Latent transforming growth factor-β: Structural features and mechanisms of activation

Latent transforming growth factor-β: Structural features and mechanisms of activation. Transforming growth factors-β are cytokines with a wide range of biological effects. They play a pathologic role in inflammatory and fibrosing diseases such as nephrosclerosis. TGFβs are secreted in a latent form due to noncovalent association with latency associated peptide (LAP), which is a homodimer formed from the propeptide region of TGF-β. LAP is disulfide linked to another protein, latent TGF-β binding protein (LTBP). LTBP has features in common with extracellular matrix proteins, and targets latent TGF-β to the matrix. Activation of latent TGF-β can be accomplished in vitro by denaturing treatments, plasmin digestion, ionizing radiation and interaction with thrombospondin. The mechanisms by which latent TGF-β is activated physiologically are not well understood. Results to date suggest an important role for proteases, particularly plasmin, although other mechanisms probably exist. A general model of activation is proposed in which latent TGF-β is released from the extracellular matrix by proteases, localized to cell surfaces, and activated by cell-associated plasmin.