Vegfr2

VEGFR2, also known as kinase insert domain receptor (KDR) or Flk-1 in mice, is a receptor tyrosine kinase that binds members of the vascular endothelial growth factor (VEGF) family. It is the principal mediator of endothelial cell responses during angiogenesis and vasculogenesis, and is predominantly expressed on vascular endothelial cells, with some expression in other cell types under specific conditions.

The receptor features an extracellular region with immunoglobulin-like domains, a single transmembrane segment, and an intracellular tyrosine kinase domain. Ligand binding to VEGFR2 induces dimerization and autophosphorylation, activating signaling pathways such as PI3K-Akt, PLCγ, Ras-MAPK, and Src family kinases. Activation promotes endothelial cell proliferation, migration, survival, and regulation of vascular permeability, as well as vessel maturation and stabilization.

VEGF-A is the principal activating ligand for VEGFR2; other VEGF family ligands may interact with the receptor in various contexts. A soluble isoform of VEGFR2 can arise from alternative splicing and may modulate signaling by sequestering VEGF ligands, acting as a decoy receptor in some settings.

Clinical significance: VEGFR2 signaling is essential for normal vascular development, and its dysregulation is linked to pathological angiogenesis in cancer and ocular diseases. Consequently, VEGFR2 is a major target of anti-angiogenic therapies. Small-molecule tyrosine kinase inhibitors such as sunitinib, sorafenib, axitinib, and others inhibit VEGFR2 signaling, though they are multi-targeted. Ramucirumab, a monoclonal antibody against VEGFR2, blocks ligand binding and is used in certain cancers. Inhibition of VEGFR2 can lead to adverse effects including hypertension, thrombosis, wound-healing impairment, and proteinuria.