MOLECULAR MECHANISMS OF CELL SUBSTRATE INTERACTIONS

细胞基质相互作用的分子机制

• 批准号: 3753584
• 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/3753584
• 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.

粘连蛋白纤维连接蛋白及其整合素受体起作用