STRUCTURE AND ROLE OF A TRANSFORMATION-SENSITIVE CELL SURFACE GLYCOPROTEIN

纤维连接蛋白是一种主要的细胞表面和细胞外基质糖蛋白

Fibronectin is a major cell surface and extracellular matrix glycoprotein that is often decreased on tumor cells, and which is involved in cell adhesion and migration. The regions of fibronectin required for interactions with cells were defined using a new direct binding assay. Crucial binding information was provided by both the sequence (Gly)-Arg-Gly-Asp-Ser and by additional distant peptide information that was needed for full binding affinity; other adhesive recognition sites may also exist on fibronectin. The peptide sequence Arg-Gly-Asp-Ser, present in fibronectin, fibrinogen and von Willebrand factor, was found to be required for platelet adhesion. The possible role of such adhesive recognition signals at one or more steps in metastasis was tested using the B16 experimental metastasis system. The peptide Gly-Arg-Gly-Asp-Ser was a non-toxic inhibitor of pulmonary tumor formation. The inhibition was dose-dependent and specific, since a conservative substitution or an amino acid transposition resulted in loss of activity. The active peptide inhibited the retention of tumor cells in the lung, suggesting an effect on early adhesive events. Our future objectives will be to complete in vitro tests of the specificity and roles of this fibronectin adhesive recognition signals in other types of cell adhesion using other adhesion molecules, and to extend our studies of peptide inhibition of metastasis by determining specificities using a full panel of peptides, by optimizing pharmacological properties, and by examining for roles of the immune system and platelets in the inhibitory process. We will also attempt to define a hypothesized second cell-recognition signal on fibronectin with possibly distinct cell-type specificity, define further the parameters defining specificity and affinity of these peptide inhibitors using novel synthetic peptide variants, and will continue sequencing of the gene and atempting to produce genetically engineered variant polypeptides with modified or novel biological activities.