MOLECULAR MECHANISMS OF CELL SUBSTRATE INTERACTIONS

纤维连接蛋白和整合素受体在这一过程中发挥着重要作用 胚胎发育，伤口愈合，以及 癌症的进展。涉及到单抗的技术， 分子和细胞生物学以及生物物理化学被用于 纤维连接蛋白与受体相互作用的分子机制 我们的长期目标是生产新型生物黏附基板 发展合理的疾病医疗干预基础 涉及异常的细胞黏附和迁移。中环 纤维连接蛋白的细胞结合区需要两个不同的序列 活性：RGD序列和PHSRN协同序列。 细菌表达的20kd的纤维连接蛋白细胞黏附片段， 由完整的第九类和第十类III模块组成 包含RGD和PHSRN序列，已被克隆并 表达。这些碎片被发现保留了完整的 归因于中央细胞结合区的生物活性 完整的纤维连接蛋白作为一种抑制剂存在于溶液中 纤维连接蛋白功能。20kd小鼠纤维连接蛋白的结构 正在使用生物物理技术对碎片进行分析。虽然 第九和第十个模块已经被发现相互作用，PHSRN 而RGD站点位于相对较远的站点，可能 不要直接互动。PHSRN的穿越空间距离 并且RGD位点足够小，可以由单个整合素跨越 受体。结合β1整合素的某些单抗 可以上调它们的配体结合活性。一种这样的激活 被命名为12G10的抗体似乎与一种“配体诱导”相结合。 构象。该抗体还能抑制血管内皮细胞的增殖 培养的细胞。这种生长停滞发生在G1/S的边界附近 细胞周期，并暗示了整合素介导的机制 调节细胞周期。

Fibronectin and integrin receptors play important roles in such processes as embryonic development, wound healing, and the progression of cancer. Techniques involving monoclonal antibodies, molecular and cell biology, and biophysical chemistry are used to elucidate molecular mechanisms of fibronectin-receptor interactions with the long-term goals of producing novel bioadhesive substrates and developing rational bases for medical intervention in diseases involving abnormal cellular adhesion and migration. The central cell-binding region of fibronectin requires two distinct sequences for activity: an RGD sequence and a PHSRN synergistic sequence. Bacterially-expressed 20 kd cell adhesive fragments of fibronectin, consisting of the complete ninth and tenth type III modules containing the RGD and the PHSRN sequences, have been cloned and expressed. These fragments have been found to retain the full biological activity attributable to the central cell binding region of intact fibronectin when present in solution as an inhibitor of fibronectin function. The structure of the 20 kd murine fibronectin fragment is being analyzed using biophysical techniques. Although the ninth and tenth modules have been found to interact, the PHSRN and RGD sites are located at relatively distant sites that probably do not interact directly. The through-space distance of the PHSRN and RGD sites is small enough to be spanned by a single integrin receptor. Certain monoclonal antibodies that bind to beta1 integrins can up-regulate their ligand-binding activity. One such activating antibody, designated 12G10, appears to bind to a "ligand-induced" conformation. This antibody can also inhibit proliferation of cultured cells. This growth arrest occurs near the G1/S boundary of the cell cycle and is suggestive of a mechanism for integrin-mediated modulation of the cell cycle.