MOLECULAR MECHANISMS OF CELL SUBSTRATE INTERACTIONS

纤维连接蛋白和整合素受体在这方面起着重要作用

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.