期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41598-017-04982-1
关键词
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资金
- Academy of Finland [202852, 204312, 265982, 272683, 273612, 273817]
- European Research Council (Marie Curie Actions FP7) [ERC-2010-AdG-268804, REA 317250]
- Leducq Foundation [11CVD03]
- Finnish Foundation for Cardiovascular Research
- Jane and Aatos Erkko Foundation
- Cancer Society of Finland
- Magnus Ehrnrooth Foundation
- K. Albin Johansson Foundation
- Belgian Science Policy Interuniversity Attraction Poles (BELSPO-IAP) [IAP p7/43-BeMGI]
- Fonds de la recherche Scientifique-FNRS [T.0026.14]
- FRFS-WELBIO [WELBIO-CR-2015A]
- Integrated Life Science Doctoral Program
- Academy of Finland (AKA) [273612, 272683, 204312, 265982, 202852, 265982, 273612, 272683, 204312, 202852] Funding Source: Academy of Finland (AKA)
- Cancer Foundation Finland sr [150065] Funding Source: researchfish
The collagen-and calcium-binding EGF domains 1 (CCBE1) protein is necessary for lymphangiogenesis. Its C-terminal collagen-like domain was shown to be required for the activation of the major lymphangiogenic growth factor VEGF-C (Vascular Endothelial Growth Factor-C) along with the ADAMTS3 (A Disintegrin And Metalloproteinase with Thrombospondin Motifs-3) protease. However, it remained unclear how the N-terminal domain of CCBE1 contributed to lymphangiogenic signaling. Here, we show that efficient activation of VEGF-C requires its C-terminal domain both in vitro and in a transgenic mouse model. The N-terminal EGF-like domain of CCBE1 increased VEGFR-3 signaling by colocalizing pro-VEGF-C with its activating protease to the lymphatic endothelial cell surface. When the ADAMTS3 amounts were limited, proteolytic activation of pro-VEGF-C was supported by the N-terminal domain of CCBE1, but not by its C-terminal domain. A single amino acid substitution in ADAMTS3, identified from a lymphedema patient, was associated with abnormal CCBE1 localization. These results show that CCBE1 promotes VEGFR-3 signaling and lymphangiogenesis by different mechanisms, which are mediated independently by the two domains of CCBE1: by enhancing the cleavage activity of ADAMTS3 and by facilitating the colocalization of VEGF-C and ADAMTS3. These new insights should be valuable in developing new strategies to therapeutically target VEGF-C/VEGFR3-induced lymphangiogenesis.
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