STRUCTURE AND ROLE OF A TRANSFORMATION-SENSITIVE CELL SURFACE GLYCOPROTEIN

纤维连接蛋白是一种主要的细胞表面和细胞外基质糖蛋白 在肿瘤细胞上经常减少， 粘附和迁移。 纤维连接蛋白的区域需要 与细胞的相互作用使用新的直接结合测定来定义。 关键的结合信息由两个序列提供， （Gly）-Arg-Gly-Asp-Ser和另外的远端肽信息， 需要完全结合亲和力;其他粘附识别位点可能 也存在于纤连蛋白上。 肽序列Arg-Gly-Asp-Ser， 在纤连蛋白、纤维蛋白原和血管性血友病因子中， 血小板粘附所必需的。 这种粘合剂的可能作用 在转移的一个或多个步骤中的识别信号使用 B16实验转移系统。 肽Gly-Arg-Gly-Asp-Ser是一种 肺肿瘤形成的无毒抑制剂。 抑制作用 剂量依赖性和特异性，因为保守取代或氨基 酸转位导致活性损失。 活性肽 抑制肿瘤细胞在肺中的滞留，表明对 早期粘连事件。 我们未来的目标是在体外完成 测试这种纤维连接蛋白粘附识别的特异性和作用 使用其他粘附分子的其他类型细胞粘附中的信号，和 为了扩展我们的肽抑制转移的研究， 通过优化药理学特性， 性质，并通过检查免疫系统和血小板的作用 in the inhibitory抑制process处理. 我们还将尝试定义一个假设的 纤连蛋白上的第二细胞识别信号， 细胞类型特异性，进一步定义特异性参数 以及使用新的合成肽的这些肽抑制剂的亲和力 变异，并将继续基因测序，并试图产生 具有修饰的或新的修饰的或新的基因工程化的变体多肽 生物活动。

Fibronectin is a major cell surface and extracellular matrix glycoprotein that is often decreased on tumor cells, and which is involved in cell adhesion and migration. The regions of fibronectin required for interactions with cells were defined using a new direct binding assay. Crucial binding information was provided by both the sequence (Gly)-Arg-Gly-Asp-Ser and by additional distant peptide information that was needed for full binding affinity; other adhesive recognition sites may also exist on fibronectin. The peptide sequence Arg-Gly-Asp-Ser, present in fibronectin, fibrinogen and von Willebrand factor, was found to be required for platelet adhesion. The possible role of such adhesive recognition signals at one or more steps in metastasis was tested using the B16 experimental metastasis system. The peptide Gly-Arg-Gly-Asp-Ser was a non-toxic inhibitor of pulmonary tumor formation. The inhibition was dose-dependent and specific, since a conservative substitution or an amino acid transposition resulted in loss of activity. The active peptide inhibited the retention of tumor cells in the lung, suggesting an effect on early adhesive events. Our future objectives will be to complete in vitro tests of the specificity and roles of this fibronectin adhesive recognition signals in other types of cell adhesion using other adhesion molecules, and to extend our studies of peptide inhibition of metastasis by determining specificities using a full panel of peptides, by optimizing pharmacological properties, and by examining for roles of the immune system and platelets in the inhibitory process. We will also attempt to define a hypothesized second cell-recognition signal on fibronectin with possibly distinct cell-type specificity, define further the parameters defining specificity and affinity of these peptide inhibitors using novel synthetic peptide variants, and will continue sequencing of the gene and atempting to produce genetically engineered variant polypeptides with modified or novel biological activities.