Latency, activation, and binding proteins of TGF-beta

The TGF-beta superfamily of growth factors consists of an increasing number of different polypeptide modulators of cell growth, differentiation, and morphogenesis. Three mammalian isoforms have been molecularly cloned. Numerous ways to regulate the expression of the TGF-beta genes have been identified. TGF-betas are, for example, subject to regulation by retinoids, steroid hormones, and vitamin D. A characteristic feature in the biology of TGF-betas is that they are usually secreted from cells in latent forms. The large latent complex consists of the small latent complex (TGF-beta and its propeptide) and a high molecular weight protease resistant binding protein, latent TGF-beta binding protein (LTBP). LTBPs are required for the proper folding and secretion of TGF-beta. TGF-beta is not just secreted from cultured cells but is deposited via LTBPs to the pericellular space, namely to the extracellular matrix. Release of these complexes and activation by proteases is under tight regulation and provides a means to rapidly increase local concentrations of TGF-beta. Biological events, where enhanced or focal proteolysis and activation of latent TGF-beta takes place, include cell invasion, tissue remodeling, and wound healing.