Fig. 2. ECM remodeling by proteolytic degradation. Cathepsins associated with membrane microdomains can degrade ECM proteins such as collagen, FN and laminin. Pro-uPA and uPAR, in complex with uPARAP, mediate the endocytosis of extracellular collagen. Such collagen is then degraded by cathepsins in intracellular vesicles. TGFβ1 signaling triggers transcriptional changes, including the upregulation of procathepsin B, which then participates in further ECM remodeling. Cathepsins also activate pro-uPA, setting off a uPA-mediated cascade of proteolytic cleavage that results in the activation of plasmin, fibrin and pro-MMPs.