Molecular Characterization and Interaction between Human VEGF-D and VEGFR-3
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Angiogenesis and lymphangiogenesis are some of the routes that cause metastasis. Vascular Endothelial Growth Factors (VEGFs) stimulate angiogenesis and lymphangiogenesis through VEGF receptors. Especially, VEGF-D and its receptor, VEGFR-3, play a pivotal role in regulating cellular processes such as survival, proliferation, and migration, thereby influencing lymphangiogenesis. The aim of this research is to clarify the molecular characteristics of VEGF-D and VEGFR-3 proteins and identify the key residues that are essential for the interaction between VEGF-D and VEGFR-3. Experiments, including size exclusion chromatography and GST pull-down assay analysis, reveal that specific residues, particularly D103 and Q110, are essential for VEGF-D/VEGFR-3 binding. Mutations in these residues induce structural alterations, resulting in reduced binding affinity and impaired activation of VEGFR-3. Moreover, this study suggests that a synthesized peptide, designed based on key residues of VEGF-D involved in binding to VEGFR-3, may act as a metastasis suppressor by competitively inhibiting the interaction between VEGF-D and VEGFR-3. Understanding these molecular interactions is expected to have significant potential to develop therapeutic peptides that can inhibit cancer cell-induced lymphangiogenesis and resolve metastasis via lymphangiogenesis across various cancer types.
Abstract
Angiogenesis and lymphangiogenesis are some of the routes that cause metastasis. Vascular Endothelial Growth Factors (VEGFs) stimulate angiogenesis and lymphangiogenesis through VEGF receptors. Especially, VEGF-D and its receptor, VEGFR-3, play a pivotal role in regulating cellular processes such as survival, proliferation, and migration, thereby influencing lymphangiogenesis. The aim of this research is to clarify the molecular characteristics of VEGF-D and VEGFR-3 proteins and identify the key residues that are essential for the interaction between VEGF-D and VEGFR-3. Experiments, including size exclusion chromatography and GST pull-down assay analysis, reveal that specific residues, particularly D103 and Q110, are essential for VEGF-D/VEGFR-3 binding. Mutations in these residues induce structural alterations, resulting in reduced binding affinity and impaired activation of VEGFR-3. Moreover, this study suggests that a synthesized peptide, designed based on key residues of VEGF-D involved in binding to VEGFR-3, may act as a metastasis suppressor by competitively inhibiting the interaction between VEGF-D and VEGFR-3. Understanding these molecular interactions is expected to have significant potential to develop therapeutic peptides that can inhibit cancer cell-induced lymphangiogenesis and resolve metastasis via lymphangiogenesis across various cancer types.
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