%0 Journal Article %J Scientific Reports %D 2017 %T Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1 %B Scientific Reports %V 7 %P 4916 %8 2017/07/07/ %G eng %U https://www.nature.com/articles/s41598-017-04982-1 %N 1 %R 10.1038/s41598-017-04982-1 %0 Journal Article %J Circulation %D 2014 %T CCBE1 enhances lymphangiogenesis via ADAMTS3-mediated VEGF-C activation %X Background—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—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—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. %B Circulation %V 129 %8 05/2014 %G eng %U http://circ.ahajournals.org/content/early/2014/02/19/CIRCULATIONAHA.113.002779.abstract %N 19 %& 1962-1971 %R http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002779 %0 Journal Article %J FASEB J %D 2006 %T Functional interaction of VEGF-C and VEGF-D with neuropilin receptors %A Kärpänen, Terhi %A Heckman, Caroline A %A Keskitalo, Salla %A Jeltsch, Michael %A Ollila, Hanna %A Neufeld, Gera %A Tamagnone, Luca %A Alitalo, Kari %X Lymphatic vascular development is regulated by vascular endothelial growth factor receptor-3 (VEGFR-3), which is activated by its ligands VEGF-C and VEGF-D. Neuropilin-2 (NP2), known to be involved in neuronal development, has also been implicated to play a role in lymphangiogenesis. We aimed to elucidate the mechanism by which NP2 is involved in lymphatic endothelial cell signaling. By in vitro binding studies we found that both VEGF-C and VEGF-D interact with NP2, VEGF-C in a heparin-independent and VEGF-D in a heparin-dependent manner. We also mapped the domains of VEGF-C and NP2 required for their binding. The functional importance of the interaction of NP2 with the lymphangiogenic growth factors was demonstrated by cointernalization of NP2 along with VEGFR-3 in endocytic vesicles of lymphatic endothelial cells upon stimulation with VEGF-C or VEGF-D. NP2 also interacted with VEGFR-3 in coprecipitation studies. Our results show that NP2 is directly involved in an active signaling complex with the key regulators of lymphangiogenesis and thus suggest a mechanism by which NP2 functions in the development of the lymphatic vasculature. %B FASEB J %V 20 %P 1462 - 72 %8 2006/Jul/ %G eng %U http://view.ncbi.nlm.nih.gov/pubmed/16816121 %N 9 %! The FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology