The Propeptides of VEGF-D Determine Heparin Binding, Receptor Heterodimerization, and Effects on Tumor Biology

Abstract

Background: VEGF-D is a secreted protein that promotes cancer metastasis; it comprises a receptor-binding domain flanked by cleavable propeptides but the functions of the propeptides were unclear. Results: Propeptides determine heparin binding, VEGF receptor heterodimerization, and rates of metastasis. Conclusion: Propeptides influence molecular interactions of VEGF-D and its bioactivity in cancer.Significance: This study defines the biological significance of VEGF-D propeptides.

VEGF-C and VEGF-C156S in the pro-lymphangiogenic growth factor therapy of lymphedema: a large animal study

“…The proteolytically processed forms of both VEGF-C and VEGF-D are known to induce formation of VEGFR-2/3 heterodimers in addition to VEGFR-2 and VEGFR-3 homodimers [20,23,[39][40][41], whereas binding of VEGF-C156S to its receptor results in VEGFR-3 homodimerization only (Fig. 1) [31].…”

“…1 Receptor signaling properties of VEGF-C, VEGF-D and VEGF-C156S. The proteolytically processed forms of VEGF-C and VEGF-D bind to both VEGFR-2 and VEGFR-3, resulting in the formation and activation of VEGFR-2 homodimers, VEGFR-2/3 heterodimers and VEGFR-3 homodimers [20,23,[39][40][41]. P processed, UP unprocessed was used as a control.…”

VEGF-C and VEGF-D Expression and its Correlation with Lymph Node Metastasis in Esophageal Squamous Cell Cancer Tissue

“…With the action of paracrine mode, VEGF-D makes receptors autophosphorylation by VEGF-D/VEGFR-3 pathways, stimulates lymphatic endothelial cell proliferation and migration of tumors and promotes lymphangiogenesis through the signal transduction in cytoplasm, consequently increasing the incidence of lymphatic metastasis of tumors. The research confirmed that VEGF-D could not only induce lymphangiogenesis in tumor tissues, but also cause the tumor cell diffusion to regional lymph nodes (Kawai et al, 2003;Harris et al, 2013).…”

Cystine knot growth factors and their functionally versatile proregions

“…In case of VEGF-C and -D, the central cystine knot domain, also referred to as VHD (VEGF homology domain), is flanked by N-and C-terminal proregions. VEGF-D can be recombinantly expressed without proregions (Harris et al, 2013). This observation indicates that the role of the proregions in the folding of the VEGF proteins may be dispensible.…”

“…This observation indicates that the role of the proregions in the folding of the VEGF proteins may be dispensible. Mutational studies with VEGF-D variants lacking either the N-or C-terminal proregion demonstrated that the proregions determine receptor heterodimerisation (Harris et al, 2013). The mutational analysis also revealed that the C-terminal proregion binds to heparin and that removal of this domain could be rate-limiting for the angiogenic and tumourigenic properties of VEGF.…”