Transforming Growth Factor-Beta and Urokinase-Type Plasminogen Activator: Dangerous Partners in Tumorigenesis—Implications in Skin Cancer

Figure 5

TGF-β processing and uPA-uPAR-dependent activation. (a) TGF-β is synthesized as a precursor protein. The signal peptide (SP) targets TGF-β precursor protein to the secretory pathway, which is cleaved during the transit through the rough endoplasmic reticulum (RER); a homodimer of protein is formed and then is cleaved by furin convertase to produce small latent complex (SLC), in which mature TGF-β remains noncovalent bounded to latency-associated peptide (LAP), being in that way as inactive form. Next, SLC by covalently binding to latent TGF-β binding protein (LTBP) produces the large latent complex (LLC); finally, LLC is secreted and stored into the extracellular matrix (ECM) for its subsequent activation. (b) uPA bounded to its uPA receptor (uPAR) activates plasminogen (Plg) to the active form plasmin (Plm); Plm can directly degrade ECM and/or may promote the activation of latent TGF-β by proteolytic cleavage within the N-terminal region of the LAP.