Figure 1

TGF-β synthesis and activation. TGF-βs are synthesized as inactive precursors that contain pre-region (Signal peptide) and pro-region (N terminal peptide - LAP). Processing of inactive form starts with proteolytic cleavage that removes signal peptide from pre-pro-TGF-βs form. After dimerization, TGF-βs are cleaved by proteases (eg. Furin) into C-terminal mature peptides and N-terminal LAP (Latency Associated Peptide). TGF-βs with LAP form small latent complexes (SLP) that are transported to extracellular matrix where can further covalently bind to latent TGF-β binding protein (LTBP) to form a large latent complexes (LLC). LTBP is able to connect inactive TGF-β forms to ECM proteins. This interaction is further supported by covalent transglutaminase-induced (TGase) crosslinks. Activation of TGF-β starts with release of LCC from ECM by proteases. Then, the mature protein is cleaved from LTBP, which is provided in vitro by acidic condition, pH or plasmin or in vivo by thrombospondin (TSP). Once the active TGF-β family member is released from the ECM, it is capable of signaling