@article {690,
	title = {The Proteolytic Activation of Vascular Endothelial Growth Factor-C},
	journal = {Lymphologie in Forschung und Praxis},
	volume = {23},
	year = {2019},
	month = {2019/12/18/},
	pages = {88 - 98},
	type = {Review},
	abstract = {The enzymatic cleavage of the protein backbone (proteolysis) is integral to many biological processes, e.g. for the break-down 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 ac-tivating 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 "ma-ture" VEGF--C, that differ in their affinity and their receptor activation potential. This processing is tightly regulated by the CCBE1 protein. CCBE1 regulates the acti-vating cleavage of VEGF-C 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 lym-phangiogenesis. Cathepsin D has also been implicated in tumor lymphangiogenesis. In addition, cathepsin D in saliva might activate latent VEGF-C 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 rele-vance 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.},
	keywords = {Lymphangiogenesis, proteinases, proteolysis, VEGF-C},
	doi = {10.5281/zenodo.3629263},
	url = {https://doi.org/10.5281/zenodo.3629263},
	author = {Lackner, Marcel and Schmotz, Constanze and Jeltsch, Michael}
}
