Glycoproteins, in which one or more carbohydrate units have been attached covalently to the protein by posttranslational processing are widely distributed. Several secretory proteins, including the immunoglobulins, are glycoproteins, as are most components of plasma membranes such as cell membrane receptors, where the carbohydrates can be involved in cell-to-cell adhesion.
Transforming growth factor .beta. (TGF-.beta.) refers to a family of multi-functional cell regulatory factors produced in various forms by many cell types (for review see Sporn et al,. J. Cell Biol., 105:1039 (1987)). Five distinct isoforms of TGF-.beta. have been identified. TGF-.beta.1 and TGF-.beta.2 have been characterized in detail. TGF-.beta. is the subject of U.S. Pat. Nos. 4,863,899; 4,816,561 and 4,742,003 which are incorporated herein by reference. TGF-.beta. binds to cell surface receptors present on various types of cells. TGF-.beta. potentiates or inhibits the response of most cells to other growth factors, depending on the cell type. TGF-.beta. also regulates differentiation of some cell types, either promoting or inhibiting proliferation of the cell. A marked effect of TGF-.beta. is the promotion of cellular production of extracellular matrix proteins and their receptors (for a review see Keski-Oja et al., J. Cell Biochem., 33:95 (1987); Massague, Cell 49:437 (1987); Roberts and Sporn, "Peptides Growth Factors and Their Receptors", Springer-Verlag (1989)).
Notwithstanding the beneficial and essential cell regulatory functions served, TGF-.beta. regulatory activity can prove detrimental to its host organism. For example, whereas growth and proliferation of mesenchymal cells is stimulated by TGF-.beta., some tumor cells may also be stimulated, using TGF-.beta. as an autocrine growth factor. In other cases the inhibition of cell proliferation by TGF-.beta. similarly proves detrimental to its host organism. An example would be the prevention of new cell growth to assist in repair of tissue damage. The stimulation of extracellular matrix production by TGF-.beta. is essential for wound healing. However, in some cases, the TGF-.beta. response is uncontrolled and an excessive accumulation of extracellular matrix results. An example of excessive accumulation of extracellular matrix is glomerulonephritis and scar tissue formation.
The transforming growth factor-.beta. receptor system in most mesenchymal and epithelial cells consists of several components (Massague, J. Ann. Rev. Cell Biol., 6:597 (1990); Lin, H. Y. et al., Cell, 68:775 (1992); Georgi, L. L. et al., Cell, 61:635 (1990); Mathews, L. S. et al., Cell, 65:973 (1991); Attisano, L. et al., Cell. 68::97 (1992); Lopez-Casillas et al., Cell, 67:785 (1991) and Wang et al., Cell, 67:796 (1991) all of which are incorporated herein by reference), one of which is betaglycan, a memubrane-anchored proteoglycan. In addition to betaglycan, the TGF-.beta. receptor system in most mesenchymal and epithelial cells consists of the type I receptor, a 53-kDa glycoprotein whose structure has not been determined yet, and the type II receptor, which belongs to the protein serine/threonine kinase receptor family. Additional cell surface TGF-.beta.-binding proteins, some of which have a more restricted distribution, have also been described.
Thus, a need exists to develop compounds that can modify the effects of cell regulatory factors such as TGF-.beta.. The present invention satisfies this need and provides related advantages as well.