Vascular endothelial growth factor receptor 1, Vascular endothelial growth factor receptor 2, Vascular endothelial growth factor receptor 3 (VEGFR1, VEGFR2, VEGFR3)

The vascular endothelial growth factor receptors (VEGFR1, VEGFR2, and VEGFR3) are single-pass transmembrane proteins of the receptor tyrosine kinase family, critical for regulating angiogenesis and lymphangiogenesis through ligand-induced dimerization and activation of their intracellular kinase domains[3][5][6][7]. Each receptor consists of seven immunoglobulin-like extracellular domains, a transmembrane helix, and a split cytoplasmic tyrosine kinase domain. - VEGFR1 (FLT1) primarily acts as a regulator by binding VEGF-A with high affinity but weak kinase activity; it can function as a decoy or modulator, though it also contributes to endothelial cell survival and maintenance[2][4][5]. - VEGFR2 (KDR/FLK1) is the main signal transducer mediating the effects of VEGF on vascular endothelium, driving angiogenic signaling, vascular permeability, and cell proliferation; it is the dominant therapeutic target in anti-angiogenic cancer therapy[2][3][5]. - VEGFR3 (FLT4) primarily mediates lymphangiogenesis but also has supporting roles in blood vessel endothelium, especially when VEGFR2 is absent; it binds VEGF-C and VEGF-D[1][2][4][5]. These receptors have overlapping as well as complementary functions in vessel growth, maintenance, and pathological neovascularization, making them major targets in anti-angiogenic and anti-lymphangiogenic drug development[3][4][5][7]. Therapies target these receptors in cancer and ocular diseases, but clinical efficacy is often limited by redundancy and compensation among the three VEGFRs and by safety liabilities arising from inhibition of physiological angiogenesis[4][5].

Other names

VEGF receptor 1 (VEGFR-1, FLT1)VEGF receptor 2 (VEGFR-2, KDR, FLK1)VEGF receptor 3 (VEGFR-3, FLT4)

Competitive inhibition of ATP binding site in kinase domain (tyrosine kinase inhibitors, e.g., sorafenib, sunitinib); Antibody-mediated blockade of ligand–receptor interaction (e.g., bevacizumab blocks VEGF ligands; ramucirumab binds VEGFR2 ECD); Ligand trap (aflibercept acts as a decoy receptor for VEGF ligands)