title: CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation.
abstract: BACKGROUND
  Hennekam lymphangiectasia-lymphedema syndrome (Online Mendelian Inheritance in Man 235510) is a rare autosomal recessive disease, which is associated with mutations in the 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 collagen- and calcium-binding epidermal growth factor domains 1 (CCBE1) interactions with the vascular endothelial growth factor-C (VEGF-C) growth factor signaling pathway, which is critical in embryonic and adult lymphangiogenesis.
  
  
  RESULTS
  By analyzing VEGF-C produced by CCBE1-transfected cells, we found that, whereas 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 protease, resulting in the mature 21/23-kDa form of VEGF-C, which induces increased VEGF-C receptor signaling. Adeno-associated viral vector-mediated transduction of CCBE1 into mouse skeletal muscle enhanced lymphangiogenesis and angiogenesis induced by adeno-associated viral vector-VEGF-C.
  
  
  CONCLUSIONS
  These results identify A disintegrin and metalloprotease with thrombospondin motifs-3 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 that 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.
authors.affiliation: Wihuri Research Institute (M.J., A.A., V.-M.L., R.K., K.A.), Translational Cancer Biology Program (M.J., S.K.J., D.T., A.A., T.H., K.A.), and Department of Biomedicine (M.J.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Biotechnology Programme, Spanish National Cancer Research Centre, Madrid, Spain (S.O.); Hubrecht Institute, Utrecht, The Netherlands (T.K.); and Helsinki University Central Hospital, Helsinki, Finland (K.A.).
authors.forename: Michael
authors.initials: M
authors.lastname: Jeltsch
authors.forename: Sawan Kumar
authors.initials: SK
authors.lastname: Jha
authors.forename: Denis
authors.initials: D
authors.lastname: Tvorogov
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.forename: Veli-Matti
authors.initials: VM
authors.lastname: Leppänen
authors.forename: Tanja
authors.initials: T
authors.lastname: Holopainen
authors.forename: Riikka
authors.initials: R
authors.lastname: Kivelä
authors.forename: Sagrario
authors.initials: S
authors.lastname: Ortega
authors.forename: Terhi
authors.initials: T
authors.lastname: Kärpanen
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000071096:ADAMTS Proteins; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D042583:Lymphangiogenesis / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology; D011348:Procollagen N-Endopeptidase / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism
chemical_list: C546964:CCBE1 protein, human; D002135:Calcium-Binding Proteins; D025521:Tumor Suppressor Proteins; D042582:Vascular Endothelial Growth Factor C; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3; D051722:ADAM Proteins; D000071096:ADAMTS Proteins; C434951:ADAMTS3 protein, human; D011348:Procollagen N-Endopeptidase
keywords: angiogenesis effect; endothelium; growth substances; metalloproteinases