Colloquium Series on Protein Activation and Cancer: Processing of VEGF-C and -D by the Proprotein Convertases (PDF)

The vascular endothelial growth factor (VEGF) family members that include VEGF-A, -B, -C, -D,
and placental growth factor (PlGF), display distinct binding affinities for their receptors VEGFR-1,
-2, and/or -3. In addition to their requirements in the initiation, development, and maintenance of
blood and lymphatic vasculature, VEGFs and VEGFRs are upregulated during neoplasia and are
involved in the remodeling of tumoral blood and lymphatic vasculature. By activating VEGFR-1
and VEGFR-2, both expressed on blood endothelial cells, VEGF-A promotes the formation of
new tumoral blood vessels and thereby accelerates tumor growth. In contrast, upregulation of
VEGF-C, a ligand for lymphatic endothelial VEGFR-3 as well as for VEGFR-2, induces the
formation of tumor-associated lymphatic vessels and thus promotes the passive metastatic dissemination
of tumor cells to regional lymph nodes. Of the VEGF family members, only VEGF-C and
-D were found to be proteolytically processed by Furin-like enzymes. This processing controls
the selective activation of VEGFR-2 and -3 signaling during tumor angiogenesis and lymphangiogenesis.
Here, we provide an overview of angiogenesis processes and discuss the importance of
VEGF-C and VEGF-D precursors processing by the proprotein convertases during the activation
of VEGFR-2 and VEGFR-3 receptors and the mediation of their functions during angiogenesis,
lymphangiogenesis, and tumorigenesis.