Translational Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, PO Box 63, Haartmaninkatu 8, Helsinki, 00014, Finland.
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.
Circulation 2014 May 19;129(19):1962-71. Epub 2014 Feb 19.
Wihuri Research Institute (M.J., A.A., V.-M.L., R.K., K.A.), Translational Cancer Biology Program (M.J., S.K.J., D.T., A.A., T.H., K.A.), and Department of Biomedicine (M.J.), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Biotechnology Programme, Spanish National Cancer Research Centre, Madrid, Spain (S.O.); Hubrecht Institute, Utrecht, The Netherlands (T.K.); and Helsinki University Central Hospital, Helsinki, Finland (K.A.).
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