FUNCTIONAL CHARACTERIZATION OF TRANSFORMING GROWTH FACTORS AND THEIR RECEPTORS

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Transforming growth factors (TGFs) are acid-stable polypeptides that induce a reversible phenotypic transformation of normal indicator cells such that they will grow in an anchorage-independent manner in soft agar, a property characteristic of transformed cells. The purpose of this project is to determine the role that endogenously-produced TGFs may play in the growth of normal and transformed cells and to characterize their mode of action at a biochemical level. To this end, polyclonal antisera have been raised to the TGFs, and development of monoclonal antibodies is in progress. The effects of these antibodies on the anchorage-dependent and -independent growth of normal and transformed cells are being investigated and will be analyzed in terms of the biochemical functions affected. Since the first step in the interaction of TGFs with the cell is binding of the growth factor to the cell surface, initial investigations have concentrated on the characterization of cell surface receptors for TGFs. Development of radioreceptor assay for TGF-beta, a TGF that depends on a second TGF (EGF or TGF-alpha) for activity, has allowed identification of a specific high affinity receptor for TGF-beta on all normal and transformed cell lines studied so far. The receptor appears to be a disulphide-linked dimer that does not undergo ligand-induced autophosphorylation or clustering. Receptor properties are modulated by transformation but binding of TGF-beta to its receptor does not appear to be a major control point in TGF-beta action. Human cell lines and tissues are being screened for an abundant source of the receptor for use as a starting material for receptor purification and as an immunogen for the production of anti-receptor monoclonal antibodies. Further characterization of the role of endogenously-produced TGFs and their interaction with the cell surface receptor should help elucidate the role these molecules may play in the process of carcinogenesis.