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2 TGF-β and the TGF-β Family

Rik Derynck, Kohei Miyazono


As outlined in the previous chapter, the biochemical characterization of human transforming growth factor-β (TGF-β), now known as TGF-β1, and the determination of its sequence through cDNA cloning provided the basis for identification of TGF-β as structurally distinct from TGF-α. The most striking characteristic that set it apart from TGF-α at that time was that TGF-β was a 25-kD disulfide-linked dimer that was reduced to a 12.5-kD band on gel following treatment with β-mercaptoethanol (Roberts et al. 1983). Following its cDNA cloning (Derynck et al. 1985), it became apparent that TGF-β did not at all resemble TGF-α to which it had been functionally compared thus far and that its polypeptide sequence was unrelated to anything known before. The predicted polypeptide sequence also clearly showed that the mature TGF-β monomer corresponded to only the carboxy-terminal third of a much larger precursor, thus requiring proteolytic cleavage (see Fig. 3 of Chapter 1). Subsequent cDNA cloning demonstrated that the polypeptide chains that define the heteromeric disulfide-linked inhibin are structurally related to TGF-β (Mason et al. 1985; Vale et al. 1986). These polypeptides are, similarly to TGF-β, encoded as carboxy-terminal polypeptides of larger precursors, and only the carboxy-terminal mature polypeptides show structural similarity with TGF-β. Thus was born the realization that there may be a family of secreted disulfide-linked dimeric polypeptides encoded as carboxy-terminal segments of larger secreted polypeptides. This realization was further borne out by the cDNA cloning of bone morphogenetic protein-2A (BMP-2A) and BMP-2B, now known as BMP-2 and BMP-4, respectively (Wozney...

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