@article {865,
	title = {Proteolytic Cleavages in the VEGF Family: Generating Diversity among Angiogenic VEGFs, Essential for the Activation of Lymphangiogenic VEGFs},
	journal = {Biology},
	volume = {10},
	year = {2021},
	month = {Jan-02-2021},
	pages = {167},
	doi = {10.3390/biology10020167},
	url = {https://www.mdpi.com/2079-7737/10/2/167},
	author = {K{\"u}nnapuu, Jaana and Bokharaie, Honey and Jeltsch, Michael}
}
@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}
}
@article {29,
	title = {Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation},
	journal = {J Clin Invest},
	volume = {115},
	year = {2005},
	month = {2005/Feb/},
	pages = {247 - 57},
	abstract = {Edema occurs in asthma and other inflammatory diseases when the rate of plasma leakage from blood vessels exceeds the drainage through lymphatic vessels and other routes. It is unclear to what extent lymphatic vessels grow to compensate for increased leakage during inflammation and what drives the lymphangiogenesis that does occur. We addressed these issues in mouse models of (a) chronic respiratory tract infection with Mycoplasma pulmonis and (b) adenoviral transduction of airway epithelium with VEGF family growth factors. Blood vessel remodeling and lymphangiogenesis were both robust in infected airways. Inhibition of VEGFR-3 signaling completely prevented the growth of lymphatic vessels but not blood vessels. Lack of lymphatic growth exaggerated mucosal edema and reduced the hypertrophy of draining lymph nodes. Airway dendritic cells, macrophages, neutrophils, and epithelial cells expressed the VEGFR-3 ligands VEGF-C or VEGF-D. Adenoviral delivery of either VEGF-C or VEGF-D evoked lymphangiogenesis without angiogenesis, whereas adenoviral VEGF had the opposite effect. After antibiotic treatment of the infection, inflammation and remodeling of blood vessels quickly subsided, but lymphatic vessels persisted. Together, these findings suggest that when lymphangiogenesis is impaired, airway inflammation may lead to bronchial lymphedema and exaggerated airflow obstruction. Correction of defective lymphangiogenesis may benefit the treatment of asthma and other inflammatory airway diseases.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/15668734},
	author = {Baluk, Peter and Tammela, Tuomas and Ator, Erin and Lyubynska, Natalya and Achen, Marc G and Hicklin, Daniel J and Jeltsch, Michael and Petrova, Tatiana V and Pytowski, Bronislaw and Stacker, Steven A and Yl{\"a}-Herttuala, Seppo and Jackson, David G and Alitalo, Kari and McDonald, Donald M}
}
@article {14,
	title = {Proteolytic processing regulates receptor specificity and activity of VEGF-C},
	journal = {EMBO J},
	volume = {16},
	year = {1997},
	month = {1997/Jul/},
	pages = {3898 - 911},
	abstract = {The recently identified vascular endothelial growth factor C (VEGF-C) belongs to the platelet-derived growth factor (PDGF)/VEGF family of growth factors and is a ligand for the endothelial-specific receptor tyrosine kinases VEGFR-3 and VEGFR-2. The VEGF homology domain spans only about one-third of the cysteine-rich VEGF-C precursor. Here we have analysed the role of post-translational processing in VEGF-C secretion and function, as well as the structure of the mature VEGF-C. The stepwise proteolytic processing of VEGF-C generated several VEGF-C forms with increased activity towards VEGFR-3, but only the fully processed VEGF-C could activate VEGFR-2. Recombinant {\textquoteright}mature{\textquoteright} VEGF-C made in yeast bound VEGFR-3 (K[D] = 135 pM) and VEGFR-2 (K[D] = 410 pM) and activated these receptors. Like VEGF, mature VEGF-C increased vascular permeability, as well as the migration and proliferation of endothelial cells. Unlike other members of the PDGF/VEGF family, mature VEGF-C formed mostly non-covalent homodimers. These data implicate proteolytic processing as a regulator of VEGF-C activity, and reveal novel structure-function relationships in the PDGF/VEGF family.},
	url = {http://view.ncbi.nlm.nih.gov/pubmed/9233800},
	author = {Joukov, V and Sorsa, T and Kumar, V and Jeltsch, M and Claesson-Welsh, L and Cao, Y and Saksela, O and Kalkkinen, N and Alitalo, K}
}
