Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1
By S. K. Jha, Khushbu Rauniyar, Terhi Karpanen, V. Leppänen, P. Brouillard, M. Vikkula, K. Alitalo, M. Jeltsch. 2017
88 citations recorded by the source corpus.
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.
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In Oncology
Citations in the corpus
- ADAMTS proteins in human disorders (2018, background): “VEGFC is located both at the cell surface and sequestered in the ECM; these localizations contribute in specific ways to proliferation of lymphatic endothelium and formation of organized lymphatic networks, respectively [33].”
- Loss of ADAMTS3 activity causes Hennekam lymphangiectasia–lymphedema syndrome 3 (2017, background): “VEGFC processing but reduces ADAMTS3 interaction with CCBE1, renders ADAMTS3 unable to retain CCBE1 at the cell surface, resulting in disruption of VEGFR3 signaling (24).”
- Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments (2023, background): “Precise mechanism of CCBE1-induced VEGF-C activation is the enhancing of cleavage activity of a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS3) and the facilitating of the colocalization of VEGF-C and ADAMTS3 [450].”