FLT-1, A RECEPTOR FOR VASCULAR ENDOTHELIAL GROWTH-FACTOR, HAS TRANSFORMING AND MORPHOGENIC POTENTIALS

A paradox of Flt-1, a tyrosine kinase receptor for vascular endothelia l growth factor (VEGF), is that the ligand cannot activate the recepto r to stimulate growth of cells that exogenously overexpress the recept or. In order to find Flt-1 kinase-dependent biological systems, we obt ained for the first time activated forms of the Flt-1 kinase in a liga nd-independent manner. Replacement of the ABL sequences in the human l eukemia oncoprotein BCR-ABL with the cytoplasmic domain of Flt-1 (BCR- FLT) followed by a retroviral random mutagenesis scheme gave constitut ively active artificial chimera BCR-FLTm with mutations within the Flt -1 sequence. Like BCR-ABL it could, but not the original BCR-FLT, tran sform Rat1 fibroblasts, abrogate cytokine dependence in Ba/F3 cells, a nd induce neurite-like structures in neuronal PC12 cells. Interestingl y, Rat1 cells transformed by BCR-FLTm formed tube-like structures in b asement membrane matrix. BCR-FLTm retroviruses may be a very useful to ol to investigate an as yet uncovered functions of the Flt-1 kinase.