VEGFR3

VEGFR3, also known as vascular endothelial growth factor receptor 3 or FLT4, is a receptor protein tyrosine kinase encoded by the FLT4 gene. It is expressed primarily on lymphatic endothelial cells, with limited expression on certain venous endothelium during development and in specific tissues.

The primary ligands for VEGFR3 are vascular endothelial growth factors C and D (VEGF-C and VEGF-D). These ligands require proteolytic processing to become mature, high-affinity ligands. Binding of VEGF-C or VEGF-D induces receptor dimerization and autophosphorylation of the intracellular kinase domain, triggering downstream signaling through pathways such as MAPK/ERK, PI3K/AKT, and PLCγ. These signals promote endothelial cell proliferation, migration, survival, and tube formation, thereby driving lymphangiogenesis. In adults, VEGFR3 also contributes to remodeling of the lymphatic vasculature during inflammation and in tumor-associated lymphangiogenesis.

Developmental and clinical relevance: FLT4 is essential for embryonic lymphatic development; loss-of-function mutations disrupt lymphatic sprouting and lead to congenital lymphedema. Milroy disease is a well-described inherited form caused by FLT4 mutations. Aberrant VEGFR3 signaling has been observed in cancer, where increased VEGF-C/-D–VEGFR3–driven lymphangiogenesis can facilitate tumor metastasis via the lymphatic system.

Therapeutic context: VEGFR3 is a target of anti-angiogenic cancer therapies. Some tyrosine kinase inhibitors with activity against VEGFR3 and monoclonal antibodies or receptor traps designed to block VEGF-C/D–VEGFR3 signaling are under investigation or used in combination regimens.