{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Collagen‐ and calcium‐binding EGF domains 1 (CCBE1) is a secreted extracellular matrix protein that plays a central role in lymphangiogenesis and vascular development. CCBE1 functions primarily by promoting the proteolytic activation of the pro–lymphangiogenic growth factor VEGF‐C through its cooperation with the metalloproteinase ADAMTS3. This proteolytic processing converts VEGF‐C from an inactive precursor into a mature, potent ligand for VEGFR3, thereby driving the budding, migration, and proliferation of lymphatic endothelial cells (LECs) necessary for the formation and proper patterning of lymphatic vessels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Detailed domain analyses have revealed that the collagen‐like regions of CCBE1 are essential for its ability to enhance VEGF‐C processing, whereas the associated EGF‐like domains, though less critical for proteolytic activation in vitro, are required for full lymphangiogenic activity in vivo. Disruption of CCBE1 function through loss‐of‐function mutations underlies congenital lymphatic disorders, such as Hennekam syndrome, which is characterized by generalized lymphatic dysplasia, lymphedema, intestinal lymphangiectasia, and even in utero hydrops fetalis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its canonical role in lymphatic vessel formation, CCBE1 is also expressed in early cardiac and vascular progenitors, contributing to coronary vasculature formation and potentially influencing the hematopoietic microenvironment in the fetal liver. Moreover, in oncologic contexts, downregulation of CCBE1—mediated by microRNAs such as miR‑330‑3p—leads to increased invasiveness and metastasis, suggesting that CCBE1 may also act as a tumor suppressor in certain cancers, including breast cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Overall, CCBE1 emerges as a multifaceted regulator that not only ensures proper lymphatic vessel morphogenesis through enhancement of VEGF‐C/VEGFR3 signaling but also participates in vascular remodeling and cell–matrix interactions during embryonic heart development. Its functional versatility highlights its importance both in developmental processes and in disease states.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marielle Alders, Benjamin M Hogan, Evisa Gjini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ng.484"}], "href": "https://doi.org/10.1038/ng.484"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19935664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19935664"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Michael Jeltsch, Sawan Kumar Jha, Denis Tvorogov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.113.002779"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.113.002779"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24552833"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24552833"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Frank L Bos, Maresa Caunt, Josi Peterson-Maduro, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.111.250738"}], "href": "https://doi.org/10.1161/CIRCRESAHA.111.250738"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21778431"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21778431"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hung M Bui, David Enis, Marius R Robciuc, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Proteolytic activation defines distinct lymphangiogenic mechanisms for VEGFC and VEGFD."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI83967"}], "href": "https://doi.org/10.1172/JCI83967"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27159393"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27159393"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "M Guy Roukens, Josi Peterson-Maduro, Yvonne Padberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional Dissection of the CCBE1 Protein: A Crucial Requirement for the Collagen Repeat Domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ Res (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCRESAHA.116.304949"}], "href": "https://doi.org/10.1161/CIRCRESAHA.116.304949"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25814692"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25814692"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Angela E Scheuerle, Nathan T Sweed, Charles F Timmons, et al. "}, {"type": "b", "children": [{"type": "t", "text": "An additional case of Hennekam lymphangiectasia-lymphedema syndrome caused by loss-of-function mutation in ADAMTS3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.40633"}], "href": "https://doi.org/10.1002/ajmg.a.40633"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30450763"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30450763"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Aruz Mesci, Xiaoyong Huang, Samira Taeb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Targeting of CCBE1 by miR-330-3p in human breast cancer promotes metastasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/bjc.2017.105"}], "href": "https://doi.org/10.1038/bjc.2017.105"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28419078"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28419078"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "C A Barton, B S Gloss, W Qu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Collagen and calcium-binding EGF domains 1 is frequently inactivated in ovarian cancer by aberrant promoter hypermethylation and modulates cell migration and survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjc.6605429"}], "href": "https://doi.org/10.1038/sj.bjc.6605429"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19935792"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19935792"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Fernando Bonet, Paulo N G Pereira, Oriol Bover, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CCBE1 is required for coronary vessel development and proper coronary artery stem formation in the mouse heart."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Dyn (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/dvdy.24670"}], "href": "https://doi.org/10.1002/dvdy.24670"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30204931"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30204931"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "João Facucho-Oliveira, Margaret Bento, José-António Belo "}, {"type": "b", "children": [{"type": "t", "text": "Ccbe1 expression marks the cardiac and lymphatic progenitor lineages during early stages of mouse development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Dev Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1387/ijdb.113394jf"}], "href": "https://doi.org/10.1387/ijdb.113394jf"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22252499"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22252499"}]}]}]}