Latent forms of TGF-beta: molecular structure and mechanisms of activation

TGF-beta proteins are produced as latent, high molecular weight complexes. The latent form of TGF-beta 1 (L-TGF-beta 1) in human platelets comprises three components: the mature TGF-beta 1 molecule, the N-terminal remnant of the TGF-beta 1 precursor in dimeric form and a novel component denoted TGF-beta 1-binding protein (TGF-beta 1-BP). Recombinant TGF-beta 1 expressed in CHO cells, which lacks TGF-beta 1-BP, is also produced as a latent form. Thus, the N-terminal remnant of the TGF-beta 1 precursor is sufficient for TGF-beta 1 latency, and it was denoted TGF-beta 1 latency-associated peptide (TGF-beta 1-LAP). The cDNA for TGF-beta 1-BP has been cloned. It is mainly composed of two different kinds of repeat sequences, i.e. 16 epidermal growth factor-like repeats and three copies of a cysteine-rich repeat hitherto not found in other proteins. The function of TGF-beta 1-BP remains to be elucidated. Activation of L-TGF-beta can be achieved by different chemical and enzymic treatments, or by incubation with certain cell types. Understanding of the physiological activation mechanisms and the in vivo roles of L-TGF-beta will be important for future clinical applications of TGF-beta.