FLT4

Flt4, also known as FLT4 or VEGFR-3, is a receptor tyrosine kinase encoded by the FLT4 gene in humans. It belongs to the vascular endothelial growth factor receptor family and is predominantly expressed on lymphatic endothelial cells, where it plays a key role in lymphangiogenesis during embryogenesis and in adult tissue remodeling. Its principal ligands are VEGF-C and VEGF-D, which require proteolytic processing to activate VEGFR-3.

Structure and signaling: VEGFR-3 is a transmembrane receptor with extracellular immunoglobulin-like domains that bind VEGF-C and VEGF-D, a single transmembrane region, and an intracellular tyrosine kinase domain. Ligand binding induces receptor dimerization and autophosphorylation, triggering downstream pathways such as PI3K-AKT and Ras-ERK, promoting lymphatic endothelial cell proliferation, migration, and tube formation. Although primarily associated with lymphangiogenesis, VEGFR-3 can contribute to angiogenesis in some contexts, including tumor-associated vessels.

Physiological and clinical relevance: In development, FLT4 is essential for formation of the lymphatic vasculature; haploinsufficiency or loss-of-function mutations cause congenital primary lymphedema, notably Milroy disease. In adults, VEGFR-3 signaling participates in lymphatic remodeling during inflammation and wound healing. In cancer, aberrant VEGFR-3 signaling in tumor lymphatics can facilitate metastasis via the lymphatic system. Therapeutic approaches targeting VEGFR-3 signaling—such as monoclonal antibodies, tyrosine kinase inhibitors, or decoy receptors—are under investigation in oncology and inflammatory diseases.