MOLECULAR MECHANISMS OF CELL SUBSTRATE INTERACTIONS

细胞基质相互作用的分子机制

• 批准号: 3775732
• 负责人: S K AKIYAMA
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3775732
• 关键词: biological signal transduction; biophysics; cell adhesion; cell cell interaction; cell migration; cellular pathology; collagenase; embryogenesis; fibronectins; integrins; molecular biology; molecular pathology; monoclonal antibody; phosphorylation; protein structure function; receptor binding; receptor expression; tumor necrosis factor alpha; tyrosine; wound healing

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.

黏附蛋白纤维连接蛋白及其整合素受体的作用 在胚胎发育、伤口愈合和 癌症等疾病的进展。涉及到单克隆的技术 抗体、分子和细胞生物学以及物理生物化学是 用于阐明纤维连接蛋白受体的分子机制 与了解这些角色的目标的交互 糖蛋白在复杂生物过程中的研究进展 生物黏附底物，为合理医疗提供依据 对涉及异常细胞黏附和 迁移。细胞对整合素结合黏附蛋白的黏附 或整合素聚集导致信号转导的形式 一种称为焦点区的细胞内蛋白的酪氨酸磷酸化 黏附蛋白激酶。纤维连接蛋白结合整合素与 可溶性配基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。 局灶性粘连的形成，表明这些结构 并不是信令发生所必需的。然而，他们的能力 不同整合素β亚基胞内结构域对酪氨酸的调节作用 磷酸化与它们自发聚集在一起的能力平行 局灶性粘连部位，表明这两者之间存在联系 流程。整合素介导的另一种跨膜信号转导 已经在人类牙周角质形成细胞中进行了研究。抗体和 与α3beta1整合素结合的Fab片段刺激 不依赖配体的92 kDa IV型胶原酶的表达 整合素的结合以及由 细胞。然而，92 kDa IV型胶原酶的表达也可以 受到转化生长因子-β1和TPA的刺激。生物活性和 细菌表达的20 kDa纤维连接蛋白细胞粘附剂的结构 跨越第九和第十类型III重复的区域进一步 特色化的。当使用非抑制性单抗进行固定时 抗体，该片段可促进细胞的黏附和迁移 与完整的纤维连接蛋白的活性相似，这表明它可能有 作为生物粘合剂和促进伤口愈合的潜在价值。 固定化的纤维连接蛋白被发现能结合肿瘤坏死因子- α(肿瘤坏死因子-α)通过其氨基末端结构域。纤维连接蛋白结合的肿瘤坏死因子- Alpha似乎还能增强整合素介导的细胞黏附 纤维连接蛋白。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发挥作用 涉及肿瘤坏死因子-α。