7 TGF-β Bioavailability: Latency, Targeting, and Activation

In the past decade, it has become apparent that cytokines and growth factors rely on a variety of mechanisms to regulate their activities in the extracellular milieu after secretion and before interaction with their cognate receptors (Flaumenhaft and Rifkin 1992; Saharinen et al. 1999). These mechanisms are both restrictive and protective, and they ensure that the signaling molecules attain proper concentration for receptor binding and are localized to the proper site. In this regard, TGF-β is released in a latent state in which its biological activity must be unmasked before the cytokine binds to its receptors. In this chapter, we consider the latent forms of TGF-β, the known mechanisms of activation, and the consequences of releasing TGF-β as a latent molecule. TGF-β STRUCTURE AND BIOSYNTHESIS TGF-β Structure TGF-β was originally isolated from several tissues as a 25-kD homodimer (Frolik et al. 1983; Roberts et al. 1983). Interestingly, the reports about TGF-β produced by normal cultured cells indicated that the bioactivity was detected only after treatment of the culture medium by extremes of pH (Branum et al. 1984; Pircher et al. 1984; Lawrence et al. 1985). This result was in contrast to the description of the purification of active TGF-β from tissues (Frolik et al. 1983; Roberts et al. 1983) and led to the idea that TGF-β was released complexed to a binding or masking protein. Subsequent experiments from several laboratories validated this hypothesis (Gentry et al. 1987; Gentry and Nash 1990) and showed that TGF-β is processed from a larger...