 4和Syndesmos在ES细胞中进行同源重组。 由于细胞-基质相互作用调节细胞增殖、迁移 生存和分化这些生物事件对于 正常发育，它们在创伤中也起着重要作用 治愈。当不受监管时，这些事件可能导致不受控制的细胞 生长和迁移，如癌症。局灶性粘连的组装和 已观察到培养细胞中肌动蛋白应激纤维的形成。 作为Will收缩的模型系统。从以下地址获得的信息 因此，拟议的研究可能适用于以下理解 指癌症中的不受控制的生长或伤口中的受控制的生长 治愈。

Cell-matrix interactions have been shown to regulate cell morphology, proliferation, migration, survival, differentiation and matrix assembly. One model for studying cell-matrix interactions involves plating cells on defined extracellular components. Thus, when fibroblasts are plated on fibronectin, they adhere, spread, form specialized structures called focal adhesions and they organized their actin cytoskeleton. There are at least two signaling pathways involved in these cellular events. One pathway involves integrins and the small GTP-binding protein rho. Integrin signaling results from interactions of cells with the cell binding domain of fibronectin. A second signaling pathway involves a cell surface heparin sulfate proteoglycan (HSPG) and results from interactions of the cell with the heparin binding domain of fibronectin. Syndecan 4 is the HSPG of focal adhesions. We have identified a novel cytoplasmic, syndesmos, which interacts with the cytoplasmic domain of syndecan-4. Both syndecan-4 and syndesmos interact with PKC-alpha and syndesmos, PKC and paxillin are part of the second signaling pathway that lead to focal adhesions and actin stress fiber formation when cells interact with fibronectin. The proposal is divided in five specific aims designed to test this hypothesis. Specifically it is proposed to analyze the molecular basis for the interactions among four molecules. The structural information gained from these analyses will be used to determine the functional significance of the structural features responsible for the interactions. This will be done in cell culture using chicken embryos fibroblasts and an avian retroviral expression system and also in mice where we propose to disrupt the genes for syndecan 4 and syndesmos by homologous recombination in ES cells. Since cell-matrix interactions regulate cell proliferation, migration, survival and differentiation these biological events are essential for normal development and they also play an important role in wound healing. When unregulated, these events can result in uncontrolled cell growth and migration as in cancer. The assembly of focal adhesions and the formation of actin stress fibers in cultured cells has been viewed as a model system for would contraction. The information obtained from the proposed studies, therefore, may be applicable to the understanding of uncontrolled growth as in cancer or controlled growth as in wound healing.