Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1
(2017) Scientific Reports — Vol. 7, n° 1, p. 4916 [1-13] (2017)
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- The collagen- and calcium-binding EGF domains 1 (CCBE1) protein is necessary for lymphangiogenesis. Its C-terminal domain was shown to be required for the activation of the major lymphangiogenic growth factor VEGF-C (Vascular Endothelial Growth Factor-C) by 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 the C-terminal domain of VEGF- C both in vitro and in a transgenic mouse model. The N-terminal domain of CCBE1 increased VEGFR-3 signaling by colocalizing pro-VEGF-C with its activating protease and the lymphatic endothelial cell surface. When 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. Abnormal localization of CCBE1 was also associated with an ADAMTS3 variant, which we identified in a lymphedema patient. 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 with VEGF-C and ADAMTS3. These new insights should be valuable in developing new strategies to therapeutically target VEGF-C/VEGFR-3-induced lymphangiogenesis.
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Jha, K. S., Rauniyar, K., Karpanen, T., Leppanen, V.-M., Brouillard, P., Vikkula, M., Alitalo, K., & Jeltsch, M. (2017). Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1. Scientific Reports, 7(1), 4916 [1-13]. https://doi.org/10.1038/s41598-017-04982-1 (Original work published 2017)