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Sci Rep. 2017 Jul 7;7(1):4916. doi: 10.1038/s41598-017-04982-1.

Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1.

Author information

1
Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, PO Box 63, Haartmaninkatu 8, Helsinki, 00014, Finland.
2
University Hospital Radiumhospitalet and K. G. Jebsen Center for Cancer Immunotherapy, Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
3
Wihuri Research Institute, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
4
de Duve Institute, University of Louvain, Brussels, Belgium.
5
Walloon Excellence in Life Sciences and Biotechnology (WELBIO), University of Louvain, Brussels, Belgium.
6
Helsinki University Central Hospital, Helsinki, Finland.
7
Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, PO Box 63, Haartmaninkatu 8, Helsinki, 00014, Finland. michael@jeltsch.org.
8
Wihuri Research Institute, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. michael@jeltsch.org.

Abstract

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/VEGFR-3-induced lymphangiogenesis.

PMID:
28687807
PMCID:
PMC5501841
DOI:
10.1038/s41598-017-04982-1
[Indexed for MEDLINE]
Free PMC Article

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