A unique signal transduction from FLT tyrosine kinase, a receptor for vascular endothelial growth factor VEGF.
Flt-1 (fms-like tyrosine kinase-1), a receptor-type tyrosine kinase of sharing similar features with two other flt-family encoded proteins KDR/Flk-1 and Flt-4, has been recently identified as a receptor for Vascular Endothelial Growth Factor (VEGF) known to induce the proliferation of vascular endothelial cells. In this study, we demonstrate that Flt-1 encodes for a 180 kDa glycoprotein, binds VEGF with high affinity, undergoes autophosphorylation but does not generate any mitogenic response in transfected NIH3T3 fibroblasts. Interestingly, the immediate early gene c-myc was not induced, whereas the c-fos was induced very weakly in Flt-1 expressing NIH3T3 cells. A comparative analysis of the Flt-1 signal cascade in the environment of endothelial cells with that of Flt-1 expressing NIH3T3 cells showed that VEGF induced phosphorylation of PLC gamma and GAP complex on tyrosine in both type of cells. However, a strong activation of MAP kinases was observed only in endothelial cells. Further, different from many other receptor tyrosine kinases, tyrosine phosphorylation of Shc protein, an important adaptor for signal transduction from many receptor kinases, was very weak in both Flt-1-NIH3T3 cells and endothelial cells. These results suggest that Flt-1 kinase utilizes a unique signal transduction system in endothelial cells, and the activation of the Flt-1 kinase is insufficient to trigger a mitogenic response in NIH3T3 fibroblasts.
Seetharam
L
L
Department of Genetics, University of Tokyo, Japan.
Gotoh
N
N
Maru
Y
Y
Neufeld
G
G
Yamaguchi
S
S
Shibuya
M
M
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division; D003432:Cross-Linking Reagents; D004261:DNA Replication; D016228:Endothelial Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D020690:GTPase-Activating Proteins; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos; D016259:Genes, myc; D006801:Humans; D008222:Lymphokines / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D003432:Cross-Linking Reagents; D016228:Endothelial Growth Factors; D020690:GTPase-Activating Proteins; D008222:Lymphokines; D011506:Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1