Arg-Gly-Asp: A versatile cell recognition signal

Fibronectin is a large extracellular glycoprotein that can mediate adhesion of cells to the extracellular matrix. Study of the cellular recognition of fibronectin has recently led to the unexpected observation that, of the approximately 2,500 amino acids in the fibronectin polypeptide, three-an Arg-Gly-Asp (RGD) tripeptide-are crucial for its interaction with its cell surface receptor. Moreover, analysis of the cell attachment sites of several other proteins that interact with cell surfaces has implicated the same amino acid triplet. These data, summarized below, establish the RGD sequence as a basic unit of a widespread cellular recognition system. The Structure of the Cell Attachment Site in Fibronectin The cell attachment site within the fibronectin molecule has been identified, sequenced, and reproduced by peptide synthesis (Pierschbacher et al., PNAS 80, 1224-1227, 1983). Analysis of progressively smaller synthetic peptides has narrowed down the active site to a tetrapeptide, Arg-Gly-Asp-Ser (Pierschbacher and Ruoslahti, Nature 309,30-33,1984; Yamada and Kennedy, JCB 99,29-38, 1984). The arginine, glycine, and aspartic acid residues are essential for activity, while the serine residue can be replaced by other amino acids (Pierschbacher and Ruoslahti, PNAS 87, 5985-5988, 1984). In rat fibronectin, the expression of a second RGD sequence is controlled by alternative mRNA splicing (Schwarzbauer et al., Cell 35, 421-431, 1983) raising the possibility that some fibronectin molecules have two distinct cell attachment sites. The synthetic peptides containing the RGD sequence mediate cell attachment directly when presented to cells as an insoluble substrate, whereas in solution they can inhibit cell attachment to fibronectin. Surprisingly, the same peptides also inhibit the attachment of fibroblasts to a number of other proteins, including vitronectin. Vitronectin is the active component of serum spreading factor and is the S-protein of the complement membrane attack complex (Jenne and Stanley, EMBO J. 4,3153-3157, 1985). Its cell attachment-promoting activity has also been localized to an RGD sequence (Suzuki et al., EMBO J. 4, 25192524, 1985). Fibrinogen contains two RGD sequences and von Willebrand factor has at least one. The binding of each of these proteins to platelets is inhibited by RGDcontaining peptides (Gartner and Bennett, JBC 260, 11891-11894, 1985; Plow et al., PNAS 82, 8057-8061, 1985) indicating that this tripeptide is important for the function of each of these proteins in platelet adhesion. The RGD sequences in the various adhesive proteins are recognized by cell Minireview