MOLECULAR MECHANISMS OF CELL SUBSTRATE INTERACTIONS

粘附蛋白纤连蛋白及其整合素受体发挥作用， 在胚胎发育、伤口愈合和 疾病的进展，如癌症。 涉及单克隆 抗体，分子和细胞生物学，以及物理生物化学， 用于阐明纤连蛋白受体的分子机制 相互作用的目标是了解这些角色， 糖蛋白在复杂的生物过程中，以开发新的 生物粘附基质，并为合理的医疗保健提供基础。 干预涉及异常细胞粘附的疾病， 迁移 细胞粘附于整合素结合粘附蛋白 或整联蛋白聚集导致信号转导的形式 细胞内蛋白质的酪氨酸磷酸化， 粘附激酶 纤维连接蛋白结合整合素的简单占据 可溶性配体片段不足以刺激酪氨酸 磷酸化 同样，酪氨酸磷酸化发生得更快， 比形成局灶性粘连，这表明这些结构， 并不需要发生信令。 然而， 不同的整合素β亚基胞内结构域介导酪氨酸 磷酸化与它们自发聚集在 粘着斑，表明这两者之间的联系 流程. 另一种形式的整合素介导的跨膜信号传导 已经在人牙龈角质形成细胞中进行了研究。 抗体和 与α 3 β 1整联蛋白结合的Fab片段刺激细胞内的 不依赖于配体的92 kDa IV型胶原酶的表达 通过整合素的结合，以及所使用的粘合剂基质， 细胞 然而，92 kDa IV型胶原酶的表达也可以 受TGF-β 1和TPA刺激。 生物活性和 细菌表达的20 kDa纤连蛋白细胞粘附剂的结构 跨越第九和第十个III型重复序列的区域已被进一步 表征了 当使用非抑制性单克隆抗体固定时， 抗体，该片段促进细胞粘附和迁移， 与完整的纤连蛋白类似的活性，表明它可能具有 作为生物粘合剂和促进伤口愈合的潜在价值。 已发现固定化纤维连接蛋白结合肿瘤坏死因子- 通过其氨基末端结构域表达TNF-α。 纤连蛋白结合的TNF- α也似乎增强整合素介导的细胞粘附， 纤连蛋白。 这些结果表明，纤维连接蛋白或纤维连接蛋白 片段可能在炎症反应的调节中起作用 包括TNF-α

The adhesive protein fibronectin and its integrin receptors play important roles in embryonic development, wound healing, and the progression of diseases such as cancer. Techniques involving monoclonal antibodies, molecular and cell biology, and physical biochemistry are being used to elucidate molecular mechanisms of fibronectin-receptor interactions with the goal of understanding the roles of these glycoproteins in complex biological processes in order to develop novel bioadhesive substrates and to provide the bases for rational medical intervention in diseases involving abnormal cellular adhesion and migration. Either cell adhesion to integrin-binding adhesive proteins or integrin clustering results in signal transduction in the form of tyrosine phosphorylation of an intracellular protein called the focal adhesion kinase. Simple occupancy of fibronectin-binding integrins with soluble ligand fragments is insufficient to stimulate tyrosine phosphorylation. Likewise, tyrosine phosphorylation occurs more rapidly than does formation of focal adhesions, suggesting that these structures are not required for signalling to occur. However, the abilities of different integrin beta subunit intracellular domains to mediate tyrosine phosphorylation parallels their abilities to spontaneously cluster at focal adhesion sites, suggesting a connection between these two processes. Another form of integrin-mediated transmembrane signalling has been investigated in human gingival keratinocytes. Antibodies and Fab fragments that bind to the alpha3beta1 integrin stimulate the expression of the 92 kDa type IV collagenase independent of ligand binding by integrins as well as the adhesive substrate being used by the cells. However, expression of the 92 kDa type IV collagenase can also be stimulated by TGF-beta1 and TPA. The biological activities and structure of the bacterially-expressed 20 kDa fibronectin cell-adhesive region spanning the ninth and tenth type III repeats has been further characterized. When immobilized using non-inhibitory monoclonal antibodies, this fragment promotes cell adhesion and migration with a similar activity as intact fibronectin, suggesting that it might have potential value as a bioadhesive and in promoting wound healing. Immobilized fibronectin has been found to bind tumor necrosis factor- alpha (TNF-alpha) via its amino-terminal domain. Fibronectin-bound TNF- alpha also appears to enhance integrin-mediated cell adhesion to fibronectin. These results suggest that fibronectin or fibronectin fragments may play a role in the modulation of inflammatory responses involving TNF-alpha.