The role of proteases in transforming growth factor-β activation

Transforming growth factor-β (TGFβ) plays a central role in a number of developmental and pathological processes. There are 3 isoforms of TGFβ (1–3) and all are sequestered in the extracellular matrix as latent complexes. Activation of this complex is the key biological checkpoint controlling TGF-β bioavailability. This process is tightly regulated in a temporal, spatial and isoform specific manner highlighting its importance. There are many different mechanisms by which TGF-β can be activated. Both serine and metalloproteinases play an important role in TGF-β activation, at least in vitro, and many of these proteases have been implicated in pathological conditions. The mechanism of activation is distinct between the different proteases, but is not conserved between the two groups. Both serine proteases, such as plasmin, and metalloproteases, such as MMP2, can directly cleave latent TGFβ, whereas others, such as thrombin and MMP14, interact with integrin mediated TGFβ activation pathways. However, further studies are still required to fully understand the relevance of all of these pathways in vivo. Currently, the best described mechanism of TGF-β1 activation in vivo is by integrins, although this process can be modulated by proteases. The primary mechanism of TGF-β2 and TGF-β3 activation has yet to be defined in vivo, although it is likely that TGF-β3 is activated in a similar manner to TGF-β1. This review describes the mechanism of protease driven TGF-β activation, and discusses the physiological and pathological relevance of this process.