A novel receptor-type tyrosine kinase gene flt (fms-like tyrosine kinase, flt-1) was isolated from human placenta cDNA library. Flt-1 receptor carries a ligand binding domain which contains seven immunoglobulin-like stretches. Further, Flt-1 tyrosine kinase domain is separated by an approximately 70 amino acid-insert region similar to the cases of Fms/Kit/PDGF-R (fms family). However, unlike the fms family members, Flt-1 insert region does not contain "Tyr-X-X-Met" motif, which is known to be important for signal transduction and for the binding of P13 kinase to the receptor. Thus, a unique structure of Flt-1 suggests that a signal transduction pathway from Flt receptor is different from that in the fms family. The expression of flt-1 gene is detectable in a variety of normal tissues, and cell fractionation studies indicate that the flt-1 mRNA is highly expressed in endothelial cell-enriched fraction. VEGF, which has recently been reported as a ligand for Flt-1 receptor, dramatically stimulated growth of endothelial cells in culture. Many human tumors were found to express VEGF mRNA but not Flt-1 message, suggesting a paracrine mechanism for tumor angiogenesis. Interestingly, VEGF could not stimulate proliferation of Flt-1-overexpressing NIH3T3 fibroblast cells. These results suggest that Flt-1 is an endothel-specific growth factor receptor and that the signal transducing pathway through Flt-1 receptor is inactive in the fibroblast background.