@article {693,
	title = {KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D},
	journal = {eLife},
	volume = {8},
	year = {2019},
	month = {2019/05/17/},
	pages = {e44478},
	abstract = {Vascular endothelial growth factor-C (VEGF-C) acts primarily on endothelial cells, but also on non-vascular targets, e.g. in the CNS and immune system. Here we describe a novel, unique VEGF-C form in the human reproductive system produced via cleavage by kallikrein-related peptidase 3 (KLK3), aka prostate-specific antigen (PSA). KLK3 activated VEGF-C specifically and efficiently through cleavage at a novel N-terminal site. We detected VEGF-C in seminal plasma, and sperm liquefaction occurred concurrently with VEGF-C activation, which was enhanced by collagen and calcium binding EGF domains 1 (CCBE1). After plasmin and ADAMTS3, KLK3 is the third protease shown to activate VEGF-C. Since differently activated VEGF-Cs are characterized by successively shorter N-terminal helices, we created an even shorter hypothetical form, which showed preferential binding to VEGFR-3. Using mass spectrometric analysis of the isolated VEGF-C-cleaving activity from human saliva, we identified cathepsin D as a protease that can activate VEGF-C as well as VEGF-D.},
	keywords = {cancer biology, Cathepsin D, kallikrein-related peptidases, KLK3/PSA, Lymphangiogenesis, mouse, VEGF-C, VEGF-D},
	isbn = {2050-084X},
	url = {https://elifesciences.org/articles/44478},
	author = {Jha, Sawan Kumar and Rauniyar, Khushbu and Chronowska, Ewa and Mattonet, Kenny and Maina, Eunice Wairimu and Koistinen, Hannu and Stenman, Ulf-H{\r a}kan and Alitalo, Kari and Jeltsch, Michael}
}
@article {588,
	title = {Factors regulating the substrate specificity of cytosolic phospholipase A2-alpha in vitro},
	journal = {Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids},
	volume = {1861},
	year = {2016},
	month = {2016/07/01/},
	pages = {1597}
}
@article {441,
	title = {CCBE1 enhances lymphangiogenesis via ADAMTS3-mediated VEGF-C activation},
	journal = {Circulation},
	volume = {129},
	year = {2014},
	month = {05/2014},
	chapter = {1962-1971},
	abstract = {Background{\textemdash}Hennekam lymphangiectasia-lymphedema syndrome (OMIM 235510) is a rare autosomal recessive disease, which is associated with mutations in the collagen- and calcium-binding EGF domains 1 (CCBE1) gene. Because of the striking phenotypic similarity of embryos lacking either the Ccbe1 gene or the lymphangiogenic growth factor Vegfc gene, we searched for CCBE1 interactions with the VEGF-C growth factor signaling pathway, which is critical in embryonic and adult lymphangiogenesis.

Methods and Results{\textemdash}By analyzing VEGF-C produced by CCBE1-transfected cells, we found that while CCBE1 itself does not process VEGF-C, it promotes proteolytic cleavage of the otherwise poorly active 29/31-kDa form of VEGF-C by the A disintegrin and metalloprotease with thrombospondin motifs-3 (ADAMTS3) protease, resulting in the mature 21/23-kDa form of VEGF-C, which induces increased VEGF-C receptor signaling. Adeno-associated viral vector (AAV) mediated transduction of CCBE1 into mouse skeletal muscle enhanced lymphangiogenesis and angiogenesis induced by AAV-VEGF-C.

Conclusions{\textemdash}These results identify ADAMTS3 as a VEGF-C activating protease and reveal a novel type of regulation of a vascular growth factor by a protein that enhances its proteolytic cleavage and activation. The results suggest CCBE1 is a potential therapeutic tool for the modulation of lymphangiogenesis and angiogenesis in a variety of diseases that involve the lymphatic system, such as lymphedema or lymphatic metastasis.},
	doi = {http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002779},
	url = {http://circ.ahajournals.org/content/early/2014/02/19/CIRCULATIONAHA.113.002779.abstract}
}
