The naturally occuring form of human soluble Endothelial Growth Factor Receptor-2 (sKDR) was cloned from a full length KDR cDNA by standard molecular methods. The soluble receptor protein consists of the first 6 extracellular domains and contains the unique C-terminal end of native human soluble VEGFR-2/KDR (CGRETILDHSAEAVGMP) generated by alternative splicing. The recombinant human sKDR is produced in a monomeric form in insect cells. The receptor monomers have a mass of approximately 105 kDa. Endothelial cells express three different vascular endothelial growth factor (VEGF) receptors, belonging to the family of receptor tyrosine kinases (RTKs). They are named VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). For Flt-1 as well as KDR naturally occuring soluble forms are described. The expression of the receptors is almost exclusively restricted to endothelial cells, but VEGFR-1 can also be found on monocytes. All VEGF-receptors have seven immunoglobulin-like extracellular domains, a single transmembrane region and an intracellular split tyrosine kinase domain. VEGFR-2 has a lower affinity for VEGF than the Flt-1 receptor, but a higher signaling activity. Mitogenic activity in endothelial cells is mainly mediated by VEGFR-2 leading to their proliferation. The binding of VEGF165 to VEGFR-2 is dependent on heparin.