Possible involvement of VEGF-FLT tyrosine kinase receptor system in normal and tumor angiogenesis.
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.
Shibuya
M
M
Department of Genetics, Institute of Medical Science, University of Tokyo, Japan.
Seetharam
L
L
Ishii
Y
Y
Sawano
A
A
Gotoh
N
N
Matsushime
H
H
Yamaguchi
S
S
D016475:3T3 Cells / Q000187:drug effects; D000581:Amidohydrolases; D000626:Aminopeptidases / Q000737:chemistry; D000818:Animals; D002874:Chromosome Mapping; D016228:Endothelial Growth Factors / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D009928:Organ Specificity; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics; D017978:Receptors, Growth Factor / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D008565:Membrane Proteins; C098069:PIGF protein, human; C490827:Pigf protein, mouse; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase