02718nas a2200205   4500008004100000245007100041210006600112260001600178300001200194490000700206520212700213653002202340653001602362653001602378653001102394100002002405700002302425700002102448856004302469       2019                        eng d00aThe Proteolytic Activation of Vascular Endothelial Growth Factor-C0 aProteolytic Activation of Vascular Endothelial Growth FactorC  c2019/12/18/  a88 - 980 v233 aThe enzymatic cleavage of the protein backbone (proteolysis) is integral to many biological processes, e.g. for the break­down of proteins in the digestive system. Specific proteolytic cleavages are also used to turn on or off the activity of proteins. For example, the lymphangiogenic vascular endothelial growth factor-­C (VEGF-­C) is synthesized as a precursor molecule that must be converted to a mature form by the enzymatic removal of C-­ and N-­terminal propeptides before it can bind and activate its receptors. The constitutive C-­terminal cleavage is mediated by proprotein convertases such as furin. The subsequent ac­tivating cleavage can be mediated by at least four different proteases: by plasmin, ADAMTS3, prostate­-specific antigen (PSA) and cathepsin D. Processing by different proteases results in distinct forms of "ma­ture" VEGF­-C, that differ in their affinity and their receptor activation potential. This processing is tightly regulated by the CCBE1 protein. CCBE1 regulates the acti­vating cleavage of VEGF­C by ADAMTS3 and PSA, but not by plasmin. During embryonic development of the lymphatic system, VEGF-­C is activated primarily by the ADAMTS3 protease. In contrast, it is believed that plasmin is responsible for wound healing lymphangiogenesis and PSA for tumor-­associated pathological lym­phangiogenesis. Cathepsin D has also been implicated in tumor lymphangiogenesis. In addition, cathepsin D in saliva might activate latent VEGF­C upon wound licking, thereby accelerating wound healing. The molecular details of proteolytic activation of VEGF­-C are only recently extensively explored, and we likely do not know yet all activating proteases. It appears that the activity of VEGF­-C is regulated for different specific functions by different proteinases. Although VEGF­-C clearly plays a pivotal role for tumor progression and metastasis in experimental animal studies, the rele­vance of most correlative studies on the role of VEGF­-C in human cancers is quite limited until now, also due to the lack of methods to differentiate between inactive and active forms.10aLymphangiogenesis10aproteinases10aproteolysis10aVEGF-C1 aLackner, Marcel1 aSchmotz, Constanze1 aJeltsch, Michael  uhttps://doi.org/10.5281/zenodo.3629263